Familial dementia with Lewy bodies with an atypical clinical presentation

The authors report a case of a 64-year-old male with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) pathology at autopsy who did not manifest the core symptoms of DLB until very late in his clinical course. His initial presentation of early executive and language dysfunction suggested a cortical dementia similar to frontotemporal lobar degeneration (FTLD). Core symptoms of DLB including dementia, hallucination, and parkinsonian symptoms were not apparent until late in the course of his illness. Autopsy revealed both brainstem and cortical Lewy bodies and AD pathology. Family history revealed 7 relatives with a history of dementia including 4 with possible or probable DLB. This case is unique because of the FTLD-like presentation, positive family history of dementia, and autopsy confirmation of DLB.     

Familial dementia with lewy bodies: a clinical and neuropathological study of 2 families

BACKGROUND: Dementia with Lewy bodies (DLB) is characterized by early dementia and associated visual hallucinations, parkinsonism, and fluctuations in cognition. Few families with DLB have been described with detailed clinical, pathological, and genetic assessments. OBJECTIVE: To investigate the clinical, neuropathological, and genetic characteristics of families with 2 or more autopsy-proven cases of DLB. DESIGN: Consecutive cases with the neuropathological diagnosis of DLB were reviewed as part of a case series. Families included in this study have 2 or more autopsy-proven cases of DLB available and a positive family history of dementia. We obtained clinical and neuropathological data on all first-degree relatives. Neuropathological evaluations included alpha-synuclein immunostaining for Lewy body detection. We conducted apolipoprotein E genotyping and sequenced the alpha-, beta-, gamma-synuclein, and parkin genes. SETTING: Subjects were selected from the neuropathology core of the University of Washington's Alzheimer's Disease Research Center. PATIENTS: The study investigated 2 families. Clinical information was obtained from 10 individuals in family 1 and 7 individuals in family 2. Neuropathological examinations were conducted in 3 individuals in family 1 and 2 individuals in family 2. MAIN OUTCOME MEASURES: Each subject was examined for the presence of clinical symptoms and neuropathological findings consistent with DLB. RESULTS: While all affected individuals presented with dementia in both families, only individuals in family 1 developed visual hallucinations and delusions. Parkinsonism, if present, occurred later in the course of illness. Neuropathological examination revealed Lewy bodies in all patients, while 1 patient from each family also met the neuropathological criteria for Alzheimer disease. All affected individuals carried at least 1 APOE (apolipoprotein E) epsilon 4 allele, while there were no nucleotide alterations in the synuclein or parkin genes. CONCLUSIONS: Familial DLB exists, although there is substantial clinical and neuropathological heterogeneity within and between families. Additional clinicopathologic and genetic studies are necessary to further our understanding of DLB.     

Clinical validation of Movement Disorder Society-recommended diagnostic criteria for Parkinson's disease with dementia

The objective of this work was to evaluate the Movement Disorders Society (MDS) Task Force-proposed screening checklist for detecting Parkinson's disease dementia (PD-D) in relation to full neuropsychological testing. An MDS Task Force has proposed diagnostic procedures for PD-D, which have not been fully validated against more extensive neuropsychological testing. PD subjects were recruited from 2 specialty centers. A neuropsychologist evaluated them for dementia as part of routine clinical care. Independent clinical neurologists administered the MDS PD-D screening checklist. Diagnosis of PD-D by the 2 methods was compared. Ninety-one PD subjects had a mean age of 66.3 (SD = 9.7) years and a mean PD duration of 8.8 (SD = 6.1) years. Seven subjects (7.7%) met all 8 screening checklist criteria from the MDS PD-D screening tool and were classified as probable PD-D. Fifteen (16.5%) subjects were classified as PD-D by full neuropsychological assessment. The screening checklist showed 100% specificity, but only 46.7% sensitivity, for diagnosing PD-D compared to the full neuropsychological assessment. PD-D cases missed by the PD-D screening tool were largely due to 2 checklist items that were not endorsed (absence of depression and Mini-Mental State Examination [MMSE] scores <26). There was moderate agreement between these 2 methods for determination of PD-D (kappa = 0.59, P < .001). The MDS-PD-D screening checklist is highly accurate for detecting PD-D if all items are endorsed. However, for cases that do not meet these criteria, full neuropsychological testing is needed to differentiate PD-D from milder cognitive impairment. Revision of the checklist by altering or eliminating the 2 problematic checklist items may improve sensitivity.     

Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease

BACKGROUND: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown. OBJECTIVES: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease). DESIGN: Survey of cognitive features. SETTING: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA. PATIENTS: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education. MAIN OUTCOME MEASURES: Dementia rating scale subscores corrected for age. RESULTS: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001). CONCLUSIONS: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease.     

Biomarkers: Parkinson disease with dementia and dementia with Lewy bodies

Dementia is a common feature in Parkinson disease (PD), the time of onset determining how patients are classified. Those patients where dementia develops prior to parkinsonism or during the first year of disease are designated as having dementia with Lewy bodies (DLB). In those where dementia develops over a year after the onset of motor signs, the condition is known as Parkinson's disease with dementia (PDD).While this seems at first sight to be a definitive way to distinguish these conditions, reality is rather different. The overlap between them is considerable, and there is much uncertainty associated with patients who have both motor symptoms and early cognitive impairment. The diagnosis is still based on medical history and clinical evaluation. It is not even certain that they can be accurately distinguished at autopsy. For this reason, the data concerning these entities have been reviewed, to examine various markers employed or measured in clinical, neuropathological, neuroimaging, and biochemical investigations. The concept of PDD and DLB being separate conditions is comparatively new, and the most promising tools with which to separate them at present are cerebrospinal fluid (CSF) markers and positron emission tomography (PET) scanning that indicate increased amyloid-β burden in DLB compared to PDD. However as yet there are no markers that unequivocally distinguish between PDD and DLB.     

Relationship between Parkinson disease with dementia and dementia with Lewy bodies

Parkinson disease (PD) and dementia with Lewy bodies (DLB) are considered Lewy body diseases (LBDs). To clarify the relation between PD with dementia (PDD) and DLB, 30 patients with LBD were divided into pathological subtypes according to the consensus guidelines for DLB. Patients with PDD showed neocortical and limbic type of LBD as well as patients with DLB. Dementia had not been noted in 2 patients with neocortical type. Our results indicate that PDD and DLB share a common pathological substrate and that the pathological subtypes of LBD show considerable overlap in clinical manifestations.     

Cognitive conditions of pathologically confirmed dementia with Lewy bodies and Parkinson's disease with dementia

The relationship between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) has been insufficiently described, and it is still problematic. Twenty-nine cases of DLB and 10 cases of PDD were investigated in the present study. DLB cases disclosed a significantly older disease onset and shorter disease duration than PDD cases (p<0.01 each). However, they showed no significant difference in dementia onset or dementia duration (p>0.05 each). Motor symptoms (parkinsonism) were suspected as the cause of the younger disease onset in PDD cases. Compared with 10 age-matched cases of definite Alzheimer's disease, both 19 DLB cases and 6 PDD cases had significantly better scores in the final test of mini-mental state examination (MMSE) and revised version of Hasegawa's Dementia Scale (HDSR) within 12 months before death, although no significant differences between DLB and PDD were indicated. DLB and PDD were suspected to show cognitive impairment of similar severity in the terminal stage. They would thus be difficult to classify as completely different entities.     

Association of arterial stiffness with cognition in patients with Lewy body disorder

The brachial-ankle pulse wave velocity (baPWV) is a marker for arterial stiffness, which is associated with cardiovascular diseases. Arterial stiffness is associated with cognitive function in the elderly and patients with Alzheimer’s disease (AD). We aimed to investigate the association between arterial stiffness and cognitive function in patients with Lewy body disorder (LBD), including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). We consecutively included 123 patients with PD, 10 patients with DLB, and 27 AD controls. Patients with PD were divided into three groups of normal cognition (PD-NC, n = 63), mild cognitive impairment (PD-MCI, n = 43), and dementia (PD-D, n = 17). Arterial stiffness, measured as baPWV, was compared between the PD-NC, PD-MCI, PD-D, DLB, and AD patients. In LBD, we analyzed the association between arterial stiffness and each cognitive domain with adjustment for covariates. Higher baPWV was significantly associated with cognitive decline in patients with LBD (baPWV in PD-D > PD-MCI > PD-NC; DLB > PD-NC). There was no significant difference in baPWV between PD-D, DLB, and AD patients. In LBD patients, higher baPWV was associated with lower mini mental state examination score (β ± SE = ?0.003 ± 0.001, p = 0.007) and more severe dementia. Higher baPWV was also associated with lower performance in attention, language, visuospatial function, memory, and executive function in LBD patients. This suggests that vascular brain injury is associated with cognitive dysfunction in LBD.     

Clinical trials in Parkinson's disease dementia and dementia with Lewy bodies

Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are pathological overlapping and important causes of dementia for which clinical trials are in their infancy. Cholinesterase inhibitors may be of benefit in DLB and PDD, as suggested by placebo-controlled clinical trials of rivastigmine and donepezil. The anti-psychotic agent clozapine has been of benefit in PD and PDD, but other agents, such as quetiapine, require adequate assessment. Barriers to trials include pathological overlap that can lead to inaccuracies in clinical diagnosis, unavailability of a consensus definition for PDD, unanswered questions regarding natural history and the paucity of validated outcome measures. Motor impairment must be considered in patients with PDD and DLB; conversely, cognitive impairment should be assessed in trials targeting motor impairment in advanced PD. Potential targets for treatment include onset of dementia, cognitive impairment, behavioral impairment, functional decline, falls, nursing home placement, mortality, quality of life and economic impact. Biomarkers including neuroimaging and cerebrospinal fluid markers are not currently established. At present PDD and DLB are distinct entities by definition. Future studies, including clinical trials and biomarker studies, will help to further define the clinical and therapeutic implications of this distinction.     

Clinical diagnosis of dementia with Lewy bodies in a Japanese dementia registry.

We found 15 patients with dementia with Lewy bodies (DLB) and 232 patients with Alzheimer's disease (AD) among 327 consecutive patients with mild to moderate dementia in a Japanese dementia registry, using the clinical criteria of the Consortium on DLB International Workshop. The percentage of females was significantly lower in DLB than in AD (p < 0.01), while age at examination, Mini-Mental State Examination score and duration of cognitive symptoms were comparable between the two diseases. Eight of the 15 DLB patients (53%) had spontaneous parkinsonism, which was observed in 6 of the 232 AD patients (2.6%). Visual hallucinations were reported by 11 of the 15 DLB patients (73%) and 8 of the 232 AD patients (3.4%). Cognitive fluctuation was positive in 13 of the 15 DLB patients (87%). We found two types of episodic cognitive deterioration: one was characterized by pronounced disturbances of attention and alertness (inattention type), and the other was characterized by marked and bizarre disturbances of orientation in time and places, and misidentification of persons (disorientation type). Systematized delusion was observed in 8 DLB patients, and 5 patients showed neuroleptic sensitivity. Patients with DLB have a unique dementia syndrome even in the stage of mild to moderate cognitive impairments. Further studies are recommended to establish diagnosis, treatment and management.     

Comparison of dementia with Lewy bodies to Alzheimer's disease and Parkinson's disease with dementia.

We compared the clinical and neuropsychological pattern of dementia with Lewy bodies (DLB) to Alzheimer's disease (AD) and Parkinson's disease with dementia (PD-d). Sixteen patients clinically diagnosed with DLB were compared with two groups of patients with PD-d (n = 15) and AD (n = 16) matched for level of dementia. Isolated cognitive impairment was the most common form of presentation in AD (93.8%) and DLB (31.3%) groups, while parkinsonism was in 100% of PD-d subjects. Psychoses associated with cognitive impairment at the beginning of the disease were more frequent in DLB patients (31.3%) than in AD (6.3%) and PD-d (0%) groups. There were no significant differences in Unified Parkinson Disease Rating Scale motor-subscale scores between DLB and PD-d patients. DLB and PD-d patients performed significantly worse on attentional functions and better on memory tests than AD. DLB patients also showed lower scores than AD subjects on visual memory, visuoperceptive, and visuoconstructive tests. No significant differences were found between PD-d group and DLB subjects on any neuropsychological test. We were unable to find any differences in cognitive tasks between PD-d and DLB subjects. Clinical features and neuropsychological deficiencies of DLB (attentional, visuoperceptive, and visuoconstructive deficits) and PD (attentional deficits) compared to AD (amnesic syndrome) can contribute to accurate identification of these entities and to the understanding of the neuropathological and neurochemical substrate underlying these diseases.     

Sonographic discrimination of dementia with Lewy bodies and Parkinson's disease with dementia

Objective To study the use of transcranial sonography (TCS) in discriminating between patients with dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). Methods Fourteen patients with DLB, 31 with PDD and 73 with PD without dementia (PDnD) were studied with TCS. Results All assessable patients with DLB, 97% with PDD, and 94% with PDnD showed at least unilateral hyperechogenicity of substantia nigra (SN). However, bilateral marked SN hyperechogenicity was present in 80% of DLB patients but only in one third of PDD and PDnD patients, and was associated with younger age at disease onset in PD but not in DLB. An asymmetry index ≥ 1.15 of bilateral SN echogenic sizes, estimated by division of larger size by smaller size, was found in 69% of PDD patients but only 20% of DLB patients. Combination of SN echogenic sizes, asymmetry indices and onset age discriminated PDD from DLB with a sensitivity of 96%, a specificity of 80% and a positive predictive value of 93%. TCS of brainstem raphe, thalami, lenticular nuclei, caudate nuclei and ventricle widths did not discriminate between DLB and PDD. Compared with PDnD patients, DLB and PDD patients exhibited significantly larger widths of third ventricle and of frontal horns. In PDD patients, scores on the Unified Parkinson's Disease Rating Scale correlated with widths of third ventricle and of frontal horns. Conclusions SN hyperechogenicity is typical for PDD and DLB.However, size, asymmetry and relation of SN hyperechogenicity to age at disease onset discriminate PDD from DLB.     

Neuropathology of Parkinson's disease dementia and dementia with Lewy bodies with reference to striatal pathology

Dementia is relatively common in Parkinson's Disease (PD). When dementia occurs in the setting of PD, it is referred to as Parkinson's disease dementia (PDD), which is distinguished from the clinical syndrome in which dementia precedes extrapyramidal features, dementia with Lewy bodies (DLB). In this report, the neuropathology of PDD and DLB is reviewed and preliminary findings are reported on striatal pathology in 28 brains, including 7 PD, 7 PDD and 14 DLB. Sections of putamen immunostained for a-synuclein and investigated with image analysis show that striatal pathology is common and that both cortical and striatal a-synuclein pathology is greater in PDD and DLB than PD. Most cases of PDD and DLB have Alzheimer-type pathology, particularly amyloid plaques, which may act in an additive or synergistic manner with a-synuclein pathology. There are few pathologic differences between PDD and DLB, despite differences in their clinical course.     

Clinical diagnosis of dementia

This paper presents recommendations deriving from the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia, concerning the clinical diagnosis of dementia. There are currently no universally accepted biological or radiological markers of dementia. In the absence of these, the diagnosis of dementia remains a clinical exercise aiming to integrate all available clinical and laboratory information. It is proposed that the currently used National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRA) criteria for diagnosis of Alzheimer’s disease (AD) be retained. The currently available vascular dementia (VaD) diagnostic criteria have variable accuracy. An integrative approach to VaD diagnosis based on all the available evidence (history, vascular risk factors, physical exam, clinical course, neuroimaging, cognitive impairment pattern) is recommended. The separation of Lewy body dementia (DLB) from Parkinson’s disease dementia (PDD) is based on the dominant clinical presenting feature of each syndrome, and relies on the duration of this feature: long duration of parkinsonian “motor” syndrome preceding dementia for PDD versus early/initial dementia accompanied by extrapyramidal symptoms for DLB. It is recognized that it is impossible clinically to characterize DLB with (pathologically) coexisting AD changes. The Frontotemporal group of dementia syndromes are discussed in regards to their typical clinical pictures, recognizing that their neuropathological substrate are not predictable from their mode of presentation. Finally, the particular rapid time sequence of evolution of the dementias due to prior disease is recognized as the clinically most useful distinguishing feature of these syndromes.     

Neuropsychiatric profiles in dementia

We compared patterns of neuropsychiatric symptoms across 4 dementia types [Alzheimer disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB), and Parkinson disease dementia], and 2 mixed groups (AD/VAD and AD/DLB) in sample of 2,963 individuals from the National Alzheimer's Coordinating Center Uniform Data Set between September 2005 and June 2008. We used confirmatory factor analysis to compare neuropsychiatric symptom severity ratings made by collateral sources on the Neuropsychiatric Inventory Questionnaire for people with Clinical Dementia Rating scores of 1 or higher. A 3-factor model of psychiatric symptoms (mood, psychotic, and frontal) was shared across all dementia types. Between-group comparisons revealed unique neuropsychiatric profiles by dementia type. The AD group had moderate levels of mood, psychotic, and frontal symptoms whereas VAD exhibited the highest levels and Parkinson disease dementia had the lowest levels. DLB and the mixed dementias had more complex symptom profiles. Depressed mood was the dominant symptom in people with mild diagnoses. Differing psychiatric symptom profiles provide useful information regarding the noncognitive symptoms of dementia.     

Definition and diagnosis of dementia with Lewy bodies

Significant advances have been made in neuropathologic identification procedures for dementia with Lewy bodies (DLB), but difficulties remain in clinical diagnosis. Consensus criteria state that the core features of DLB are fluctuating cognition with pronounced variation in attention and alertness, recurrent visual hallucinations and spontaneous motor features of parkinsonism. At least two of these features must be present for the diagnosis of probable DLB. Assessments of the validity of the consensus criteria against autopsy generally indicate high specificity but varying sensitivity. More detailed assessments of core diagnostic features or better operationalization, particularly of fluctuating cognition, may help improve the diagnostic guidelines. Greater utilization of some features described as supporting the diagnosis (such as auditory hallucinations) and the potential inclusion of additional symptoms (such as REM sleep behavioral disorder) also may be useful. In addition, the potential role of more detailed neuropsychology and neuroimaging in the diagnostic process needs to be evaluated, although it is important that changes to the diagnostic criteria are based on empirical evidence. Other key issues pertain to the classification of DLB patients with concurrent Alzheimer's disease and the differentiation of DLB and Parkinson's disease dementia based on less than a 1-year history of parkinsonism preceding the dementia.     

Quantifying fluctuation in dementia with Lewy bodies, Alzheimer's disease, and vascular dementia

BACKGROUND: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in the major dementias, particularly dementia with Lewy bodies (DLB), where it is one of three core clinical diagnostic features. OBJECTIVES: To examine the frequency, characteristics, and diagnostic utility of FC in dementia using clinical, attentional, and EEG markers. Method:- A total of 155 subjects (61 with AD, 37 with DLB, 22 with vascular dementia [VaD], 35 elderly controls) received clinical evaluation for FC using a semiquantified measure applied by experienced clinicians and 90-second cognitive choice reaction time (CRT) and vigilance reaction time (VIGRT) trials. Forty subjects also received an evaluation of mean EEG frequency across 90 seconds. RESULTS: Patients with DLB had a greater prevalence and severity of FC than did patients with AD or VaD rated using clinical, attentional, and EEG measures. The 90-second cognitive and EEG trials demonstrated that FC occurs on a second-to-second basis in patients with DLB. Patients with VaD had a higher prevalence of FC than did those with AD, although the profile of FC was different from that expressed by DLB cases. Optimal cutoff values on the clinical scale achieved good discrimination between the dementia groups (sensitivity 81%, specificity 92%, DLB versus AD; sensitivity 81%, specificity 82%, DLB versus VaD; sensitivity 64%, specificity 77%, VaD versus AD). CONCLUSION: Standardized assessment methods demonstrate that FC is significantly more common and severe in DLB than in other major dementias. The periodicity of FC is different in DLB and VaD cases, with important implications for the underlying causal mechanisms and for differential diagnosis.     

Spectrum of Parkinson's disease, Parkinson's dementia, and Lewy body dementia

Dementia occurs more commonly in individuals with Parkinson's disease (PD) than in the age-matched general population. Dementia in PD may result from a mixture of cortical and subcortical dementia syndromes caused by a variety of underlying pathologic processes and neurochemical deficits. A primary dementia syndrome has been described that shares several pathologic and clinical characteristics with PD. Dementia with Lewy bodies (DLB) accounts for 15% to 20% of all dementia syndromes in old age, which makes it second only to Alzheimer's disease in prevalence. The relationship between dementia in PD and DLB has not been fully resolved but may be considered useful in terms of neuropathologic substrate, clinical features, and response to treatment.