Dementia in Parkinson Disease: Current Concepts in Neuropathology, Neuroanatomy and Neurochemistry

From a clinical point of view, a better clarity regarding the nature of dementia in Parkinson disease and other parkinsonian disorders came with theories that two types of dementia could occur in neurodegenera- tive disorders. These were coined “subcortical” dementia and “cortical” dementia (Albert, Feldman, and Willis 1974; Cummings 1986). The entity “subcortical” dementia was associated with Parkinson disease and was characterized by problems with attention and deficits in spatial working memory and cognitive planning similar to those seen in animals with pre- frontal damage (Mishkin 1957; Shallice 1982). Descriptions of “subcortical dementia” were often ascribed to a slowness of thought or “bradyphrenia” that results in prolonged cognitive processing time most evident when tasks become more complex (Zimmerman et al. 1992; Cooper et al. 1994). “Cortical” dementia had Alzheimer disease as its prototype and centered on language abnormalities and the presence of apraxia and agnosia (Cum­mings 1986). While the terms “subcortical” and “cortical” dementia are now rarely used, they nonetheless have set a valuable framework to under­stand how cognitive dysfunction in Parkinson disease might be rationally organized.

The best present-day correlate to “subcortical” dementia is executive cognitive dysfunction. Executive cognitive function represents a battery of intellectual functions centered on attention span, concentra­tion, and memory. Inclusive in these functions is an assortment of compli­cated processes that are involved in decision-making such as anticipation, judgment, motivation, social/ethical appropriateness, and goal-directed behavior. A fundamental requirement of executive cognitive function involves the ability to store and hold information on-line so that it can be continuously accessed in order to plan and change strategies. These func­tions, as will be discussed later in this post, are believed to be mediated through dopaminergic pathways involving midbrain neurons in the sub­stantia nigra and ventral tegmental area that are either directly or indirectly distributed to the prefrontal cortex. The concept of executive cognitive function implies the requirement of networks to process information from multiple areas of brain as a necessary part of decision making.

At the core of this processing lies “working memory,” which involves prefrontal dopaminergic neurons that have the capacity to maintain firing as a probable method of storing information when tasks are being planned and executed (Goldman-Rakic 1996). One can envision initiating an activ­ity that requires a wide range of information to accomplish. For example, throwing an initial punch in a fight would not only require the gathering of visual, proprioceptive, and motor information but would also process more complicated data such as the ethics and social consequence of such an action. In addition, long-term memory information would be likely included (e.g., What happened when I previously performed this action?). The process of storing all information as it is gathered prior to actual out­put appears to be an important function of prefrontal neurons mediating working memory. The prefrontal area is ideally situated to receive infor­mation from the neocortex as well as the limbic system. A more complete gathering and maintaining of information in prefrontal areas prior to ini­tiating a motor or cognitive task could be viewed as a neurochemical/ neurophysiological correlate for the concept of logic. That is, all input has been considered for a task and consequently the output has been a decision based on the processing of the most complete database possible. Conversely, an inability to employ a full database because either the pre- frontal working memory cells cannot receive information from all parts of the brain or they cannot maintain a firing rate as information is gathered would result in an output that has not considered a full complement of potentially available information for planning. The result may be more impulsive appearing behavior that appears illogical.

One of the best tests capable of demonstrating executive cognitive dys­function in Parkinson disease and the role of “working memory” is the Wisconsin Card Sorting Test. In this test “stimulus cards” with shapes of different colors, designs, and quantities are initially presented to the sub­ject. Without informing the subject, the examiner then decides whether additional cards to be given to the subject will be matched to the stimu­lus cards by color, design, or quantity. The examiner tells the subject only whether the match of the new additional cards to the stimulus cards is right or wrong. Consequently, by trial and error, the subject learns how he or she should be matching the cards. The matching rules are subse­quently changed (without informing the subject) and the subject must change strategy to learn and apply new rules. The test measures how long it takes the subject to learn the correct strategy a well as how long it takes to acquire the new strategy (“change sets”). Consequently, the Wisconsin

Card Sorting Test gives information on how well the subject can plan and change strategies based on goal-directed behavior, all of which are fun­damental skills related to executive function. It provides information on both impulsive and perseverative tendencies. It is easy to envision how tasks associated with the Wisconsin Card Sorting Test would depend heavily on maintaining activity in working memory cells since decisions are closely based on information gathered in previous successful match­ing attempts. In early Parkinson disease patients, deficits are seen in the Wisconsin Card Sorting Test with a prominent feature being the tendency to perseverate; that is, patients find it difficult to learn new strategies when the task has changed (Canavan et al. 1989; Paolo et al. 1996). Clinically, behavioral perseveration is frequently manifested in some patients when they seem unable to change their actions even when such previous behav­ior has resulted in an unwanted outcome (e.g., persistent falling because of not using an available cane or walker, continuing to drive a car despite previous accidents). Others have also found problems in early Parkinson disease involving visual working memory with a sparing of verbal work­ing memory (Bradley, Welch, and Dick 1989). Of interest is the observation that there appears to be preservation of visual working memory for shapes (Postle, Jonides, and Smith 1997; Owen et al. 1997). It is suggested that the visual working memory deficits become more evident in early Parkinson disease only when more complex executive function tasks are added to the testing paradigms such as set shifting (Owen 2004). Abnormalities in the Ravens Progressive Matrices and Tower of London Test also suggest that the greatest deficits are evident when tasks are changed and new strate­gies need to be used (Farina et al. 2000; Owen, James, and Leigh 1992). Per­severation of previous strategies and inconsistent performance on newly acquired strategies tend to predominate.

The Ravens Progressive Matri­ces tests a subject’s ability to find patterns in an apparent chaos of visual scenes by having the subject complete the last image in a series. The Tower of London Test and its variations involve a test subject moving colored beads among different pegs on a pegboard in order to replicate the design of the examiner. Subjects are scored by the number of moves undertaken to replicate the examiner’s design with the fewest moves resulting in the best score. In both tests subjects learn the strategy being employed, which is then changed, and the new strategy needs to be discovered and applied. While working memory deficits in visual spatial tasks have been espe­cially noted in Parkinson disease, verbal memory tests using “working memory” have also proven problematic in Parkinson disease. There is no evidence for language deficits (i.e., aphasia) but rather apparent deficits in the executive function of planning speech. As expected and similar to previously described visual spatial testing, deficits are most notable with greater complexity in the task. Testing that requires multiple simultaneous levels of processing results in the greatest deficits. Patients appear to be less able than control subjects to develop strategies that integrate and pri­oritize information to perform more complex memory tasks. For example, when interference is interjected into a memory testing paradigm deficits become more clearly evident (Taylor, Saint-Cyr, and Lang 1990; Cooper, Sagar, and Sullivan 1993). There would appear to be an inability to main­tain information in “working memory” when extraneous information is being introduced.

It is evident that executive cognitive dysfunction occurs early in Par­kinson disease with the greatest involvement mediated through “working memory” in prefrontal areas. These executive deficits are more evident when tasks become more complicated and especially when new rule changes must be incorporated. The next section discusses the dopaminer­gic pathways believed to mediate these processes.

Psychosocial Interventions in Dementia Care

It is probably not difficult for anyone to understand that the term psy­chosocial is a combination of the words psychological and social. Despite the simple explanation of the word itself, defining what psychosocial interventions exactly are is not so simple. In dementia literature several definitions could be found for psychosocial interventions and no abso­lute criteria exist to determine whether a certain intervention for people with dementia should be classified as psychosocial or not. Although psychosocial interventions are always nonpharmacological, nonphar- macological interventions are not necessarily psychosocial. They should not simply be seen as an alternative to drugs. Whereas pharmacologi­cal treatments are developed to fit symptoms of a disease, psychosocial interventions should fit the person and caregiver who suffer from dis­ease symptoms.

The aim of psychosocial interventions is to optimize the quality of life of people with dementia and their caregivers and could be directed to the patient, the caregiver, or both. Psychosocial interventions could be defined as

Interventions usually involving interaction between people, to sup­port cognition, emotion, personal relationships and a sense of con­trol in people with dementia and their family caregivers, through valued, meaningful activity and social integration.1

Psychosocial interventions became part of dementia treatment in the 1970s. At first interventions focused on the functional symptoms of the disease aiming at rehabilitation and compensation of functioning. Later psychosocial interventions became more emotion-oriented, focusing on the person with dementia and his or her own experiences and coping strategies. These days psychosocial interventions focus on the person with dementia as a whole at any stage of the disease, taking into account the persons functional capacities and subjective experiences and feelings.

Theoretical models are often used to explain and explore coping with and adaptation to dementia symptoms. A popular model that is used to develop new psychosocial treatment strategies is the stress-coping model of Lazarus and Folkman (1984) . In this model feelings of stress are explained by the way a person appraises a stressful situation and the extent to which he or she feels capable of coping with it. Stress is consid­ered a product of the interplay between the environment and the person and reducing stress could be achieved by changing a person’s perception of stressors and providing strategies to cope (for further reading on psy­chosocial models see Finnema et al. 2000).

To date no treatment exists that can cure or at least stop progression of any type of dementia. Logically, the treatments available for people with dementia and their caregivers focus on postponing cognitive decline as long as possible, alleviating behavioral and psychological symptoms dur­ing the course of the disease, and alleviating stress of caregivers. Psycho­social interventions could be effective in treating symptoms and problems related to dementia.

Professionals working in dementia care often use clinical guidelines to help them decide which treatment is most appropriate in the case of specific symptoms or situations. In many countries dementia guidelines are avail­able for geriatricians, neurologists, nurses, general practitioners, and other professionals working in dementia care. Guidelines ideally summarize the scientific evidence and best practice that is currently available and most dementia guidelines emphasize the importance of psychosocial interven­tions in the treatment of people with dementia and their caregivers. Many guidelines even recommend that psychosocial interventions should be the first choice when treating behavioral and psychological disease symptoms. The difficulty with recommendations on psychosocial interventions, how­ever, is that these are often stated rather generally. Whereas a recommen­dation for a pharmaceutical could be very clear about the dose that should be given, for how long, and when the pharmaceutical treatment should be stopped, this is far more difficult for a psychosocial intervention.

Psychosocial interventions interfere with the interaction between a person’s psychological state and social environment. Although the symptom(s) to be treated could be the same, the psychological state and social environment differ for each person with dementia. It is up to the healthcare professional to match the situation of a single person with the most appropriate psychosocial intervention. Unfortunately, directions on how to individualize psychosocial interventions are not provided by most dementia guidelines. Yet, treatment success largely depends on a person­alized approach.

Another difficulty for dementia guidelines is that scientific evidence for the effectiveness of psychosocial interventions in dementia care is growing fast. It could take months to years to develop a high-quality and evidence- based guideline, and by the time it is published new evidence is already available. Dementia guidelines should therefore be updated every few years to keep up with scientific evidence but this is done not that often.

The aim of this post on psychosocial interventions in dementia care is to summarize current knowledge and evidence for the use of psycho­social interventions in dementia care. It is not meant to give a full and systematic overview of all available evidence but to show the broad range of effects that psychosocial interventions could have in the treatment of behavioral, cognitive, and functional symptoms of people with dementia and the treatment of family caregivers.

Problems in dementia care are diverse and dementia-care services and organizations should provide access to a range of psychosocial inter­ventions that can be personalized to individual patients and caregivers. Directions on how to personalize psychosocial interventions and the basic outline of a care plan are given at the end of this post. These direc­tions are useful for professional caregivers as well as family caregivers, and apply to the different settings where people with dementia reside, at home, day care, residential care, or nursing home.

Psychosocial interventions described in dementia literature comprise a great variety of strategies and techniques and are used to manage demen­tia symptoms during the whole course of the disease. Psychosocial treat­ments could start right after diagnosis and be used till the end stage of the disease. Psychosocial interventions are available that help people with dementia to cope after they have received the diagnosis and people are still aware of their memory problems, or teach them how to use memory
aids. When the disease progresses interventions could focus on meeting the needs of the person with dementia regarding social and recreational activities, self-care, and daily structure. At the more severe stages inter­ventions could help to ease behavioral disturbances and stimulate interac­tion with others.

Scientific evidence for the effectiveness of psychosocial interventions in the treatment of dementia symptoms is scarce when applying the “gold standard” of randomized controlled trials (RCTs). The Cochrane Library,2 which includes systematic reviews and meta-analyses about the efficacy and effectiveness of treatments for many diseases and conditions, is con­sidered a reliable source of evidence-based practice and used as such by many healthcare professionals. Systematic reviews for different psychoso­cial interventions in dementia care could be found in this database but for all these interventions evidence is inconclusive.

This lack of evidence is caused by insufficient high-quality research and not because psychosocial interventions are found to be ineffective. The interventions for which some evidence is available show positive results in favor of the psychosocial intervention but more high-quality studies are needed. Negative effects of interventions are seldom reported as side effects, contrary to most pharmacological interventions used in dementia care. Personal privacy and ethical aspects could be an issue when using some psychosocial interventions, like tracking devices or subjective barri­ers for people who wander or certain sensory stimulation techniques.

The effectiveness for specific psychosocial interventions is hard to prove not only because RCTs are difficult to conduct but also because it is increasingly recognized that psychosocial care should be tailor made. Finding no effects or even undesired effects from psychosocial interven­tions could indicate that the patient’s needs and preferences did not match the specific intervention. For instance, some people prefer doing things alone or being more physically active whereas others prefer group activi­ties or like to listen to music. It is often stated in study reports of psycho­social interventions that although no overall group effect was found there seemed to be a subgroup within the study sample who benefited from that specific intervention.

Evidence for the effectiveness of one standard package of psychosocial interventions that can be recommended to all people with dementia will probably never be found. The evidence for tailored psychosocial interven­tions is growing rapidly. During the last decade, promising effects have been described in systematic reviews and papers reporting high-quality randomized controlled trials. An overview of these findings is described here.

Neuropsychiatry of Dementia: Nonpharmacologic Interventions for Inappropriate Behaviors

In the past, it was not believed that persons with dementia retained high­er-level needs or functions. We have since learned, however, that although persons with dementia differ from cognitively intact persons in their ability to articulate and independently meet higher-level needs, these needs are present nonetheless (Cohen-Mansfield and Werner 1995). Evidence shows that a large proportion of dementia-related behavior problems stem from an incongruence between the needs of the person who suffers from demen­tia and the degree to which his or her environment fulfills these needs (Bar­ton, Findlay, and Blake 2005; Cohen-Mansfield and Werner 1995; Palmer et al. 1999). In fact, it is our experience as well as that of other researchers that many behavior problems constitute a response to physical pain or dis­comfort (Cohen-Mansfield et al. 1990; Douzjian, Wilson, and Shultz 1998), feelings of loneliness or isolation (Cohen-Mansfield and Werner 1997), boredom (Buettner and Kolanowski 2003; Ice 2002), or sensory deprivation (Cohen-Mansfield 2000b). Thus, many “problematic behaviors” may rep­resent a cry for help, a result of unmet needs, or an inadequate attempt to fulfill those needs. For example, Hancock, Woods, Challis and Orrell (2006) found that sensory or physical disability (including mobility problems and incontinence) needs, mental health needs, and social needs of persons with dementia in residential care were often unmet and were associated with psychological problems such as anxiety and depression. Due to such find­ings, it is critical that the evaluation and care of unmet needs become the guiding principles of good, domain-specific patient care.

Nonpharmacologic interventions aim to address what we have learned to be the most important etiologic basis of behavioral problems in demen­tia. Similar to the notion of “person-centered care” (Touhy 2004), this approach can be better described as “informed care,” a treatment approach that is based on knowledge of the needs of persons with dementia in gen­eral and the individual in particular. Care can be enhanced by an approach of rehabilitation and restorative care, yet the main focus is that of improv­ing overall well-being and addressing the needs of the older individual with dementia, even when those needs are not obvious or articulated. Admittedly, the implementation of this type of care is more complex than prescribing a psychoactive medication, and the identification of the needs to be fulfilled is more difficult than articulating the specific psychi­atric syndrome from which the patient may be suffering. However, these interventions avoid the potentially harmful side effects that result from pharmacologic treatments (Ballard et al. 2009; Folks 2003; Gill et al. 2009). Also, reducing inappropriate behaviors via sedation with psychoactive medication can potentially rob the person with dementia of the very lim­ited resources he or she has in either expressing or attending to his or her needs (Cohen-Mansfield 2000a; Fisher and Swingen 1997), thereby dimin­ishing the ability of caretakers to detect and address the true underlying need. Most important, nonpharmacologic interventions aim to improve the quality of life of the person with dementia.

In summary, the importance of utilizing a nonpharmacologic approach for inappropriate behaviors associated with dementia is threefold: (a) it aims to address the psychosocial/environmental underlying reasons for the behavior, which have been documented in prior research, thus increas­ing quality of life; (b) it avoids the limitations of pharmacologic interven­tions, namely adverse side effects, drug-drug interactions, and limited efficacy (Cohen-Mansfield et al. 1999); and (c) when medication is effica­cious, it may mask the actual need and reduce the already compromised communication by the older person, thereby limiting the caregiver’s abil­ity to properly care for that person.

Depression and Dementia

Another factor that complicates the diagnosis of depression in demented persons is that often a demented patient does not communicate his or her depressive symptoms in a way that is amenable to diagnosis. It has been hypothesized that demented patients may not be aware of their depres­sive symptoms (Chemerinski et al. 2001), and in many cases, caregiver accounts are necessary in order to accurately assess whether or not a patient is depressed. Demented patients often report themselves to be less depressed than do their caregivers and clinicians. For instance, a study of 75 outpatients with diagnosed AD compared concordance of ratings of depression between the patient, caregiver, and clinician. They found that patients rated themselves as less depressed than did their caregivers and clinicians and that results did not vary by severity of dementia (Teri and Wagner 1991). Similar results were found in a smaller study of 31 AD patients and their caregivers; caregivers reported more depressive symp­toms than did the patients themselves and concordance between ratings did not vary according to the depression status of the caregiver (Moye, Robiner, and Mackenzie 1993) . Another study examined whether there were specific symptoms of depression that differed between caregiver and patient reports (Mackenzie, Robiner, and Knopman 1989). They found that patient ratings identified only 14% of the sample as depressed while caregiver ratings identified one-half of the sample as depressed. Discor­dance was noted for specific symptoms including patients’ loss of interest or pleasure, irritability, fatigue, and feelings of worthlessness.

Another complexity to diagnosis of depression in demented patients is that many depression screening instruments were not developed spe­cifically for older populations and the validation of these scales among demented older persons has been sparse. The Geriatric Depression Scale (GDS) (Sheikh and Yesavage 1986), Hamilton Rating Scale for Depression (HRSD) (Hedlund 1979), the Cornell Scale for Depression (Alexopoulos et al. 1988), and the DSM-IV criteria (American Psychiatric Association

1994)   have been most widely compared in the published literature. Differ­ences in the rates of depression among demented persons based on these various different screening tools have been compared in a number of stud­ies. A large study of 288 outpatients with dementia found the prevalence of depression to be 8.0% according to the GDS, 7.4% using the HRSD, and 6.3% according to DSM-IV criteria (Brodaty and Luscombe 1996) . Rates of depression also differed by dementia subtype among the scales. Depression was more likely to be diagnosed in vascular dementia than in Alzheimer’s disease using the HRSD and the GDS, whereas rates accord­ing to the DSM-IV criteria did not differ by dementia subtype. Of note is the low prevalence of depression in this study compared to the previously described literature in this post.

Provisional criteria for the diagnosis of depression of Alzheimer’s disease (NIMH-dAD) were developed as part of a workshop sponsored by the National Institute of Mental Health (Olin, Katz, et al. 2002; Olin, Schneider, et al. 2002). The NIHM-dAD criteria are similar to the DSM-IV criteria for major depression, but incorporate modifications to address specific characteristics of depression in AD. For instance, the NIMH- dAD require three or more symptoms of depression rather than the five required for major depression; these criteria include irritability and social isolation or withdrawal as candidate symptoms of depression, and include ‘decreased positive affect or pleasure’ instead of loss of interest or pleasure, and require that the symptoms occur during the prior two-week period and represent change from previous function, but do not require that their symptoms occur every day. Validation studies of the NIMH- dAD are underway.

A recent study compared the NIMH-dAD to the Cornell Scale for Depression in Dementia, the GDS and the DSM-IV criteria among 101 patients with AD (Teng et al. 2008) . They found that the frequency of depression was significantly higher using the NIMH-dAD (44%) than that obtained using the DSM-IV criteria for major or minor depression (36%) or using the established cut-points on the GDS (33%) and the Cornell Scale for Depression in Dementia (30%). The authors suggest that, compared to the DSM-IV criteria and the other scales, the NIMH-dAD criteria are less
stringent with respect to the requirements for frequency and duration of symptoms, resulting in higher prevalence estimates.

One recent study examined the validity of the Cornell Scale for Depres­sion and the GDS in 145 patients over the age of 65 who were either depressed only, demented only, demented and depressed, or control sub­jects (Korner et al. 2006). They found that while the scales were equally valid for assessing depression in an elderly population, the Cornell Depression Scale retained its sensitivity and specificity (93% and 97%, respectively using a cut-point of >6) in demented subjects. In contrast, the validity of the GDS diminished in the demented population. It is possible that the symptoms assessed using the GDS are more ambiguous in dementia or may overlap with symptoms experienced in dementia, altering the valid­ity of this instrument among demented persons.

Overall, these findings suggest that diagnosis of depression in patients with dementia is challenging and may require consideration of results from numerous depression screening tools as well as caregiver reports. Use of depression scales that focus on symptoms not shared by depression and dementia may also enhance reliability and validity of assessment. Validity of screening tools in demented populations should be consid­ered before choosing a screening instrument. Incorporating reports from patients, caregivers, and clinicians may provide the most complete and accurate picture of the patient’s emotional state.

Light Therapy for Managing Symptoms of Dementia: Promising Results

In persons with dementia, cognitive decline is usually accompanied by challenging symptoms such as sleep-wake disturbances, inability to man­age daily activities, communication difficulties, depression, mood swings, agitation, aggression, and wandering (Department of Health 2009, 7-8). The stress of these symptoms on family caregivers is a major risk factor for institutionalization of the person with dementia (Hogan et al. 2007, 366). Managing these symptoms can not only enhance the well-being of those with dementia and their family caregivers but can also have cost benefits for them and the health care system (Alzheimer Society of Canada 2010, 8-9; Hux et al. 1998,457).

Because of the increased risk of falls and fractures, increased confu­sion, decrements in self-care (McCurry et al. 2000, 611), and risk of death among older adults with some medications (e.g., conventional and atypi­cal antipsychotic drugs; Wang et al. 2005, 2335), nonpharmaceutical inter­ventions should be the first choice of treatment. Drug treatment should be considered only after nonpharmaceutical approaches have failed and reversible medical and environmental causes have been ruled out (Hogan et al. 2007, 369; McCurry et al. 2000, 611). Although the evidence is insuffi­cient regarding the effectiveness of several nonpharmacological interven­tions, such as music, snoezelen (multisensory stimulation), reminiscence therapy, validation therapy, aroma therapy, massage therapy, and light therapy, the relative risk of using these approaches is low (McCurry et al. 2000, 611) and persons with dementia may benefit from them (Hogan et al. 2007, 369). This post examines the evidence specifically related to light therapy in managing symptoms of dementia.

With normal aging, people aged 65 years and over may experience changes in core body temperature, melatonin rhythm, and the circadian rest-activity cycle, which may present as fragmented nocturnal sleep, multiple and prolonged awakenings in the second half of the night, and increased daytime napping (Campbell et al. 1995, 151, 154; McCurry et al. 2000, 613) . These abnormalities and other related disturbances such as rest-activity cycle disruptions and sundowning are more frequent and pronounced in older adults with Alzheimer’ s disease (AD) (McCurry et al. 2000, 604). The neurobiological basis of these behavioral disorders is related to degenerative changes in the suprachiasmatic nucleus (SCN) of the hypothalamus that result in the loss of the expression of vasopres­sin (AVP) mRNA. Indeed, Liu et al. (2000, 314, 318) revealed that the total amount of AVP-mRNA expressed in the SCN was three times lower in persons with AD than in age- and time-of-death matched controls. In addi­tion, the amount of AVP-mRNA was three times higher during the day­time than at night in control adults aged 60 to 80 years whereas no clear diurnal rhythm was observed in persons with AD. These findings suggest that the neurological basis of the circadian-rhythm disturbances that are responsible for behavioral rhythm disorders is located in the SCN. Liu and colleagues (2000, 320) emphasize that the loss of neurons expressing AVP- mRNA in the SCN does not necessarily mean that the neurons have died; they may still be present but inactive and no longer able to express AVP- mRNA. Reactivation of SCN neurons expressing AVP-mRNA was shown to be possible in studies of aged rats. Lucassen, Hofman, and Swabb (1995, 263) revealed that exposure to bright light appeared to reverse age-asso­ciated decrease in AVP-mRNA in old rats. As in the studies of aged rats, stimulation with light may positively affect the SCN neurons in aging humans and specifically in persons with dementia.

The circadian pacemaker in the SCN is synchronized with the 24-hour day by “zeitgebers” or triggers of which light is the most important. Light impinging on the retina is transduced into neural activity that reaches the SCN through the retinohypothalamic and possibly the geniculo-hypo- thalamic tracts. Light leads to changes in the firing rates of specialized neurons in the SCN that in turn affect circadian rhythms (van Someren et al. 1996, 260). However, in older adults with dementia most zeitgebers are reduced due to diminished social contacts, age-related deficiencies in the eye (e.g., macular degeneration, cataracts, blindness), day-length (e.g., winter months have fewer external light cues), and less exposure to suf­ficient outdoor or bright light (Burns et al. 2009, 718; Gasio et al. 2003, 3; McCurry et al. 2000, 607). Reduced sensory input is likely to lower the “general level of excitement” that is thought to play an important role in the entrainment of circadian rhythms (Burns et al. 2009, 711-712; van Someren et al. 1996, 260). Thus, an environment weak in phase prompts coupled with neuropathological damage causing poor sensitivity to such prompts can result in rhythm disorders. A decreased ability to maintain a stable circadian pattern of daytime arousal and nocturnal quiescence may contribute to sleep disruptions (Ancoli-Israel et al. 2002, 282; Burns et al. 2009, 711-712; McCurry et al. 2000, 604), cognitive dysfunction (Liu et al. 2000,  314; McCurry et al. 2000, 604), behavioral disturbances (e.g., agita­tion and sundowning; Burns et al. 2009, 711-712; Haffmans et al. 2001, 106; McCurry et al. 2000, 605), functional impairment (McCurry et al. 2000, 604), and depression (Liu et al. 2000, 314; McCurry et al. 2000, 608) in per­sons with dementia.

Trials that Examined the Effectiveness of Light Therapy

The following description of the evidence builds on a recent Cochrane Review (Forbes et al. 2009) with the addition of one study (Burns et al. 2009) which was retrieved following the Cochrane Review publication. In total, nine randomized controlled trials (RCTs; eleven articles) that examined the effectiveness of light therapy in managing the symptoms of dementia are included (Ancoli-Israel, Gehrman, et al. 2003; Ancoli-Israel, Martin, et al. 2003; Burns et al. 2009; Dowling et al. 2005, 2007, 2008; Gasio et al. 2003; Graf et al. 2001; Lyketsos et al. 1999; Mishima, Hishikawa, and Okawa 1998; Riemersma-van der Lek et al. 2008), with a total of 421 participants, of whom 324 completed the studies. Participants in the included trials were diagnosed with dementia (n = 13, 3%), probable AD (n = 318, 76%), vascular dementia (n = 55, 13%), mixed dementia (n = 5, 1%) or another type of dementia (n = 30, 7%). It is interesting to note that few participants were diagnosed with mixed dementia, defined as the coexistence of AD and vascular dementia. Mixed dementia is one of the most common forms of dementia with a prevalence range of 20-40% of persons with dementia (Zekry, Hauw, and Gold 2002, 1431, 1432).

Four of the trials were conducted in the United States (Ancoli-Israel, Gehrman et al. 2003, 22) Ancoli-Israel, Martin, et al. 2003, 194) Dowling et al. 2005, 738; Dowling et al. 2007, 961; Dowling et al. 2008,239; Lyketsos et al. 1999, 520), one was conducted in Austria (Graf et al. 2001, 726), one in Japan (Mishima, Hishikawa, and Okawa 1998, 647), one in the Nether­lands (Riemersma-van der Lek et al. 2008, 2642), one in Switzerland (Gasio et al. 2003, 207), and one in the United Kingdom (Burns et al. 2009, 711). All participants were residents in a long-term care/seniors facility.

Sources of Bright Light

Seven trials used a Brite-Lite box (e.g., Apollo Light Systems, Orem, Utah) which was approximately 24 inches wide by 12 inches high by 3 inches deep and placed one meter from the participant’s head. The Brite- Lite utilized cool-white florescent, nonultraviolet, full-spectrum light bulbs with special ballast to augment the brightness. The treatment groups received light therapy ranging from 2,500 to 10,000 lux and the control groups received dim red light or dim, low-frequency blinking light, less than 300 lux, either in the morning or evening, for 1-2 hours, for 10 days to 10 weeks. There were two exceptions: the use of dawn-dusk simulation (maximum 400 lux) or placebo dim red light (< 5 lux) (Gasio et al. 2003, 211) and the use of ceiling mounted light fixtures (Riemersma-van der Lek et al. 2008, 2643). The Dawn-Dusk Simulator included a computer algo­rithm that drove an electronic controller connected to an overhead halo­gen lamp placed behind a diffusing membrane behind each participant’s bed. The ceiling-mounted fixtures were Plexiglas diffusers containing an equal amount of Philips TLD840 and TLD940 florescent tubes, which were installed in the common living area. The lights were kept on between approximately 0900 and 1800 hours with the aim of an exposure of ±1000 lux (Riemersma-van der Lek et al. 2008, 2643-2644).

Effects of the Light Therapy

Several outcomes were measured following exposure to light therapy: cognition, function, sleep, behavioral disturbances, and psychiatric dis­turbances. These are each discussed below.

Cognition

Four studies ( Burns et al. 2009, 712 ; Gasio et al. 2003, 208 ; Graf et al. 2001,  726; Riemersma-van der Lek et al. 2008, 2646) used the Mini-Mental State Examination (MMSE), a commonly used screening tool that concen­trates on the cognitive aspects of mental function: orientation, immediate recall, attention and calculation, delayed recall, and language (Folstein, Folstein, and McHugh 1975). Morning bright light (10,000 lux) was com­pared with standard fluorescent-tube light (100 lux) in Burns et al. (2009, 713), evening bright light (3,000 lux) was compared with dim light (100 lux) in Graf et al. (2001, 726), all-day bright light (1,000 lux) was compared with dim light (300 lux) in Riemersma-van der Lek et al. (2008, 2643-2644), and dawn-dusk simulation with light up to 400 lux was compared with dawn-dusk simulation with dim red light (<5 lux) in Gasio et al. (2003, 209-210). The data in the Burns et al. (2009, 715) and Riemersma-van der Lek et al. (2008, 2647) studies were combined because the light therapy was administered in the morning or all day and their light intensities were considered bright light. The pooled data revealed no effect following 14 to 42 days of treatment (MD = 1.34, 95% CI -0.89 to 3.57, p = 0.24). Riemers- ma-van der Lek et al. (2008, 2647) data revealed similar results after one year of treatment (MD = 1.70, 95% CI -1.03 to 4.43, p = 0.22), and after two years of treatment (MD = 3.60, 95% CI -1.05 to 8.25, p = 0.13). Graf et al. (2001, 726) administered evening bright light for 10 days that had no effect on cognition (MD = 0.70, 95% CI -4.90 to 6.3, p = 0.81). Similarly, the Gasio et al. (2003, unpublished data provided by authors) study employing the dawn-dusk simulation revealed no effect at endpoint (MD = 0.46, 95% CI -14.14 to 15.06, p = 0.95) and at follow up (three weeks after treatment) (MD = -0.50, 95% CI -10.68 to 9.67, p = 0.92). Thus, none of the trials dem­onstrated a significant change in cognition as a result of the light therapy.

Function

One study (Riemersma-van der Lek et al. 2008, 2646) measured func­tional limitations using Nurse-Informant Activities of Daily Living (NI- ADL). This scale was an adaptation of the Katz ADL scale (Katz et al. 1963) and includes six items that measure competence in feeding, continence, transferring, going to toilet, dressing, and bathing (Holmes et al. 1990). After six weeks of treatment, light therapy had a positive effect in attenu­ating the increase in functional limitations (MD = -5.00, 95% CI -9.87 to -0.13, p = 0.04). After one year of treatment, there was no significant effect (MD -5.00, 95% CI -11.16 to 1.16, p = 0.11); however, a significantly less steep increase in functional decline was observed after two years of light therapy (MD = -16.00, 95% CI -26.21 to -5.79, p = 0.002). These significant findings show support for the benefit of light therapy in lessening functional decline in persons with dementia.

Sleep

Sleep latency, defined as the amount of time between reclining in bed and the onset of sleep (Venes 2001, 1200), was measured using wristwatch- size actigraphs in trials conducted by Gasio et al. (2003, 215) and Riem- ersma-van der Lek et al. (2008, 2646) . However the data from these two studies could not be pooled due to differences in light intensity. Findings from Riemersma-van der Lek et al. (2008, 2651) revealed that there were no significant improvements in sleep onset latency after six weeks of treat­ment (MD = 6.00, 95% CI -12.34 to 24.34, p = 0.52), one year of treatment (MD = 5.00, 95% CI -24.79 to 34.79, p = 0.74), and after two years of treat­ment (MD = 10.00, 95% CI -11.33 to 31.33, p = 0.36). Similarly, data from Gasio et al. (2003, 214) revealed that dawn-dusk simulation did not signifi­cantly reduce sleep latency after three weeks of treatment (MD = -79.00, 95% CI -327.17, 169.17, p = 0.53) and after three weeks of follow-up (MD = -62.00, 95% CI -216.55 to 92.55, p = 0.43).

Seven studies measured total night sleep duration following ten days (Ancoli-Israel, Gehrman, et al. 2003, 26), two weeks (Burns et al. 2009, 712), three weeks (Gasio et al. 2003, 207), four weeks (Lyketsos et al. 1999, 521), ten weeks (Dowling et al. 2005, 740; Dowling et al. 2008, 240), and one and two years of treatment (Riemersma-van der Lek et al. 2008, 2646) that consisted of bright-light therapy (>2500 to 10,000 lux) for one to two hours in the morning (Ancoli-Israel, Gehrman, et al. 2003, 26; Burns et al. 2009, 713; Dowling et al. 2008, 240; Lyketsos et al. 1999, 521), afternoon/evening (Ancoli-Israel, Gehrman, et al. 2003, 26; Dowling et al. 2005, 740), all day bright light (1000 lux) (Riemersma-van der Lek et al. 2008, 2643), or dawn- dusk simulation (400 lux) morning and evening (Gasio et al. 2003, 209-210). The treatment groups were compared with control groups who received dim light. Unfortunately, Ancoli-Israel, Gehrman, et al. (2003, 30) reported only the combined findings from the treatment and control groups data, and Lyketsos et al.’s (1999, 521) study was a crossover design and did not appear to have utilized analyses appropriate to a paired design. Thus, the data from these studies were excluded from the analyses. Combined data from Burns et al. (2009, unpublished data provided by authors), Dowling et al. (2005, 741), Dowling et al. (2008, 243), and Riemersma-van der Lek et al. (2008, 2648) combined data revealed no effect of morning to all-day bright light on total night sleep duration (MD = 18.16, 95% CI -5.63 to 41.95, p = .13). Evening bright light (Dowling et al. 2005, 741) revealed similar findings (MD = 10.00, 95% CI -59.22 to 79.22, p = .78). Data from Riemersma-van der Lek et al. (2008, 2648) also revealed that bright light had no effect on night-sleep duration after one year (MD = -36.00, 95% CI -84.21 to 12.21, p = .14) and two years of treatment (MD = -36.00, 95% CI -121.69 to 49.69, p = .41). Data from Gasio et al. (2003, 214) were ana­lyzed separately due to the lower intensity of treatment light. No effect was found after three weeks of treatment (MD = 143.00, 95% CI -637.66 to 923.66, p = .72), or at follow-up (MD = 110.00, 95% CI -77.22 to 297.22, p = .25).

Four studies (Ancoli-Israel, Gehrman, et al. 2003, 25) Dowling et al. 2005, 740) Gasio et al. 2003, 210) Mishima, Hishikawa, and Okawa 1998, 649) measured night-time activity counts. Unfortunately, reported data from Ancoli-Israel, Gehrman, et al. (2003, 30) and Mishima, Hishikawa, and Okawa (1998, 650) were not appropriate for inclusion in the meta­analyses. The findings from Dowling et al. (2005, 740) and Gasio et al. (2003, 214) could not be combined due to the differences in intensity of the light therapy. Dowling et al. (2005, 740) measured activity scores per night for both morning and afternoon treatment groups compared with control groups after 10 weeks of treatment. No effect on nighttime activ­ity scores was found when bright light was administered in the morning (MD = 855.78, 95% CI -867.84 to 2579.40, p = .33), or afternoon (MD = -78.60, 95% CI -627.17 to 469.97, p = .78). In Gasio et al. (2003, 214) activity for each participant was averaged in one-hour bins and then over seven consecutive days of baseline, treatment, and follow-up. No effect on night activity was found after three weeks of treatment (MD = -20.60, 95% CI -46.52 to 5.32, p = .12) and after three weeks of follow-up (MD = -24.70, 95% CI -52.70 to 3.30, p = .08). Dowling et al. (2005, 740, and 2008, 243) also measured the number of nighttime awakenings. Again, there was no effect on the number of nighttime awakenings after 10 weeks of treatment in either the morning bright-light exposure (MD = -2.37, 95% CI -8.75 to 4.01, p = .47) or evening exposure (MD = -4.38, 95% CI -11.61, 2.86, p = .24). In summary, a significant change in sleep latency, total nighttime duration, nighttime activity counts, and number of nighttime awakenings was not observed following light therapy.

Behavioral Disturbances

Behavioral disturbances (e.g., agitation) were measured in six stud­ies using several instruments: (1) Agitated Behavior Rating scale (ABRS; Ancoli-Israel, Martin, et al. 2003, 196), which measured agitation, manual manipulation, searching and wandering, escape behaviors, tapping and banging, and verbal agitation (Bliwise and Lee 1993); (2) Behavioral Pathol­ogy in AD scale (Behave-AD; Lyketsos et al. 1999, 522), which measured paranoid and delusion ideation, hallucinations, activity disturbances, aggressiveness, and anxiety and phobias (Reisberg et al. 1987); (3) Neu­ropsychiatric Inventory (NPI; Gasio et al. 2003, 208, Dowling et al. 2007, 964-965), which measured the severity and frequency of delusions, hal­lucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibi- tion, irritability/lability, apathy, and aberrant motor activity (Cummings et al. 1994); and (4) Cohen-Mansfield Agitation Inventory (CMAI; Burns et al. 2009, 712; Riemersma-van der Lek et al. 2008, 2646), which measured aggressive behavior, physically nonaggressive behavior, verbal agitation, and a global rating of agitation (Cohen-Mansfield, Marx, and Rosenthal 1989). In two studies (Ancoli-Israel, Martin, et al. 2003, 199; Dowling et al. 2007, 968) behavioral disturbances were compared between morning light therapy exposure and afternoon/evening light therapy and assessed in the morning and evening shifts (Ancoli-Israel, Martin, et al. 2003, 199). The findings from Lyketsos et al. (1999, 522-523) could not be included in the analyses for reasons cited above.

With light therapy administered during the morning or day time, behavioral disturbances measured by ABRS scores (Ancoli-Israel, Mar­tin, et al. 2003, 196), NPI scores (Dowling et al. 2007, 964-965), and CMAI scores (Burns et al. 2009, 712, Riemersma-van der Lek et al. 2008, 2646) were pooled. The results revealed that light therapy administered during the morning or daytime had no effect on behavioral disturbances (SMD = -0.04, 95% CI -0.33 to 0.26, p = .80) following 10 to 50 days of light therapy. Similarly, no effect on behavioral disturbances was observed in the evening assessment following 10 days of treatment (MD = 0.11, 95% CI -0.23 to 0.45, p = .52; Ancoli-Israel, Martin, et al. 2003, 199), after five days of follow-up measured in the morning (MD 0.02, 95% CI -0.23 to 0.27, p = .87; Ancoli- Israel, Martin, et al. 2003, 199), in the evening (MD 0.07, 95% CL -0.26, 0.40, p = .67; Ancoli-Israel, Martin et al. 2003, 199), following one year of treat­ment (MD = -2.00, 95% CI -11.71to 7.71, p = .69; Riemersma-van der Lek et al. 2008, 2647), and after two years of light therapy (MD = -9.00, 95% CI -21.34 to 3.34, p = .15; Riemersma-van der Lek et al. 2008, 2647).

To assess behavioral disturbances following the administration of after­noon or evening light therapy, ABRS scores (Ancoli-Israel, Martin, et al. 2003, 199) and NPI scores (Dowling et al. 2007, 968) were pooled. The results revealed that light therapy administered in the afternoon or evening had no effect on reducing behavioral disturbances when assessed during the morn­ing (SMD = 0.16, 95% CI -0.31 to 0.64, p = .50) following 10 to 50 days of light therapy (Ancoli-Israel, Martin et al. 2003, 199; Dowling et al. 2007, 968) or when assessed during the evening (MD 0.07, 95% CI -0.26 to 0.40, p = .67) following 10 days of treatment (Ancoli-Israel, Martin, et al. 2003, 199). Simi­lar results were found after five days of follow-up during morning assess­ments (MD 0.10, 95% CI -0.16 to 0.36, p = .46; Ancoli-Israel, Martin, et al. 2003, 199) and during evening assessments (MD 0.11, 95% CI -0.23 to 0.45, p = .53; Ancoli-Israel, Martin et al. 2003, 199). In summary, light therapy whether administered in the morning/all day or afternoon/evening had no significant effect on behavioral disturbances at the end of treatment or on follow-up when assessed during the morning and evening.

Psychiatric Disturbances

Dowling et al. (2007, 964-965) and Riemersma-van der Lek et al. (2008, 2646)   used the NPI to measure psychiatric disturbances. Their pooled data revealed no significant change after 42 to 50 days of light therapy (MD = 1.77, 95% CI -6.34 to 9.87, p = .67), after one year (MD = -0.30, 95% CI -2.73 to 2.13, p = .81), and after two years (MD = -3.30, 95% CI -7.03 to 0.43, p = .08). In addition, there was no effect when light therapy was administered in the afternoon (MD = 7.90, 95% CI, -0.46 to 16.26, p = .06; Dowling et al. 2007, 969). Gasio et al. (2003, 208) also used the NPI to examine psychiatric symptoms following three weeks of dawn-dusk simulation or dim red light therapy. No effect was observed following the treatment (MD = -3.19, 95% CI -9.83 to 3.45, p = .35) and after three weeks of follow-up (MD = -4.17, 95% CI -13.37 to 5.03, p = .37).

Five studies measured depression: Dowling et al. (2007, 964-965) used the depression/dysphoria domain of the NPI-Nursing Home version (NPI-NH), a modified version of the NPI (Iverson et al. 2002); Gasio et al. (2003, 208) used the Geriatric Depression Scale (GDS; Sheikh and Yesvage 1986); and Burns et al. (2009, 712), Lyketsos et al. (1999, 522), and Riemers- ma-van der Lek et al. (2008, 2646) used the Cornell Scale for Depression in Dementia (CSDD; Alexopoulos et al. 1988). Lyketsos et al. (1999, 524) reported that no significant differences in scores of depression were found between groups at each time point. However, raw data were not reported and could not be retrieved. Pooled data (Burns et al. 2009, 715) Dowling et al. 2007, 968; Riemersma-van der Lek et al. 2008, 2647) revealed no effect on depression following 14 to 50 days of light therapy (SMD = 0.06, 95% CI -0.55 to 0.67, p = .85). In addition, Riemersma-van der Lek et al. (2008,

2647) data revealed no effect on depression using CSDD scores at one year (MD = -.30, 95% CI -4.36 to 3.76, p = .88) and after two years of treatment (MD -4.40, 95% CI -10.82 to 2.02, p = .18). However, administering the light therapy in the afternoon resulted in an effect after 50 days of treat­ment (MD = 3.20, 95% CI 0.86 to 5.51, p = .007) favoring the control group (Dowling et al. 2007, 968). These results should be viewed with caution due to the small sample size (n = 17). Analysis of the data provided to the authors by Gasio et al. (2003) revealed no effect on depression scores after three weeks of treatment (MD = -0.82, 95% CI -4.33 to 2.69, p = .65) or at follow-up (MD = -1.29, 95% CL -3.99, 1.41, p = .35).

Apathy and indifference were measured using a domain of the NPI-NH (Iverson et al. 2002) following 50 days of treatment (Dowling et al. 2007, 969). There was no effect on apathy or indifference in either the morning administration of bright light (MD = 1.00, 95% CI -2.21 to 4.21, p = .54) or afternoon administration (MD = 0.40, 95% CI -3.00 to 3.80, p = .82). In summary, there is no significant evidence that bright light improves psy­chiatric symptoms in persons with dementia.

The Cochrane Review on light therapy and dementia (Forbes et al. 2009) with the addition of the trial by Burns et al. (2009) revealed little sig­nificant evidence of benefit of light therapy on cognition, function, sleep, behavioral disturbances, and psychiatric disturbances associated with dementia. Light therapy was shown to have an effect on two outcomes of interest. The Riemersma-van der Lek et al. (2008, 2647) data revealed that light therapy had a positive effect in attenuating the increase in func­tional limitations after six weeks and after two years of light therapy. The sample size was adequate at six weeks (n = 87) but by two years the sam­ple size was only 26 participants. By ensuring an adequate sample size at follow-up, the effect of light therapy in limiting functional decline may be even greater as the power to detect a difference would be increased. The Dowling et al. (2007, 968) data revealed that the lack of afternoon bright- light therapy improved depression in the control group. However, these results should be viewed with caution as the sample size was small (n = 17; Dowling et al. 2007, 968). No significant evidence was found that light therapy decreases the decline in cognition, shortens sleep latency time, increases nocturnal sleep time, decreases nighttime activity, decreases behavioral disturbances, or improves psychiatric symptoms. These nonsignificant results may have been related to small sample sizes that contribute to insufficient power to detect a difference, if one is present. Notable exceptions were the Ancoli-Israel, Gehrman, et al. (2003, 25) and Ancoli-Israel, Martin, et al. (2003, 195) trials that included 92 participants and the Riemersma-van der Lek et al. (2008, 2645) study that included 94 participants at baseline. Clearly further research with larger sample sizes is required which examines all of the outcomes of interest.

Only one trial (Riemersma-van der Lek et al. 2008, 2653) examined adverse effects of light therapy. No adverse effects were reported; on the contrary, light therapy significantly reduced the ratings of irritability, diz­ziness, headache, constipation, and inability to sleep (Riemersma-van der Lek et al. 2008, 2653). Reporting of adverse events should be included in every intervention trial.

Unfortunately, Ancoli-Israel, Gehrman, et al. (2003), Lyketsos et al. (1999), and Mishima, Hishikawa, and Okawa (1998) did not report the data needed to conduct a meta-analysis (e.g., means and standard deviations at baseline and endpoints for the treatment and control groups) for some of the outcomes of interest. Authors need to report these data or be willing to provide the data on request. In addition, two studies (Lyketsos et al. 1999, 521, Mishima, Hishikawa, and Okawa 1998, 649) used crossover designs and did not conduct analyses appropriate to a paired design. Although participants received no light treatment for one to four weeks prior to being crossed over to the other group, it is unknown if there is a carry-over effect from the two to four weeks of exposure to the light therapy. Some studies (e.g., Ancoli-Israel, Gehrman, et al. 2003, 32) suggest that the effects of light therapy on nocturnal sleep may persist beyond the five-day treatment, while McCurry et al. (2000, 614) concluded that the benefits to sleep from increased bright light decline almost immediately once exposure is discon­tinued. Until the evidence is stronger, participants should not be regarded as generating independent data in the two phases of a crossover design.

Another plausible reason for the lack of strong evidence of the effec­tiveness of light therapy was the heterogeneity within several of the trials in regard to participants’ diagnosis and severity of dementia. Three trials (Ancoli-Israel, Gehrman, et al. 2003, 25; Ancoli-Israel, Martin, et al. 2003, 201; Dowling et al. 2005, 2008) were notable exceptions as only participants with AD were included. Persons with AD have a degenerative disease that is characterized by neurofibrillary tangles, usually in the hippocampus as well as the entorhinal cortex. As AD progresses, the pathology spreads to the lateral temporal cortex as well. Senile plaques occur later on (Chert- kow et al. 2007, 274). On the other hand, persons with vascular dementia have heterogeneous brain pathology; their response to light therapy may depend on the areas in which ischemic damage has occurred (Mishima, Hishikawa, and Okawa 1998, 653). Few participants were diagnosed with mixed dementia (1%), although it is now recognized that mixed dementia is one of the most common forms of dementia (Zekry, Hauw, and Gold 2002,  1432). It may be that those with AD with a vascular component were included with participants diagnosed with only AD. This was the practice in the Canadian Study of Health and Aging (Zekry, Hauw, and Gold 2002, 1432). Attempts should be made to accurately diagnose the participants with diagnostic procedures such as positron emission tomography (PET) neuroimaging, which have been recognized as key diagnostic modalities (Zekry, Hauw, and Gold 2002, 1435). In addition, accurately determining the severity of the disease is also important as it is possible that persons with mild to moderate AD with more intact SCNs and who are more receptive to other “zeitgebers” or triggers will have a greater response to light therapy than persons with severe AD (Ancoli-Israel, Martin, et al. 2003,  201).

Culture and geographic location are other factors that may influence the results of the review as trials were conducted in six different countries. For example, the participants from Japan may have experienced close family ties and well-developed informal care that may mask the symp­toms of dementia (Zekry, Hauw, and Gold 2002, 1435). Geographic loca­tion is also a potential risk factor as participants in the United Kingdom may have experienced longer winters that resulted in fewer opportunities to be exposed to natural light than participants in more southern countries (Burns et al. 2009, 719). Subgroup analyses in the review could not be com­pleted due to the small sample sizes. Investigators need to be sensitive to the importance of controlling for these differences in pathology, severity of dementia, and culture when designing studies that examine the effec­tiveness of light therapy. Otherwise, the degree of influence these factors may have on the effectiveness of bright-light exposure is unknown, mak­ing it difficult to predict who is most likely to benefit from the treatment.

Shochat et al. (2000) examined light exposure among elderly residents living in nursing homes. On average, healthy older adults are exposed to light above 2000 lux for 59 minutes a day. People with AD living at home are exposed to 29 minutes a day of light above 2000 lux, while institu­tionalized residents with dementia spent a median of 10.5 minutes per day (mean = 34; SD = 63) exposed to light above 1000 lux and a median of 4 minutes (mean = 19; SD = 39) per day exposed to light over 2000 lux (Shochat et al. 2000, 373, 374, 375). Clearly, there is a need to enhance resi­dents’ natural exposure to light and to bright-light exposure in long-term care facilities. How best to carry this out is less clear.

Most trials in the review incorporated some form of a Brite Lite box, and two trials used other forms of light therapy. Gasio et al. (2003, 211) used dawn-dusk simulated light therapy that exposed the participants to natu­ral amounts of light at dawn and dusk. However, the intensity (<400 lux) and duration of the natural light at dawn and dusk may be insufficient to be effective in changing sleep, behavior, and/or psychiatric disturbances. Indeed, several studies have revealed that the minimum therapeutic dose of light for treating depression and regulating circadian rhythms is approximately 2000 lux over one to two hours (e.g., Sloane et al. 2005, 280-281). Riemersma-van der Lek et al. (2008, 2643) used ceiling-mounted light fixtures with Plexiglas diffusers in the common living room.

These approaches to enhancing light exposure for long-term care residents are less invasive and demanding of the residents and staff than the traditional Brite-Lite box. Use of a Brite Lite box requires participants to sit in front of the box for one to two hours. However, persons with moderate to severe dementia may find it difficult to remain seated and to stay awake for this period of time (Ancoli-Israel et al. 2002, 286; Sloane et al. 2005, 281). Some studies (e.g., Burns et al. 2009, 713) attempted to overcome this problem by having a research nurse present during the treatment period to engage all participants in conversation and to distract them if they attempted to leave. Under usual circumstances, it may be difficult to find the resources to have a staff member sit with and engage the residents for one to two hours. Burns et al. (2009, 719) recommends wall-mounted light boxes placed at eye level for the residents seated during breakfast. Ancoli-Israel, Gehrman, et al. (2003, 34) suggests increasing ambient light to 2000 lux in multipurpose rooms where residents spend much of their time may be the most efficient approach for improving the symptoms of dementia related to circadian activity rhythms. Since studies that evaluate the impact of increasing ambient light on the symptoms of dementia often incorporate a non-RCT design (e.g., Sloane et al. 2007, 1525), systematic reviews should also include these study designs to ensure that all of the best available evidence is presented.

The best time of day to offer light therapy remains inconclusive although trials that administered light therapy in the morning, afternoon, evening, and all day were included in this systematic review. Evening bright-light treatment is beneficial for sleep-maintenance problems in older adults as well as for persons who are phase-advanced, that is, falling asleep in the early evening and awakening too early in the morning (Campbell et al. 1995, 153). Morning light exposure is most beneficial for persons who are phase-delayed, that is whose sleep onset and morning rising are pushed to later hours (McCurry et al. 2000, 613). Individuals with AD have been reported to have phase-delayed activity (Satlin et al. 1995, 769) . How­ever, other studies (e.g., Ancoli-Israel et al. 2002, 282) have not supported the expected direction of change in individuals with AD. Ancoli-Israel, Gehrman, et al. (2003, 33-34) report that the timing of light required to achieve a phase advance or phase delay may be different in people with AD owing to the deterioration of the SCN, and recommends increasing light exposure throughout the day and evening. Most recently, Burns et al. (2009, 719) report that their use of light therapy at 10:00 am for two hours reduced the chance of residents receiving light therapy on or before their temperature nadir (lowest point), which has been suggested to shift the diurnal rhythm in the opposite expected direction. Burns et al. (2009, 719) also found that light therapy was only effective during the winter months and not during the summer months when there was increased opportu­nity to natural exposure of light. Clearly further research is required in this area.

In addition, community-based light-therapy research is needed. All of the participants in the included studies resided in long-term care/seniors facilities. However, light-therapy modalities implemented in residen­tial facilities may not translate readily to a home setting as they may be impractical, unacceptable, and/or overly expensive for the family care­giver and person with dementia residing in the community (McCurry et al. 2000, 614). Although there is no known research that has examined the impact of being exposed to natural daylight, persons residing in the com­munity (and those residing in long-term care facilities with assistance of healthcare aides or volunteers) can greatly increase their daily light expo­sure by spending time outdoors. For example, typical lux levels outside on a cloudy day range from 8,000 to 10,000 lux; interior daytime exposure sitting near windows equals approximately 1000 lux (McCurry et al. 2000, 614). As with all dementia care, a light-therapy plan that makes sense to the person with dementia, the family caregiver and healthcare provider,
and which targets factors that are both relevant and modifiable in their situation, is more likely to be effective than a “one size fits all” approach (McCurry et al. 2000, 621).

Given the methodological shortcomings of the trials included in this review, there is not good evidence that light therapy is effective or ineffective. An exception is the well-designed longitudinal RCT by Riemersma-van der Lek et al. (2008, 2643), which found that light therapy had a positive effect in atten­uating the increase in functional limitations. Further well-designed research is required to compare different light-therapy approaches (e.g., light boxes, ambient light, natural light), to determine the most appropriate illumination intensity, frequency, time of day, and duration of the intervention with per­sons with AD, vascular dementia, and mixed dementia at different levels of severity of the disease (see Table 1). Outcomes that contribute to the qual­ity of life of persons with dementia, cost implications, and adverse effects of light therapy also need to be examined. What is clear from the evidence is that older adults and especially persons with dementia should be spending more time outdoors in natural light (see Table 1). Healthcare aides, vol­unteers, and family caregivers are in an ideal position to take persons with dementia for a daily walk that would increase their exposure to light and possibly alleviate some of their challenging symptoms. This is a potentially easy solution to managing very difficult symptoms of dementia.

Table 1

Recommendations to Improve Methodological Quality of Trials

Well-designed RCTs that include random generation of subjects and concealed allocation to groups are the preferred design of choice. When RCTs are not fea­sible, the best available evidence should also be included in a systematic review, recognizing the potential risk of biases.

Sample sizes should be large enough to detect a difference if one is present.

Samples should be as homogenous as possible in terms of dementia diagnosis, level of severity, culture, and geography.

Trial authors should report the information needed to conduct a meta-analysis or be willing to share this information with the authors of a review.

Further research is needed to determine the most effective and feasible bright-light modality, time of day to administer the treatment, length of treatment, and the influence of season on the outcomes.

Reporting of adverse events should be included in every intervention trial.

Research on the effectiveness of light-therapy modalities in the home setting is also needed.

In long-term care facilities, increase the use of BriteLite boxes mounted to the wall at residents’ eye level during breakfast.

Increase the use of ceiling-mounted light fixtures with Plexiglas diffusers in the common living rooms.

Healthcare aides, volunteers, and family caregivers are in an ideal position to take persons with dementia for a daily walk, which will increase their exposure to nat­ural light.

Increasing exposure to light is especially important after the autumn equinox and before the spring equinox.

Behavioral and Psychological Symptoms of Dementia: Treatment with Antipsychotics

In November 1906 the German psychiatrist Alois Alzheimer delivered a lecture at the 37th Conference of South-West German Psychiatrists in Tubingen reporting the case of Auguste D. (Alzheimer 1906). According to Dr. Alzheimer’ s description, the first noticeable symptom of illness shown by this 51-year-old woman was a strong feeling of jealously toward her husband. At times, believing that people were out to murder her, she started to scream loudly. At times, she seemed to have auditory hallu­cinations. Very soon, she showed rapidly worsening memory loss. She was disoriented in her flat and wandered aimlessly from room to room. After four years of illness, Auguste D. died. Dr. Alzheimer performed an autopsy and found in her brain tissue a large amount of senile plaques and neurofibrillary tangles (NFT) which are known to be the peculiar pathological lesions of Alzheimer’ s disease (AD). More than 100 years ago, Dr. Alzheimer described a case of AD with behavioral and psycho­logical symptoms of dementia (BPSD) such as delusions, hallucinations, agitation, and wandering.

The term BPSD has been introduced in 1996 in a consensus statement of the International Psychogeriatric Association and describes a wide spectrum of noncognitive symptoms of dementia including agitation, verbal and physical aggression, psychotic symptoms (delusions and hal­lucinations), oppositional behavior, socially inappropriate behavior, apa­thy, anxiety, sleep disturbances, and wandering (Finkel 2002). It has been
estimated that up to 90% of patients with AD may show at least one of these symptoms during the course of the disease (Benoit et al. 2005; Chan et al. 2003; Lyketsos et al. 2002). They may be manifest at any stage of AD although they have been less frequently reported in the early stages of the disease (Bozeat et al. 2000; Cummings et al. 1996). BPSD are also present in dementia syndromes other than AD, such as dementia with Lewy bodies or frontotemporal lobar degeneration, where they may appear also in the early stages.

BPSD have a tremendous impact on patients’ and families’ quality of life (Fitten 2006; Levy et al. 1996). Families struggle to manage patients with BPSD. Caregivers of patients with BPSD are at high risk of distress, depression and burn-out (Benoit et al. 2006). These symptoms are a pri­mary reason for patients’ institutionalization (Cohen et al. 1993). Patients with BPSD show accelerated cognitive deterioration; they are at high risk of functional decline, disability, hospitalization, emergency room visits and death (Scarmeas et al. 2005). Finally, BPSD have been associated with an enormous increase in costs of care (Herrmann et al. 2006; Alzheimer’s Association 2009). In our aging society, where the number of AD cases is growing fast and approaching 35 million worldwide, BPSD represent a major public health issue and a disruptive condition for families and soci­eties (Alzheimer Disease International 2009).

Although BPSD are generally considered treatable symptoms, their management represents a serious challenge for physicians and caregivers. Several therapeutic options are available and they include nonpharmaco- logical and pharmacological strategies. According to clinical guidelines, nonpharmacological interventions must represent the first-choice strat­egy of treatment for BPSD (American Geriatrics Society and American Association for Geriatric Psychiatry 2003; Alexopoulos et al. 2005; Expert Consensus Panel for Dementia 2005). Nonpharmacological treatments for dementia include a variety of interventions targeting the patient, the family, and the environment. They include music therapy, massage/touch therapy, physical exercise, aromatherapy, light therapy, environmental manipulation, reminiscence therapy, behavior management, multisensory stimulation, and validation therapy. To date, evidence supporting the use of such techniques in clinical practice is limited and mostly derives from clinical studies with small sample size and weak study designs (Hulme et al. 2010; Hersch and Falzgraf 2007). Moreover, most nonpharmacological interventions have been tested among community-dwelling patients and require specific caregiver training to be applied. Nonetheless, it is strongly recommended to consider a pharmacological approach to BPSD only after nonpharmacological strategies have failed to control these symptoms.

To date, antipsychotic medications represent the most efficacious phar­macological option for the treatment of BPSD, although several psycho­tropic medications including cholinesterase inhibitors, benzodiazepines, antidepressants, N-methyl-D-aspartate receptor modulators, and anticon­vulsants have been suggested to be beneficial in controlling some specific symptoms (Madhusoodanan et al. 2007; Jeste et al. 2008).

The aim of this post is to describe the brain anatomical and bio­chemical abnormalities underlying BPSD and the main pharmacological properties of antipsychotics, to review the evidence regarding the efficacy and safety of antipsychotics in patients with dementia, and to provide the reader with practical recommendations for the daily management of BPSD.

Etiological processes underlying BPSD are yet to be fully understood. Multiple biologic and nonbiologic factors are believed to contribute to the development of BPSD. Psychological factors such as a patient’s premorbid personality and response to stress, social factors such as environmental changes and stressful events, caregiver factors such as caregiver distress and reaction to patient’s behavior interact with genetic aspects and neu- robiological abnormalities in determining the onset of BPSD, the pat­tern of symptoms, and their severity (Meins, Frey, and Thiesemann 2008; Zuidema et al. 2010).

Genetic studies have suggested that several chromosomal abnormali­ties may represent a risk factor for the development of BPSD. A mutation of the presenilin 1 gene on chromosome 14 has been linked with depres­sion and psychosis in AD (Harvey et al. 1998). Serotonin and dopamine are brain chemical neurotransmitters that bind specific cellular receptors, thus allowing communication among neuronal cells and nerve fibers. In particular, serotonin is believed to play a major role in modulating mood, emotion, and sexuality while dopamine is thought to mediate behavior, some aspects of cognition, sleep, attention, mood, and motor activity. The term genetic polymorphism indicates a specific variation of a gene. Polymorphisms of brain serotonin and dopamine receptor genes may predispose to the development of BPSD. In particular, visual and auditory hallucinations have been associated with polymorphisms of serotonin receptor genes (5HT2A 102-T/C and 5HT2c Cys23ser) (Holmes et al. 1998). Variation of the dopamine receptor DRD1 and DRD3 genes have been associated with an increased risk of developing psychotic and aggressive symptoms in AD patients (Sweet et al. 1998). Psychosis and aggressive behavior in combination have been associated with a genetic polymorphism of serotonin transporter (5-HTTPR II genotype) (Sweet et al. 2001). Finally, genetic variations of the brain-derived neurotrophic factor (BDNF) have been related to depression in AD patients (Borroni, Costanzi, and Padovani 2010).

It has been shown that the pathology of different brain regions is respon­sible for the development of different BPSD. It has been documented that relative to patients who do not develop psychosis, those exhibiting psy­chotic symptoms have a greater density of NFT in the brain neocortex (Farber et al. 2000). Higher NFT concentration has also been reported in the orbitofrontal cortex of AD patients with agitation (Tekin et al. 2001). Neurofunctional-imaging studies have documented that psychosis is associated with a decreased metabolism of the prefrontal, left frontal-tem­poral and right parietal areas (Lopez et al. 2001; Sultzer et al. 2003). Other psychotic symptoms such hallucination and delusional misidentification have been associated with low neuron count in the CA1 area of the hip­pocampus and in the dorsal raphe (Forstl et al. 1994).

Abnormalities of multiple neurotransmitter systems have been identi­fied in the brain of patients with dementia. The decrease of brain acetyl­choline levels is responsible for memory impairment, cognitive symptoms, and delirium in AD (van der Cammen et al. 2006). The decrease in cho­linergic activity may result in a relative increase of the dopaminergic and noradrenergic activity, which would lead to psychotic symptoms, behav­ioral disturbances, and aggression (Engelborghs et al. 2008; Herrmann, Lanctot, and Khan 2004; . Also, reduced levels of serotonin have been found in different brain regions of AD patients (Lanctot, Herrmann, and Mazzotta 2001). Most pharmacological treatments for BSPD include medi­cations able to either increase or decrease or modulate the activity of such neurotransmitters.

Antipsychotics, also called neuroleptics, are the mainstay of pharma­cological treatment for BPSD. A list of the most commonly used anti­psychotic medications described by chemical structure and drug name is reported in Table 1 .

The so-called conventional, typical, or first-generation antipsychotics have been used since the 1950s for the treatment of schizophrenia. Accord­ing to their chemical structure, conventional antipsychotics are classified in phenotiazines, butyrophenones, and thioxanthenes. All conventional agents share high affinity for the D2 dopamine receptor. Although their mechanism of action has not been fully clarified, they are believed to exert their action by blocking the D2 receptors in the mesolimbic pathway (Xib- eras et al. 2001). It has been documented that the efficacy of these drugs is strictly correlated with the occupancy rate of D2 receptors. D2 occupancy rate has been shown to predict the clinical response to haloperidol.

Table 1

Antipsychotic Medications

Chlorpromazine, Promazine,

Levomepromazine, Acepromazine, Triflupromazine, Fluphenazine, Perphenazine, Prochlorperazine, Trifluoperazine, Acetophenazine, Periciazine, Thioridazine, Mesoridazine

Haloperidol, Droperidol, Trifluperidol, Bromperidol, Benperidol, MelperoneSertindole, Molindone, ZiprasidoneFlupentixol, Clopenthixol, Chloprothixene, Thiothixene, ZuclopenthixolSulpiride, Remoxipride, Amisulpride, LevosulpirideClozapine, Loxapine, Olanzapine,Risperidone, Iloperidone, Paliperidone

A thresh­old of 65% occupancy rate provides a good separation between responders and nonresponders to treatment (Kapur et al. 2000). Therapeutic action of conventional antipsychotics is often achieved together with the onset of extrapyramidal side effects (EPS) and tardive dyskinesia. EPS include dys­tonia (uncontrollable muscle contractions that can cause painful twisting of parts of the body, especially the neck), akathisia (a disabling form of internal or external restlessness that can lead to the complete inability to sit still and to the constant urge to be moving), parkinsonism (a set of symptoms that resemble symptoms of Parkinson’s disease, e.g., tremor, stiffness of trunk, arms, or legs, difficulty in starting movement, gait and balance distur­bances). Tardive dyskinesia is usually a side effect of long-term treatment with antipsychotics and consists of repetitive, involuntary and purposeless body or facial movements such as tongue protrusion, eye blinking, move­ments of fingers, arms, or legs. These cumbersome side effects as well as other side effects such as hyperprolactinemia result from the occupancy of D2 receptors in the basal ganglia (Nordstrom et al. 1993; Farde et al. 1992).

Second-generation antipsychotic drugs have been described as “atypi­cal” because they were found to exert antipsychotic effect with significant lower propensity to cause EPS and hyperprolactinemia. These advantages can be explained examining the pharmacodynamic characteristics of atyp­ical antipsychotics. These compounds, while showing affinity for D2 dop­amine receptors, target multiple receptor systems in the brain including D1, D3, D4, D5 dopamine receptors, 5HT1, 5HT2, 5HT3, 5HT6, 5HT7 sero­tonin receptors, alpha 1 and 2 adrenergic receptors, H1 histamine recep­tors, M1 acetylcholine receptors, and glutamate receptors. In particular, reduced EPS observed with second-generation antipsychotic drugs have been explained with their high 5HT2/D2 occupancy ratio (Meltzer, Mat- subara, and Lee 1989). According to a recent hypothesis, the fast dissocia­tion of atypical antipsychotics from the D2 receptor would be the potential mechanism by which these drugs have an antipsychotic effect without causing EPS or prolactin elevation (Kapur and Seeman 2001).

Clozapine is the prototype of these newer medications. This drug has demonstrated low affinity for both D1 and D2 dopamine receptors, along with high affinity for D4 dopamine receptor and serotonin receptors (5HT2 and 3) (Kapur, Zipursky, and Remington 1999). It also has an antigluta- matergic action (Lidsky et al. 1993), as well as alpha-2 receptor affinity and M1 cholinergic receptor blocking activity (Factor 2002). The blockade of dopamine receptors exerted by clozapine is evident especially in the mesolimbic pathway but not in the nigro-striatal system (Baldessarini and Frankenburg 1991). This selectivity may in part explain the low incidence of side effects. Nearly two decades ago, risperidone was introduced in the market. To date, it is the most frequently prescribed atypical antipsy­chotic. Its pharmacodynamic profile is characterized by a high 5HT2/D2 affinity ratio. However, a similar proportion of D2 receptors occupied by risperidone and haloperidol has been documented with a dose-dependent propensity of this atypical agent to cause EPS (Kapur et al. 1995). Olan­zapine was introduced shortly after risperidone, and it has a pharmaco­dynamic profile similar to that of clozapine (Factor 2002). Quetiapine was the fourth atypical antipsychotic marketed. It has a chemical structure similar to clozapine and a multireceptor activity but it acts selectively in the limbic system (Richelson 1996; Jibson and Tandon 1998). A 5HT/D2 occupancy ratio similar to that of other atypical antipsychotics has been documented for ziprasidone although its affinity for D2 receptors is high ( Fischman et al. 1996 ).

Very recently paliperidone, a derivate of risperidone and iloperidone, has been marketed. Their mechanism of action is yet to be established although both drugs have shown affinity for D2 dopamine receptors and 5HT2A serotonin receptors (Madhusoodanan and Zaveri 2010; Citrome 2009).

Relative to other drugs of this class, the atypical sertindole exerts a selective activity binding the D2, 5HT2 and alfa-1 adrenergic receptors. Also, its action is prevalent in the limbic system (Hertel 2006).

Atypical antipsychotics include sulpiride and amisulpride, which are compounds belonging to the chemical class of benzamides. These drugs are highly selective blockers of the D2 and D3 receptors with a preferential limbic activity. They have also been shown to modulate dopamine release by binding presynaptic receptors (Schoemaker et al. 1997).

Aripiprazole is a newer antipsychotic agent that has been identified as the “third-generation” antipsychotic. It is considered a stabilizer of the dopamine/serotonin system due to its peculiar pharmacological profile (Burris et al. 2002). In pharmacodynamics, a drug is defined as an antago­nist if it binds to a given receptor and produces a full inhibition of that receptor. A drug is defined as an agonist if it binds to a given receptor and produces a full activation of that receptor. A drug is defined as a partial agonist if it competes with the natural neurotransmitter for a given recep­tor but it is able to activate that receptor to a lesser degree than its natural neurotransmitter would do, thus causing an attenuated response. Aripip- razole acts as a partial agonist at the D2 dopamine receptors. It also binds serotonin receptors acting as an antagonist of the 5HT2A receptors and as partial agonist of the 5HT1A receptors.

None of the available antipsychotics to date has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of BPSD. This is due to the fact that, despite a general clinical perception of effi­cacy reported by physicians, scientific evidence of efficacy is modest and derives from a limited number of randomized clinical trials (RCTs). None­theless, antipsychotic medications are widely used off-label as first-line agents for the pharmacological treatment of BPSD.

Since their approval in the 1950s for the treatment of schizophrenia, conventional antipsychotics have been systematically used for the treat­ment of BPSD. They are prescribed in spite of a substantial lack of scien­tific evidence supporting their use in dementia. Few RCTs investigating
the efficacy of conventional agents for the treatment of BPSD have been conducted between the 1960s and the late 1980s (Schneider, Pollock, and Lyness 1990; Barnes et al. 1982; Lonergan, Luxenberg, and Colford 2002). These studies have provided evidence on the effect of haloperidol and thioridazine while the effect of other conventional agents in dementia has been neglected by clinical research. Data from these early studies showed a modest advantage of conventional antipsychotics over placebo with a nearly 40% placebo response. Also, according to some of these studies, the observed superiority of conventional antipsychotics over placebo would be limited to symptoms of aggression. The validity of such find­ings is questionable due to the fact that these studies were characterized by small sample sizes and possible lack of power to detect any effect of antipsychotics.

Atypical antipsychotics have been approved by the FDA exclusively for the treatment of schizophrenia and marketed in the 1990s. Although not approved for BPSD, these drugs rapidly became the gold standard of care for BPSD shortly after their introduction in clinical practice. This was due to the fact that atypical antipsychotics had shown a substantial advantage over conventional medications: They were able to exert anti­psychotic effect without causing EPS and tardive dyskinesia (Gerlach 2000; Mossman and Lehrer 2000; Collaborative Working Group on Clinical Trial Evaluations 1998). Scientific societies of physicians and experts in the field developed clinical practice guidelines and consensus statements to promote the off-label use of atypical antipsychotics for the treatment of BPSD in spite of the limited number of RCTs documenting the efficacy and safety of these agents in dementia (American Geriatrics Society and American Association for Geriatric Psychiatry 2003) . In the late 1990s, atypical agents accounted for more than 80% of antipsychotic prescrip­tions in dementia (Glick et al. 2001; Liperoti et al. 2003). At this time, ris­peridone, olanzapine, quetiapine, and aripiprazole are the only atypical antipsychotics that have been investigated in RCTs conducted on patients with dementia (see Table 2 ).

Three placebo-controlled RCTs have shown that, compared to pla­cebo, risperidone may be beneficial on psychotic symptoms and aggres­sion at doses of 1 mg and 2 mg per day (Katz et al. 1999; De Deyn et al. 1999; Brodaty et al. 2003). These studies were conducted on patients with Alzheimer’s disease, vascular dementia, or mixed dementia on a 12-week time period.

Two placebo-controlled RCTs have suggested that olanzapine may im­prove behavioral symptoms, psychosis, and aggression at doses of 5 to 10 mg per day compared with placebo (De Deyn et al. 2004; Street et al. 2000).

Randomized Placebo-Controlled Clinical Trials of Atypical Antipsychotics in Patients with BPSD risperidone

vs.

quetiapine vs. placebo

mean dose 5.5 mg; risperidone mean dose 1 mg; quetiapine mean dose 56.5 mgrisperidone, both superior to quetiapine and placebo

These studies were conducted among patients with dementia for a 10-week and 6-week period of time, respectively. In contrast with these data, a recent study on patients with moderate to severe psychotic symptoms of dementia randomly assigned to receive a flexible dose of olanzapine (2.5-10.g per day), risperidone (0.5-2 mg per day) or placebo demon­strated similar improvement of BPSD in the three treatment groups with higher discontinuation rate due to adverse events in the olanzapine and risperidone groups (Deberdt et al. 2005).

More recently, the impact of stopping long-term antipsychotic treat­ment was investigated in a small sample of nursing home residents with BPSD who were receiving haloperidol, risperidone, or olanzapine (Ruths et al. 2008) . Study participants were randomized to either stop or con­tinue antipsychotic treatment. Findings from this study documented that BPSD remained stable or improved in nearly 50% of residents who dis­continued the treatment and in almost all those who continued to receive antipsychotics.

A small placebo-controlled RCT conducted on a sample of 40 patients with dementia and parkinsonism found that quetiapine 120 mg per day was not effective for controlling psychotic symptoms and agitation although well tolerated (Kurlan et al. 2007). More recently, the effect of quetiapine (median dose 200 mg per day) was not superior to that of pla­cebo in a small RCT conducted on patients with AD and BPSD for six weeks (Paleacu et al. 2008). Negative findings derived also from a late study that compared the effect of quetiapine, rivastigmine (an inhibitor of the enzyme acetylcholinesterase, which is used for treating cognitive symptoms of dementia), and placebo on agitation and cognition in a sam­ple of 93 institutionalized patients with dementia (Ballard et al. 2005). This study demonstrated no effect of quetiapine or rivastigmine on improv­ing agitation and an increased cognitive decline associated with the use of quetiapine. In contrast with these data, quetiapine at high daily dose (200 mg per day) has been found effective in a placebo-controlled RCT conducted on a sample of 333 institutionalized patients with dementia and agitation who were randomized to quetiapine 200 mg per day, quetia- pine 100 mg per day, or placebo for a 10-week period (Zhong et al. 2007). Finally, quetiapine and haloperidol appeared both superior to placebo and effective in controlling psychotic symptoms in a large study conducted on 284 patients with AD and BPSD randomized to flexible doses of quetia- pine (median daily dose 96.9 mg), haloperidol (median daily dose 1.9 mg), or placebo for 10 weeks (Tariot et al. 2006). Quetiapine resulted also better tolerated than haloperidol, which was associated with an increased risk of parkinsonism.

To date, a very limited number of RCTs have examined the effect of aripiprazole on BPSD. Aripiprazole at a mean dose of 10 mg per day appeared as beneficial as placebo on delusions and hallucinations and well tolerated in a 10-week study conducted on 208 outpatients with AD (De Deyn et al. 2005). More recently, the efficacy of aripiprazole has been documented in a large RCT conducted on 487 institutionalized patients with AD and BPSD for 10 weeks (Mintzer et al. 2007). In this study, com­pared with placebo, aripiprazole was effective at a dose of 10 mg per day for controlling psychotic symptoms and agitation. Finally, aripiprazole 15 mg per day was superior to placebo and effective for treating behavioral symptoms, agitation, anxiety, and depression in 10-week study on 256 institutionalized patients with BPSD. In this study, aripiprazole showed no effect on psychotic symptoms (Steim et al. 2008).

According to the CATIE-AD (Clinical Antipsychotic Trials of Interven­tion Effectiveness-Alzheimer’s Disease), a large multicenter, double-blind, placebo-controlled, effectiveness trial on outpatients with AD and psycho­sis, aggression or agitation, olanzapine (mean dose 5.5 mg per day) and risperidone (mean dose 1.0 mg per day) for the treatment of BSPD were equally beneficial and superior to placebo and quetiapine (mean dose 56.5 mg per day) (Schnedier et al. 2006). However, these benefits were evident only among those patients who tolerated these medications and did not discontinue them due to side effects. According to authors ; conclusions potential side effects associated with antipsychotic medications in demen­tia may outweigh possible benefits.

A comprehensive review of the available placebo-controlled RCTs has been conducted by Ballard and White for the Cochrane collaboration to determine the effectiveness of atypical antipsychotics for the treat­ment of psychiatric and behavioral symptoms in Alzheimer’ s disease (Ballard and Waite 2006). The authors analyzed 16 placebo-controlled RCTs among which only 6 studies were published in full in peer- reviewed journals at the time of completion of the review. According to the Cochrane authors, evidence suggests that both risperidone and olan­zapine may reduce aggression and risperidone may also reduce psycho­sis compared to placebo. However, an increased risk of extrapyramidal symptoms and adverse cerebrovascular events associated with atypi­cal antipsychotics would outweigh the modest effectiveness of these medications. For these reasons, authors conclude that the use of atypical antipsychotics in clinical practice would not be suitable and should be limited to those patients presenting with significant distress and risks associated with BPSD.

Vascular Cognitive Impairment and Dementia

Tables 2 and 3 summarize two sets of diagnostic criteria for vascular dementia, the California (Chui et al. 1992) and NINDS-AIREN (Roman et al. 1993) criteria. These criteria are similar, in that they require evidence of strokes, both clinically and by imaging studies (and not just white mat­ter changes on MRI), and also evidence of cognitive impairment. Both make clear that definite vascular dementia can be diagnosed only with neuropathology, usually an autopsy study, so that the most a clinician can diagnose is “probable” or “presumed” vascular dementia. Both sets of criteria include either supporting and contravening factors, in the case of the California criteria (e.g., aphasia without an infarct on MRI in the language area would favor Alzheimer’s disease) or “typical features” in the NINDS-AIREN criteria; both listings contain clinically useful items. There are some important differences. The California criteria utilize only ischemic strokes, whereas the NINDS-AIREN criteria allow both infarc­tions and hemorrhages. The California criteria also include more explicit rules for imaging evidence of strokes, and they require progressive cogni­tive dysfunction, whereas the NINDS-AIREN criteria specify only that the dementia and cerebrovascular disease must be “reasonably related,” usu­ally meaning onset of cognitive problems within 3 months of a stroke.

Table 1

Hackinski Ischemic Score

Evidence of associated atherosclerosis

Source: Hachinski et al. 1975

Note: Patients with a total score of > 7 are considered to have multi-infarct dementia; those scoring < 4 have primary degenerative dementia.

The following factors support the diagnosis of IVD: history of TIA’s, hypertension, or other risk factors for cerebrovascular disease; early gait disorder; extensive deep white matter disease; focal abnormalities on PET or SPECT functional brain imaging. Against ischemic vascular dementia were: absence of focal neurological signs other than cognitive abnormali­ties; and presence of aphasia, apraxia, or agnosia without appropriate lesions on CT or MRI scans.

Source: Chui et al. 1992.

The diagnosis of vascular dementia, by these criteria, also must include a decline in memory and at least two other domains of intellectual ability, with resultant impairment of activities of daily living. Single strokes are permitted, if the other criteria apply. The NINDS-AIREN criteria also emphasize typical clinical features of impairment of multiple cognitive domains, usual presence of focal neurological signs, gait abnormalities, mood changes, psychomotor slowing, and extrapyramidal signs. Against vascular dementia were early onset and progres­sive worsening of a deficit in memory or other cognitive functions, in the absence of focal lesions on CT or MRI scans; absence of focal neurological signs, other than cognitive ones; and absence of infarcts on brain imaging studies.

Source: Roman et al. 1993.

The diagnosis of vascular dementia, by these criteria, also must include a decline in memory and at least two other domains of intellectual abil­ity, with resultant impairment of activities of daily living. Single strokes are permitted if the other criteria apply. The NINDS-AIREN criteria also emphasize typical clinical features of impairment of multiple cognitive domains, usual presence of focal neurological signs, gait abnormalities, mood changes, psychomotor slowing, and extrapyramidal signs. Against vascular dementia were early onset and progressive worsening of a deficit in memory or other cognitive functions, in the absence of focal lesions on CT or MRI scans; absence of focal neurological signs, other than cognitive ones; and absence of infarcts on brain imaging studies.

Neuropsychological Profile of Dementia with Lewy Bodies

Neuropsychological Profile of Dementia with Lewy Bodies | Health tips img#wpstats{display:none} Health tips empower your best health and live longer!Home pageDiet & FitnessDietDiet tipsFitnessCardioStrengthYogaDiseasesAlphabeticalAids & HivAllergiesBack PainCancerBreast CancerCervical CancerColon CancerLung cancerProstate CancerCholesterolCold & FluDiabetesHeart DiseaseOsteoporosisFamily HealthChild’s healthMen’s healthWomen’s healthLegalHealth InsuranceLife careNutritionEat rightRecipesMind and BodyBeautySkin careMindAnxietyDepressionHeadachesPersonalityStressWellnessAgingChild’s healthOral careQuit SmokingMen’s healthSleepWomen’s healthMenopause Your Are Here: Health tips ? Mind and Body ? Mind ? Neuropsychological Profile of Dementia with Lewy Bodies

Neuropsychological Profile of Dementia with Lewy BodiesNovember 14, 2013 - Jean-Paul Marat + - Mind - Tagged: Alzheimer, Alzheimers Disease, dementia, Dementia with Lewy bodies, Lewy body, Parkinson's disease - no comments(adsbygoogle = window.adsbygoogle || []).push({});Dementia with Lewy bodies (DLB) is considered to be the second most common form of neurodegenerative dementia after Alzheimer’s disease (AD). It is characterized neuropathologically by the presence of Lewy bodies; those are detectable in post-mortem brain biopsies. The clinical core features of DLB are fluctuation in cognitive function, recurrent visual hallucinations, and the spontaneous features of parkinsonism. Those core features, however, demonstrate a low frequency in patients with AD. If those features were clearly present, then it would be simple to differenti­ate DLB from AD. However, not all patients with DLB manifest such core features early in the course of the disease. It is therefore often difficult to accurately diagnose DLB, especially at the initial presentation.

The need for an early and accurate diagnosis of DLB in order to admin­ister the proper clinical treatment has been emphasized by reports of severe neuroleptic sensitivity and the preferential response to cholinest- erase inhibitors in these patients. Therefore, the ability to accurately diag­nose the cause of dementia could be of great medical benefit. An analysis of the neuropsychological profile was carried out, while various brain imaging techniques were also investigated with the aim of establishing an early diagnosis of DLB. The neuropsychological profile of DLB consists of a poor attentional, executive, and constructional function and a better short- and medium-term recall than those of AD. In the present post, the history of research, pathology, clinical symptoms, cognitive profiles, and differential clinical diagnosis of DLB is reviewed.

HISTORY OF RESEARCHLewy bodies were first seen and linked to Parkinson’s disease (“paral­ysis agitans”) in 1912 by the German neurologist Frederic Lewy. Lewy bodies appear as spherical masses that displace other cell components. There are two morphological types of Lewy bodies, namely, brainstem and cortical types. A brainstem Lewy body is an eosinophilic cytoplas­mic inclusion that consists of a dense core surrounded by a halo, mea­suring approximately 10 nm in diameter, of radiating fibrils, the primary structural component of which is alpha-synuclein. Hematoxylin and eosin staining is not sufficient for the detection of cortical Lewy bodies and it is also not capable of detecting Lewy neurites. Initially, Lewy did not ascribe any neurobehavioral significance to the Lewy bodies observed in posten­cephalitic parkisonian patients in 1912.

Okazaki et al. reported two cases of elderly patients of European extraction who exhibited progressive dementia and quadriparesis in flex­ion (Okazaki et al. 1961). The neuropathology of these two patients was characterized by the presence of numerous Lewy bodies in the cerebral cortex as well as in the brainstem. Although these inclusion bodies lacked the distinctive halo of brainstem Lewy bodies, this group of investigators established an association between these cerebral inclusions and demen­tia. Their report did not receive much academic attention for approxi­mately 15 years. However, Ikeda et al. reported a dementia case involving a young person with parkinsonism (Ikeda et al. 1975).

Kosaka et al. reported an autopsied case with progressive dementia and parkinsonism, and the neuropathologic features demonstrated the wide­spread presence of Lewy bodies thoroughout the central nervous system as well as Alzheimer’s changes (Kosaka et al. 1976). Kosaka described three cases with a distribution of cortical Lewy bodies (Kosaka 1978). Thereafter, many similar cases were reported in Japan. In addition, Kosaka and Meh- raein reported German cases with progressive dementia and parkinsonism (Kosaka and Mehraein 1979). The neuropathology of these cases was char­acterized by the widespread occurrence of Lewy bodies. These were the first cases reported in Europe. Kosaka et al. examined 20 cases with “Lewy body disease” and classified this disease pathologically into three types: brainstem, transitional, and diffuse (Kosaka et al. 1980). Yoshimura con­firmed their findings and proposed the term “diffuse Lewy body disease” (DLBD) (Yoshimura et al. 1983). Kosaka et al. suggested that DLBD had been overlooked in both European and American countries, since only a few DLBD cases had been reported in those countries (Kosaka et al. 1984). Since 1985, a number of DLBD cases have been reported in both North American and European countries.

Similar terminology has been proposed by several researchers, such as diffuse cortical Lewy body dementia, senile dementia of Lewy body type, and Lewy body variant of Alzheimer’s disease. To resolve the confusion in naming this disease, the generic term “dementia with Lewy bod­ies” (DLB) was proposed to include those disorders in the first Interna­tional Workshop on Lewy Body Dementia held in Newcastle-upon-Tyne in 1995. The results of this workshop were reported in 1996 (McKeith et al. 1996) . Consensus criteria for clinical and pathologic diagnosis of DLB were thereafter published. The clinical criteria for probable DLB showed sufficient specificity, but poor sensitivity. From this standpoint, the revised criteria for the clinical diagnosis of DLB were thereafter pro­posed at the third international workshop meeting on DLB held in New­castle-upon-Tyne in 2003 and later were published in 2005 (McKeith et al. 2005). Recently DLB, Parkinson^ disease (PD), and Parkinson’s disease dementia (PDD) have been identified as belonging to the spectrum of Lewy body disease.

PATHOLOGYFrom a pathological standpoint, DLB is a common disorder of the alpha-synuclein metabolism characterized by the development of abnor­mal cytoplasmic inclusions, called Lewy bodies, throughout the brain. A Lewy body is the pathologic aggregation of alpha-synuclein. It is also associated with intermediate filaments, chaperone proteins, and elements of the ubiquitin-proteasome system.

DLB was originally defined as a clinicopathologic entity with a spe­cific constellation of the clinical features, and a descriptive approach was proposed for assessing the neuropathology of this disease (McKeith et al. 1996). The only neuropathologic requirement for DLB was the presence of Lewy bodies somewhere in the brain of a patient with a clinical history of dementia. Other pathologic features, such as senile plaques and neuron loss (frequently seen in AD), could also occur; however, they are not either inclusive or exclusive to the diagnosis of DLB. As increasingly sensitive methods for detecting Lewy bodies have been developed, as many as 60% of AD cases may thus be considered to meet the pathologic criteria for DLB based on the 1996 criteria. In addition, none of these patients nor­mally demonstrated the clinical symptoms of DLB.

New recommendations have thus been proposed which take into account both the extent of Lewy-related pathology and AD-type pathol­ogy in assessing the degree of certainty that the neuropathologic findings explain the DLB clinical symptoms.

Lewy bodies are present in DLB as well as in PD. In addition, there is a loss of dopamine-producing neurons (in the substantia nigra) similar to that seen in PD and a loss of acetylcholine (ACh)-producing neurons (in the nucleus basalis of Meynert [NBM]and elsewhere) similar to that seen in AD. Cerebral atrophy (or shrinkage) also occurs as the cerebral cortex degenerates. Autopsy series have revealed the pathology of DLB to often be concomitant with the pathology of AD. Namely, when Lewy body inclusions are found in the cortex, they often co-occur with the AD pathology found primarily in the hippocampus, including neurofibrillary tangles (abnormally phosphorylated tau protein), senile plaques (amyloid protein deposits), and granulovacuolar degeneration. Kosaka and col­leagues proposed two distinct pathological subtypes of DLB: (1) the com­mon form, found in approximately 75% of cases, with a mixed Lewy body and amyloid pathology; and (2) the pure form, with only the Lewy body pathology ( Kosaka 1990 ).

Within DLB, the loss of cholinergic (ACh-producing) neurons is thought to account for the degradation of cognitive and emotional functioning, as in AD, whereas the loss of dopaminergic (dopamine-producing) neurons is thought to account for the degradation of motor control, as is observed in PD. Therefore, DLB is similar to the dementia resulting from both AD and PD. In fact, DLB is often confused in its early stages with AD and/or vascular dementia (multi-infarct dementia). The overlap of neuropathol­ogies and presenting symptoms (cognitive, emotional, and motor) may therefore make an accurate differential diagnosis difficult to make.

CLINICAL SYMPTOMSAccording to the revised criteria for the clinical diagnosis of DLB (McKeith et al. 1996), the clinical diagnosis of probable or possible DLB essentially requires a progressive disabling mental impairment. At least two of three core features are sufficient for the diagnosis of probable DLB, and one for possible DLB. The three core features consist of fluctuation, visual hallucinations, and parkinsonism. The suggestive clinical features include rapid eye movement (REM) sleep behavior disorder, severe neu­roleptic sensitivity, and a low dopamine transporter uptake in the basal ganglia as demonstrated by either single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging.

In the absence of two core features, the diagnosis of probable DLB can also be made if dementia plus at least one suggestive feature is present with one core feature. Possible DLB can be diagnosed with the presence of dementia plus one core or suggestive feature.

Progressive Disabling Mental Impairment

A progressive disabling mental impairment is a mandatory require­ment for the diagnosis of DLB. This leads to the development of global dementia, sometimes over a period of months but more commonly over a period of several years. The rate of longitudinal cognitive decline for DLB is equivalent to that for AD; however, the risk of mortality for DLB is higher than that for AD. The greater risk for a progression of noncognitive symptoms (e.g., parkinsonism) for DLB than for AD is considered to result in the clinically meaningful differences in these two disorders.

The demonstration of cognitive impairment by formal testing of the mental status such as the Mini-Mental State Examination (MMSE) is an essential component in establishing the diagnosis. However, prominent or persistent memory impairment may not necessarily occur in the early stages because of the relative preservation of confrontation naming and short- and medium-term recall as well as recognition for patients with DLB. In such cases, a prominent or persistent memory impairment become usually evident with progression over time.

Parkinson’s Disease Dementia (PDD) and DLB

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. It is characterized by the progressive degeneration of dopamin­ergic neurons in the substantia nigra and the accumulation of Lewy bod­ies in the surviving neurons. PD belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slow­ing of the physical movement (bradykinesia), and, in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of a decreased stimulation of the motor cortex by the basal ganglia, nor­mally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symp­toms may include a high-level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.

Many patients with PD develop dementia, typically 10 years or more after the onset of motor symptoms. Such patients are diagnosed to have Parkinson disease dementia (PDD). The term PDD should be used to
describe dementia that occurs in the context of well-established PD. The term DLB should be diagnosed when dementia occurs either before or concurrently with parkinsonism. When a patient developed parkinsonism more than one year before developing dementia, then a diagnosis of PDD is given. When parkinsonism and dementia begin within one year or if the parkinsonism starts after the onset of dementia, then a diagnosis of DLB is made. This is called the “one year rule.” The clinical distinction between DLB and PDD is based solely on the temporal sequence in the appearance of symptoms. No major differences between DLB and PDD have been found in any variable examined, including the cognitive pro­file, attentional performance, neuropsychiatric features, sleep disorders, autonomic dysfunction, type and severity of parkinsonism, neuroleptic sensitivity, and responsiveness to cholinesterase inhibitors. Upon autopsy, DLB and PDD are also difficult to distinguish because abnormal neuronal alpha-synuclein inclusions are the common pathologic process of both PDD and DLB.

Fluctuation

Fluctuation in the cognitive function is common in DLB. In the earliest stages, patients may show deficits in their cognitive function and global performance that alternate with periods of normal or near-normal perfor­mance. Fluctuation may be based on pronounced variations in attention and alertness. DLB patients may show improved performance in response to environmental novelty and increased arousal (sometimes confounding formal cognitive testing), but these effects are usually only short-lived. The periodicity and amplitude of fluctuations are variable, both between the subjects and within the same individual. They are described as occur­ring rapidly (lasting minutes or hours), as well as slower (weekly or monthly) variations. Substantial changes in the mental status and behav­ior may therefore be seen both within the duration of a single interview and/or between consecutive examinations. No typical diurnal pattern of fluctuation has been identified in DLB. Some patients identify the variable cognitive state themselves, but generally the most productive approach for identifying such fluctuation is via a reliable informant.

The fluctuations resemble signs of delirium without any identifiable precipitants of such mental-status changes. The report of fluctuations in DLB is widely discrepant and it ranges from 13% to 85% with a low clinician inter-rater reliability. There are inconsistencies among studies regarding what is considered sufficient to constitute the designation of fluctuations. To some degree, most people can experience some variability
in cognition, abilities, or alertness. Therefore, for clinical purposes, it is imperative to identify those aspects of fluctuations that are particularly prominent to DLB and that can be consistently elicited from informant reports. The differential diagnosis of fluctuating cognition may include several conditions, including delirium due to medication toxicity or inter­current illness. There are substantial difficulties inherent in defining and quantifying fluctuating cognition, particularly later in the illness when variability may become submerged in progressive cognitive deterioration. Questions such as “are there episodes when his/her thinking seems to be quite clear and then later becomes muddled?” were previously suggested as useful probes, but a recent study found 72% of both AD and DLB care givers respond positively. The study using the Mayo Fluctuations Com­posite Scale (Ferman et al. 2004) suggested that 4 of 19 items of structured questionnaire assessing fluctuations were found to significantly differenti­ate DLB from AD. These four items are as follows:

1.   Are there times when the patient’s flow of ideas seems disorganized, unclear, or not logical?2.    How often is the patient drowsy and lethargic during the day?a.    All the time or several times a dayb.    Once a day or less3.    How much time does the patient spend sleeping during the day (before 7: 00 pm)?c.    2 hours or mored.   Less than 2 hours”4.    Does the patient stare into space for long periods of time?Three or more “positive” responses from caregivers to these four ques­tions yield a positive predictive value of 83% for the clinical diagnosis of DLB against an alternate diagnosis of AD. Conversely, two or less “posi­tive” responses yield a negative predictive value of 70% for the absence of a clinical diagnosis of DLB in favor of AD.

Visual Hallucinations

Visual hallucinations, which are typically recurrent, formed, and detailed, have been described by most groups investigating DLB. Visual hallucinations appear to be the only psychotic symptom that reliably dis­criminates DLB from AD. They are generally present early in the course of illness. Hallucinations in other modalities, particularly auditory, may also occur in DLB but do so less frequently. Informant-based assessment tools such as the Neuropsychiatric Inventory (NPI) are helpful both to screen for visual hallucinations and to assess their severity and frequency but do not always distinguish them from hallucinations in other sensory modalities. Caregivers tend to underreport visual hallucinations and patients with mild to moderate cognitive impairment can contribute use­ful information about their presence and quality. Patients with mild to moderate DLB tend to remember their experience of visual hallucina­tions because of their relatively preserved memory function.

Prominent cognitive impairment on visuoperceptual and spatial functions may be one of the causes of visual hallucination. Patients with DLB with visual hallucinations show more profound visuoperceptual dysfunction in comparison to those without hallucinations. There is considerable over­lap between true visual hallucinatory symptoms (in the absence of an adequate external stimulus) and other perceptual disorders, including misidentification syndromes and visual agnosias. Patients may describe visual hallucinations, such as seeing faces emerging out of the patterns on chair cushions. Typical themes are animate objects of people or ani­mals intruding into the patient’ s home. Inanimate objects can also be seen. Abstract perceptions such as characteristics on walls or ceiling are not unusual. The visual hallucinations are characteristically seen and described in considerable detail. Emotional responses vary through fear, amusement, or indifference, and a degree of insight into their unreality is often present. The precise descriptions of visual hallucination in DLB are similar to those described in association with delirium due to systemic disturbances.

Antiparkinsonian medications, such as levodopa or anticholinergics could also be the cause of visual hallucinations as a side effect. Antiparkin­sonian medications are often used for parkinsonisan symptoms in patients with DLB. However, their role of the hallucinatory symptoms of DLB has not yet been systematically investigated. Visual hallucinations that do not recede, or vanish very slowly, after the withdrawal of antiparkinsonian medications in PD patients may therefore be predictive of a subsequent progressive cognitive decline and dementia.

Increased numbers of Lewy bodies in the anterior and inferior tempo­ral lobe and amygdale at autopsy are associated with the presence and onset of visual hallucinations. Each of these areas is implicated in the gen­eration of complex visual images. Brain perfusion imaging demonstrates a reduced occipital uptake in areas identified as primary and secondary visual cortex in DLB patients. Visual hallucinations are associated with greater deficits in cortical acetylcholine and their presence may predict a good response to cholinergic therapy.

Parkinsonism

The severity of extrapyramidal motor features in DLB is generally similar to that of age-matched patients with PD either with or without dementia with an average 10% annual progression rate. Rigidity and bra- dykinesia are the usual extrapyramidal symptoms, while other common findings are hypophonic speech, masked faces, a stooped posture, and a slow and shuffling gait. Resting tremors are less common, especially in older individuals. The assessment of motor features may be complicated by the presence of a cognitive impairment. The order of onset of mental and motor symptoms is variable, particularly in older patients who often present with a complex admixture of extrapyramidal and mental symp­toms of almost simultaneous onset.

In advanced AD and other dementias, parkinsonian signs may also be found. Parkinsonism appearing for the first time late in the course of a dementia is therefore consistent with a diagnosis of DLB, but it is not spe­cific for it. Neuroleptics, even at low doses, may induce parkinsonism in elderly or demented patients. DLB may thus be distinguished from drug- induced parkinsonism by the persistence of motor symptoms after the withdrawal of neuroleptics.

Levodopa responsiveness in DLB is almost certainly less than that in uncomplicated PD, possibly because of intrinsic striatal degeneration and the fact that a significant proportion of the parkinsonian symptoms may be non-dopaminergic in origin. However, levodopa can be used for the motor disorder of both DLB and PDD. Medication should generally be introduced at low doses and thereafter be increased slowly to the mini­mum required dose in order to minimize any potential disability without exacerbating the psychiatric symptoms. However, the administration of anticholinergics should be avoided.

REM Sleep Behavior Disorder (RBD)

There is a clear electroencephalographic (EEG) difference between sleep and the waking state in the human brain. EEG is the recording of electrical activity along the scalp produced by the firing of neurons within the brain. The EEG during sleep is divided into at least two categories. One type of sleep was found to be associated with the occurrence of dreams and the other with nondream sleep. Since dream sleep was found to be accom­panied by episodes of REM, this state is often called REM sleep. Non­dream sleep is also called non-REM sleep. Another prominent component of REM sleep is the profound paralysis of the skeletal muscles. REM sleep paralysis has been shown to be due to a small region of the dorsal pons, the nucleus subcoeruleus. A lesion to this nucleus abolishes the REM sleep paralysis. A very dramatic observation is that during REM sleep, cats with such lesions were observed to become very active and agitated, as if they were acting out an emotionally charged dream episode. Additional nuclei and neurotransmitters of the lower brainstem participate in the process of muscle atonia that occur during REM sleep.

Patients with DLB often show the REM sleep behavior disorder (RBD), which is manifested by vivid and often frightening dreams during REM sleep without muscle atonia. Patients therefore appear to “act out their dreams” vocalizing, flailing limbs, and moving around the bed sometimes violently. Vivid visual images are often reported, although the patient may have little recall of these episodes. The history is obtained from the bed partner, who may report many years of this sleep disorder prior to the onset of dementia and parkinsonism. RBD is frequently associated with an underlying synucleinopathy—PD, DLB, or multiple system atrophy (MSA)—and only rarely with other neurodegenerative disorders such as AD. Associated sleep disorders in DLB including excessive daytime drowsiness may also contribute to the fluctuating pattern. Screening ques­tions about the presence of day- and nighttime sleep disturbance should always be asked, facilitated by the use of sleep questionnaires, particu­larly those that query bed partners about a history of repeated episodes of “acting out dreams.” The diagnosis of RBD may also be confirmed by polysomnography.

Severe Neuroleptic Sensitivity

Neuroleptics (also called antipsychotics) are a group of psychoactive drugs commonly but not exclusively used to treat psychosis, which is typ­ified by schizophrenia, but can also be present in severe bipolar disorder, as well as many other conditions. Neuroleptics were originally developed to treat schizophrenia. Recently, these drugs have also come to be used to treat nonpsychotic disorders. For example, some neuroleptics (haloperidol) are used to treat Tourette syndrome, whereas aripiprazole and risperidone are prescribed in some cases of Asperger syndrome. Some neuroleptics such as quetiapine have multiple uses including acting as an augmenta­tion agent in the treatment of mental illness such as anxiety, insomnia, autism, and obsessive-compulsive disorder. Neuroleptics (antipsychotics) are broadly divided into two groups, the typical antipsychotics and the atypical antipsychotics. Atypical antipsychotics are generally considered to be more effective for the treatment of psychiatric symptoms, such as delusion or hallucination, and to have fewer adverse effects, including parkinsonism, in comparison to typical antipsychotics. The behavioral and psychological symptoms of dementia (BPSD) are common and prob­lematic in clinical practice and represent a significant part of the day-to- day workload of the old-age psychiatry teams in hospitals, institutions, and community settings. Atypical antipsychotics may be used off-label to treat BPSD, particularly in care homes for the elderly.

A severe adverse reaction to medication with neuroleptics often occurs in patients with DLB. Neuroleptics can bring about the appearance or severe exacerbation of extrapyramidal signs in DLB. Severe neuroleptic reactions include rigidity, reduced consciousness, pyrexia, falling, pos­tural hypotension, and collapse. Approximately 50% of all patients with DLB receiving typical or atypical antipsychotic agents do not react so adversely. Therefore, a history of neuroleptic tolerance does not rule out a diagnosis of DLB. In contrast, a positive history of severe neuroleptic sen­sitivity is strongly suggestive of DLB. The deliberate use of neuroleptics as a diagnostic tool for DLB should be avoided because a previous study reported that a high morbidity and mortality associated with neuroleptic sensitivity reactions of DLB which are characterized by the acute onset or exacerbation of parkinsonism and impaired consciousness.

Dopamine Transporter Imaging

Functional imaging of the dopamine transporter (DAT) defines the integrity of the nigrostriatal dopaminergic system and currently has its main clinical application in assisting the diagnosis of DLB. Imaging with specific ligands for DAT provides a marker for presynaptic neuronal degeneration. DAT imaging is abnormal in idiopathic PD, MSA, and pro­gressive supranuclear palsy. Low striatal DAT activity also occurs in DLB but it is normal in AD, thus making DAT scanning particularly useful for distinguishing DLB from AD.

Depression

Depression is common in both DLB and PDD and there have been no systematic studies of its management to date.

Neuroimaging

The ability to diagnose the cause of dementia could be of great medical benefit. Magnetic resonance (MR) imaging, SPECT, and PET have been investigated with the aim of establishing an early diagnosis. PET has higher sensitivity and higher spatial resolution than SPECT, thus making it more appropriate for the diagnosis of early-stage dementias (Ishii and Minoshima 2005). However, SPECT has the advantage of lower cost and has been widely used in general hospitals, and therefore it is useful in many clinical examinations. During the last several years, a voxel-based analysis of brain PET and SPECT images has been widely applied for the clinical diagnosis of AD and dementia using PET or SPECT. To promote further objective and reproducible data, there has also been recent inter­est in the development and application of automated algorithms for brain PET/SPECT images. Ishii et al. (2009) developed a fully automated diag­nosis system for early AD and dementia with Lewy bodies (DLB) using the NEUROSTAT program for the analysis of FDG-PET images (Kono et al. 2007) . Ishii et al. (2009) further developed this system to provide a fully automated diagnosis of early-stage neurodegenerative dementia. They aimed to distinguish AD/DLB from non-AD/DLB dementia and then DLB from AD for therapeutic decisionmaking. According to their report, diagnoses by experienced neuroradiologists were more accurate in patients with very mild AD than those by radiologists whose subspecialty were not neuroradiology, although their accuracy slightly decreased when diagnosing DLB. The problem is that it is very difficult to distinguish a patient with mild DLB from a patient with mild late-onset AD. On the con­trary, this automated system is independent of observer skill and showed good results comparable to those achieved by experienced observers. The automated diagnosis system’s diagnostic value was therefore considered to be comparable to that of experienced neuroradiologists.

NEUROPSYCHOLOGICAL PROFILEThe clinical diagnosis of DLB can be difficult because of the variability and the overlap of symptoms between DLB and other related dementias, notably AD. The clinical manifestation of DLB and AD can be very similar. Both DLB patients and AD patients may initially present with a progres­sive cognitive decline without any other neurological abnormalities. The clinical diagnosis of DLB is supported and facilitated by the revised cri­teria for the clinical diagnosis of DLB (McKeith et al. 2005). In most stud­ies examining the clinical criteria for the operational diagnosis of DLB, the specificity of the diagnosis has been high, but the sensitivity has been poor.

From a neuropsychological standpoint, patients with DLB tend to manifest greater attentional and visuospatial cognitive impairments than
those with AD, whereas patients with AD involve more profound episodic memory impairment than those with DLB. Using those neuropsychologi­cal differences, a careful cognitive assessment may therefore aid in the differential diagnosis between DLB and AD. Neuropsychological research on DLB can provide theoretical insight into the nature of the underlying impairments. There has been a need for studies examining the neuropsy­chological profile of DLB and the contribution of a neuropsychological evaluation to the diagnostic workup. In the rest of this post, the cog­nitive functions of patients with DLB including the attentional function, visuoperceptual and executive functions, and memory function will be reviewed.

Attentional Function

Attention is the cognitive process of selectively concentrating on one aspect of the environment while ignoring other things. Attention has also been referred to as the allocation of processing resources. Attention is a multi-dimensional concept that describes different aspects of processing and responding to information, including automatic processes such as visual orienting and higher-level processes of attentional control.

There have been studies demonstrating a greater attentional impair­ment in DLB than in AD. Hansen et al. (1990) compared nine patients with DLB with nine patients with AD. More severe deficits of attentional function (digit span sub-test from the Wechsler Adult Intelligence Scale- Revised [WAIS-R]) were seen in DLB. Sahgal et al. (1992) reported that DLB patients had significantly greater impairment on a computerized delayed matching-to-sample task. Ayre et al. (1998) used the Cognitive Drug Research Computerized Assessment System for Dementia Patients (COGDRAS-D) computerized test battery to compare attention in 46 patients with AD and 24 patients with DLB. The DLB group performed significantly worse on simple reaction time (SRT) and choice reaction time (CRT) tasks and digit vigilance (VIG) in comparison to the AD group. Ballard et al. (2001) compared 85 patients with DLB with 80 patients with AD using the COGDRAS-D. They reported a slowed processing speed, attentional impairments, and fluctuations in attentional impairments to be significantly more severe in DLB than AD patients. The DLB patients were significantly more impaired than the AD patients on all tests of attention and fluctuating attention.

In both DLB and AD, most measures of attentional performance and most indices of fluctuating attention were significantly correlated with the MMSE score. The severity and fluctuation of attentional impairments are
particularly pronounced in DLB patients with MMSE scores of 10 or less. They concluded that their results confirmed that the attentional deficits and fluctuations in attention are substantially more severe in DLB patients than in patients with AD. A number of other factors, such as parkinsonism with a slowed motor speed, depression, or a general slowing of the cogni­tive processing speed could theoretically have contributed to these find­ings. They noticed that deficits of attention became more pronounced with increasing dementia severity and, hence, that these deficits need to be interpreted within the context of overall cognitive deficits. Oda et al. (2009) compared 26 patients with DLB with 78 patients with AD and dem­onstrated that patients with AD had significantly greater scores on the weighted sum score of the attention of Wechsler Memory Scale-Revised (WMS-R) than did patients with DLB (P = 0.0010).

The overall pattern is consistent, with DLB patients thus showing a significantly greater impairment on a range of attentional tasks. Both neuropsychological and clinical observations strongly suggest that DLB patients experience great difficulty in maintaining attention. The neural basis of the attentional impairment in DLB requires further investigation, but it is likely that a dysfunction of the basal forebrain cholinergic system is involved. Several lines of evidence support this proposal. Cholinergic neuronal loss and the depletion of choline acetyltransferase are seen early in DLB (Tiraboschi et al. 2002). The administration of anticholinergic drugs can disturb the attention and cause hallucinations, whereas cholinesterase inhibitors can improve cognition in DLB.

Visuoperceptual Function

Visuoperceptual function is the ability to perceive an object’s visual properties (such as shape, color, and texture) and apply semantic attri­butes to the object, which includes the understanding of its use, previous experience with the object and how it relates to others.

Numerous studies have observed greater impairments in DLB in com­parison to AD on visuoperceptual tasks. Ala et al. (2001) compared 17 patients with autopsy-confirmed DLB and 27 patients with autopsy- confirmed AD by using copies of the double pentagon from the MMSE. They showed that only two patients with DLB drew the pentagon accept­ably, in contrast with 16 AD patients, and that an unacceptable copy of the pentagon was associated with DLB with a sensitivity of 88% and a specificity of 59%. They concluded that their results confirmed the greater visuoperceptual impairment of patients with DLB than for the patients with AD and thus suggested that the pentagon copying task of the MMSE may be useful in a diagnostic sense. Cormack et al. (2004) reported that patients with DLB were found to draw significantly worse double penta­gons than those with AD or PD. In their report, a correlation between the MMSE score and the pentagon drawing score was observed in patients with AD; however, DLB patients did not show any significant correlation between the MMSE scores and the pentagon drawing score.

)n order to investigate the hypothesis that DLB patients have a dif­ferent neuropsychological basis to their drawing impairments in com­parison to the other dementia groups, the global cognitive performance of subjects was measured using the cognitive section of the Cambridge Mental Disorders in the Elderly Examination (CAMCOG). As a result, the pentagon copying scores were found to correlate significantly with all CAMCOG subscales except for the visual and recent memory in the AD group, whereas the scores of DLB patients’ scores only significantly correlated with Praxis and Perception. This result suggested that construc­tional disability was proportionate to global cognitive impairment in the AD group, but there was a dissociation of the constructional ability from the global cognitive ability in the DLB group. Mori et al. (2000) addressed problems in visual perception in patients with DLB and compared them with patients with AD. They assessed the visual perception of 24 patients with DLB and 48 patients with DLB using a subset of the object and spatial vision test battery. The discrimination of the object size task was used to examine elementary visual perception, the form discrimination task was used to examine more complex visuoperceptual function that requires the analysis of two-dimensional visual stimuli, the overlapping figure identi­fication task was used to examine the ability to actively extract concrete shapes and to recognize objects, and the visual counting task was used to examine the ability to explore and identify the spatial relationship of visual stimuli to count targets without duplication or omission. They found that DLB subjects performed more poorly than the AD group, not only in discriminating size and form and visual counting, but also in iden­tifying overlapping figures. Moreover, DLB subjects with visual hallucina­tions performed significantly worse on the overlapping figures task.

Oda et al. reported that patients with DLB scored significantly worse on the Block Design, Object Assembly, and Digit Symbol subtests of the WAIS-R than did patients with AD (Oda, Yamamoto, and Maeda 2009). Because the set of the Block Design, Object Assembly, and Digit Symbol is considered to be involved in visual perception/processing meaning­ful stimuli and visual organization, these results were considered to sug­gest that patients with DLB have a more severe impairment of both their visual perception of meaningful stimuli and visual organization than do

AD patients. They also showed that except for Comprehension, Similari­ties, and Object Assembly, all subtests and IQ of the WAIS-R showed a significant correlation with the MMSE score in the AD group. This sug­gests that the fall in IQ is proportional to the global cognitive impairment in the AD group. However, in the DLB group, no correlation was found between all subtests of the WAIS-R and MMSE score. There seemed to be a dissociation of the IQ from the global cognitive abilities in the DLB group. They ascribed the lack of any correlation between the global cog­nitive impairment and the fall in intellectual ability in the DLB group to a selective impairment of the visuoperceptual function in addition to a global cognitive impairment.

The fact that visual perceptual disturbances in patients with DLB pre­dispose them to experience visual hallucinations has important clinical implications. First, because visual hallucinations are among the strongest diagnostic predictors of DLB, the neuropsychological assessment of visual perceptual and constructional functions is critical in suspected DLB and its differentiation from AD. Indeed, visuoconstructional tasks, in combi­nation with other tests, can differentiate DLB from normal aging and from AD with high sensitivity and specificity. Furthermore, a poor performance on visuoperceptual and constructional tasks may indicate the need for more careful monitoring regarding the occurrence of hallucinations.

It is likely that the occipital dysfunction is implicated in visuoperceptual abnormalities of DLB and both the ventral occipitotemporal and dorsal occipitoparietal streams have been implicated. The visuoperceptual dys­function in DLB can be attributed to accentuated damage in the occipital lobes. Albin et al. (1996) demonstrated the regional glucose metabolism to decrease in the occipital association cortex and primary visual area in six patients with autopsy proved DLB. In the study of Ishii et al. (1998), using 18F-fluorodeoxyglucose and PET, the glucose metabolic rate in the occipi­tal cortices was found to be significantly lower in patients with probable DLB than in controls with probable AD matched for age, sex, disease dura­tion, and MMSE score, despite similar decreases in the parietotemporal lobe in patients with DLB and AD. Similarly, a SPECT study demonstrated the occipital blood flow to be significantly lower in patients with DLB than in patients with AD. Therefore, in DLB, not only does the parietotemporal damage provoke visuocognitive dysfunctions, but occipital damage also causes disturbances of visual sensations, while also intensifying the higher- order visuocognitive dysfunctions. Defective visual perception, resulting in illusions including distortions of form, size, movement, or color, in com­bination with general defects such as confusion and mental deterioration may cause a sense of strangeness or inexplicable familiarity.

The mechanism of occipital involvement and visuoperceptual deficits in DLB is highly speculative. Bashir et al. (1998) reported a unique patient with DLB who initially complained of heaviness in the right upper extremity and then subsequently developed a dense left homonymous hemianopsia during the course of rapidly progressing dementia. Their patient fulfilled all the consensus criteria for the clinical diagnosis of probable DLB: their case exhibited a progressive cognitive decline, parkinsonism, visual hallu­cinations, and fluctuating agitation, confusion, and depression. The neuro- pathologic findings in their patient fulfilled the diagnostic criteria for DLB, proposed by the Consortium on Dementia with Lewy Bodies (McKeith et al. 1996). In addition, their patient exhibited a striking predominance of neurofibrillary tangles in the right inferotemporal and occipital cortices. However, in general, the pathologic features of DLB (including Lewy bod­ies) hardly affect the occipital lobes. In a PET study with (+)-[11C]-dihydro- tetrabenazine, a greater reduction of the blood-to-brain ligand transport occurred in occipital cortex in DLB than in AD. Bodis-Wollner (1990) spec­ulated that in patients affected by PD, as well as in the monkey model of this disease, the visual defects may be caused by a systemic dopaminergic deficiency. Conversely, involvement of the occipital cholinergic system also has been assumed. The activity of a cholinergic enzyme, namely choline acetyltransferase, is reportedly lower in the temporoparietal and occipital neocortex in patients with DLB in comparison to those with AD.

Memory

Memory is one’ s ability to remember the information that one has received previously. From the neuropsychological standpoint, there are three main stages in the process of memory: registration, storage, and recall. In the registration stage, one enters new information. In the stor­age stage, one stores registered information whether one is conscious of it or not. In the recall stage, one draws upon stored information when it is required. Persons with a normal memory function can fail to recall learned information (e.g., an examinee who forgets something he has studied). In many such cases, one is able to recall forgotten information with the aid of a hint or a cue. This means that the main problem of normal forgetfulness is in the recall stage, not in the storage stage. One cannot draw upon the stored information by the aid of a hint or a cue if he or she has failed to store it in the storage stage. Patients with dementia often fail to recall the registered information even if they are given a hint or a cue. This suggests that patients with dementia therefore have problems in the storage stage of the processing memory.

With regard to memory, in general, DLB subjects perform better on tests of episodic (declarative) memory than do AD patients, and this appears to be particularly true on tests of verbal rather than visual memory. Shi- momura et al. (1998) demonstrated that patients with DLB scored signifi­cantly better (P < 0.05) on the verbal memory subtest of the Alzheimer Disease Assessment Scale (ADAS) than did AD patients who were com­parable in the global severity of dementia and the global assessment of cognitive impairment. To determine the degree to which elementary visual perceptual dysfunction may contribute to a visual memory impairment in DLB, Oda et al. (2009) compared DLB patients with AD patients using the WMS-R. In that study, the DLB group showed significantly better scores than did the AD group on Verbal Memory (P < 0.0001) and Delayed Recall (P < 0.0001) of the WMS-R. However, the DLB and AD groups demon­strated comparable scores on Visual Memory (26.31 ± 12.64 vs. 26.42 ± 9.81, respectively; P = 0.9222). The authors speculated that the selective visuo- perceptual impairment in DLB may explain this similarity: namely, the relatively well preserved short- and medium-term recall would compen­sate for the severe visuoperceptual impairment in the DLB group on the visual memory tasks. Lambon et al. (2001) reported that both DLB and AD groups exhibited impaired performance across a range of tasks designed to assess semantic memory. Whereas patients with AD showed equivalent comprehension of written words and picture stimuli, patients with DLB demonstrated more severe semantic deficits for pictures than words.

The major pathological substrate of more severe amnestic deficits in AD relative to DLB likely reflects the burden of neurofibrillary tangles in the entorhinal cortex and surrounding medial temporal lobe regions in AD.

Neuropsychological Differentiation from AD

The diagnosis of DLB can be difficult, in particular when trying to differentiate it from AD. Neuroimaging techniques such as SPECT and PET have the ability to differentiate DLB from AD with high sensitivity and specificity. Neuroimaging techniques are often extremely costly and require a complex clinical setting whereas neuropsychological examina­tions tend to have a low cost and are practical in the general clinical set­ting. In addition, there are many neuropsychological differences between DLB and AD. The third report of the DLB consortium mentioned that a “double discrimination” can help differentiate DLB from AD, with the rel­ative preservation of confrontation naming and short- and medium-term recall as well as recognition, and a greater impairment on verbal fluency, visual perception, and performance tasks (McKeith et al. 2005).

The MMSE is one of the widely used and validated tests for measuring the level of global cognitive impairment. The MMSE is commonly used in medicine to screen for dementia. It is also used to estimate the severity of cognitive impairment at a given point in time and to follow the course of cognitive changes in an individual over time. In the time span of about 10 minutes it samples various functions, including arithmetic, memory, and orientation. The MMSE test consists of simple questions that cover various cognitive functions, such as orientation, registration, attention, recall, and visual construction. Therefore, the score of each subtest may be useful information for both diagnosing dementia as well as the total score. Ala et al. (2002) reported a retrospective study in which pathologically confirmed cases of AD and DLB could be differentiated on the basis of a subscore derived from the MMSE. Based on the greater impairment of the attentional and visuospatial functions, and the relative preservation of memory function in DLB compared with AD, they derived a weighted score, calculated as follows:

Ala score = Attention – 5/3 Memory + Construction

An Ala score <5 was associated with a pathological diagnosis of DLB with a sensitivity of 82% and a specificity of 81%. By using the Ala score and the z-score in the medial occipital lobe from a brain SPECT study, Hanyu et al. (2006) derived a combined index of SPECT/MMSE that achieved a high discrimination between DLB and AD with a sensitivity of 81% and a specificity of 85%. According to their report, patients with DLB and AD could be distinguished by their performance on a single dementia instrument of the MMSE. The DLB group performed significantly worse than the AD group on the Attention and Copy design, while the AD group demonstrated poorer performance than the DLB group on the Word Recall. Oda et al. (2009) derived a weighted score consisting of the Object Assembly subtest of the WAIS-R and the Logical Memory II subtest of the WMS-R to differentiate DLB from AD15 that had a sensitivity of 81% and a specificity of 76%.

SUMMARY AND CONCLUSIONSGiven that DLB is a relatively new disease concept, most of the work so far has been concerned with the first step of the characterization and description of DLB as a separate disease. Most of these studies suggest that in the early stages of the disease, DLB patients tend to exhibit pro­nounced visual-perceptual, attentional, and frontal executive impairments, whereas the memory functions are generally less impaired than in AD patients. However, given the overlap and variability of the symptoms, the neuropsychological profile of DLB has not yet been clearly distinguished from that of AD. In the future, the challenge of DLB research will lie in developing a theoretical model that can link evidence from pathophysi­ological and imaging studies with clinical and neuropsychological data, which will therefore facilitate the treatment of this disease.

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