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 ImpairmentA 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 DLBParkinson’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 todescribe 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.FluctuationFluctuation 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 HallucinationsVisual 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.ParkinsonismThe 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 SensitivityNeuroleptics (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 ImagingFunctional 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.DepressionDepression is common in both DLB and PDD and there have been no systematic studies of its management to date.NeuroimagingThe 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 FunctionAttention 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 FunctionVisuoperceptual 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 doAD 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.MemoryMemory 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 ADThe 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 + ConstructionAn 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.Share this Health tip:Share on Tumblr Pin ItMorePocketPrintEmailGoogle+
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