Update on dementia with lewy bodies

Dementia with Lewy bodies (DLB) presents to a range of specialists and involves a number of management challenges. The nosologic status of the disorder is controversial, especially its clinical overlap with Parkinson’s disease-related dementia and its pathologic distinction from Alzheimer’s disease. This article considers some of the controversies surrounding DLB with reference to recent literature. Emphasis is given to clinical topics, including the clinical phenomenology, differential diagnosis, and the treatment of core features of the disease.     

Neuropsychiatric aspects of dementia with lewy bodies

Neuropsychiatric symptoms are prominent clinical features of dementia with Lewy bodies (DLB). Visual hallucinations have been reported to be particularly common. Auditory hallucinations, delusions, and depression also may be characteristic to DLB. Misidentification delusions may be more common than with other types of delusional syndromes. Supersensitivity to neuroleptic drugs is common, making treatment of these symptoms difficult, and newer, atypical compounds have been recommended. However, supersensitive reactions to these medicines have been reported. Patients with DLB, especially those with visual hallucinations, are reported to have a marked cholinergic deficit, and cholinergic drugs may be beneficial in reducing the neuropsychiatric symptoms.     

路易体痴呆八例临床分析

目的探讨路易体痴呆的临床特征,诊断和治疗。方法对8例临床诊断的路易体痴呆患者的资料进行回顾性分析。结果8例患者的首发症状均为波动性认知功能障碍,伴随持续存在的视幻觉和帕金森综合征表现。主要为中度痴呆,视空结构能力损害明显;波动性认知功能障碍(FC)评分为4~10,平均7 4±2 1,为轻至中度波动;统一帕金森病等级量表(UPDRS)评分为31 ~71,平均47 8±14 3。1例有快眼动相(REM)睡眠行为障碍的患者REM睡眠期颏下肌电图出现大量电活动。8例患者头部MRI及CT扫描均显示脑萎缩。1例脑单光子发射计算机体层摄影术(SPECT)检查显示纹状体多巴胺功能受损。左旋多巴和胆碱酯酶抑制剂盐酸多奈哌齐治疗有效。结论路易体痴呆的临床特征为波动性认知功能障碍、持续存在的视幻觉和锥体外系运动功能障碍,诊断以病史、神经心理测试和影像学检查为依据,左旋多巴、胆碱酯酶抑制剂可分别改善患者的锥体外系症状和认知功能障碍。     

Predictors of survival in dementia with lewy bodies and Parkinson dementia

Retrospective analysis of 243 autopsy-confirmed cases of dementia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD) showed an average age at symptom onset of 67 years and a median survival of 5 years from symptom onset. Older age at onset, fluctuating cognition, and hallucinations at onset predicted shorter survival; initial parkinsonism with delayed dementia significantly improved survival. Associated Alzheimer pathology also shortened survival. When adjusted for age, gender, and Alzheimer pathology, fluctuating dementia at symptom onset was identified as best predictor of poor outcome.     

Family history of dementia: dementia with lewy bodies and dementia in Parkinson's disease

Parkinson's disease with dementia (PD-D) and dementia with Lewy bodies (DLB) may result from the same neurodegenerative process with different temporal and spatial courses. The authors report an association between DLB and family history of dementia in a comparison study between patients with a clinicopathological diagnosis of PD-D and DLB. Findings suggest that positive family history for dementia is associated with DLB with a yet unknown mechanism.     

Diagnostic criteria for dementia with lewy bodies reconsidered.

The validity of the consensus criteria for dementia with Lewy bodies (DLB) has been questioned. The authors, therefore, performed analyses of 242 published cases with clinicopathological correlation of DLB. The prevalence of specific consensus criteria in 69 patients reported on by the Newcastle and Nottingham groups in England (Group N) were compared with their prevalence in papers from all other investigators (Group O). Analysis of the entire sample (Groups N and O combined) revealed 64% with parkinsonism, 66% with co-occurring parkinsonism and dementia, 39% with visual hallucinations (VH), and 30% with cognitive fluctuations (CF). Group N had significantly more CF and co-occurring parkinsonism and dementia. Dopaminergic drugs were associated with the presence of VH. Although selection factors may have contributed to investigator differences, parkinsonism and co-occurrence with dementia appear to be the most consistent diagnostic criteria for DLB.     

Hallucinations predict attentional improvements with rivastigmine in dementia with lewy bodies

The aim of this analysis of the effects of cholinergic therapy in dementia with Lewy bodies was to determine whether rivastigmine-induced benefits in attention and memory could be predicted by the presence of visual hallucinations. At study entry, 74% of patients were hallucinators and 26% were non-hallucinators. The population was analyzed for two-factor scores: power of attention (PoA) and quality of memory (QoM). A significant effect over placebo on PoA was observed in hallucinators at weeks 12 (p = 0.023) and 20 (p = 0.0019), while no treatment effects were seen in non-hallucinators. Significant treatment effects on QoM were not observed in either subgroup. Visual hallucinations predicted greater improvements in PoA, but not QoM. This may reflect the greater cholinergic deficits in areas of the brain responsible for visual hallucinations, offering greater potential for attentional improvement.     

Neuropsychological comparison of Alzheimer's disease and dementia with lewy bodies

BACKGROUND/AIMS: The present study examined the patterns of memory and cognitive performance associated with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). METHODS: A battery of standardized neuropsychological tests was administered to individuals with these disorders as well as to a group of cognitively intact controls. The battery included measures of memory (learning, recall and recognition), language, visuospatial ability, psychomotor speed, executive functioning and mood. All subjects (n = 115) were evaluated at a memory disorder clinic and were diagnosed based on published criteria. RESULTS: The controls outperformed both dementia groups on all cognitive measures. With respect to memory, the DLB group scored significantly higher than the AD group on measures of word list free recall and recognition (p < or = 0.001). In other cognitive domains, the AD group performed significantly better than the DLB group on constructional praxis, sustained attention, phonemic fluency, spatial judgment, psychomotor speed and working memory (all p < or = 0.01). CONCLUSION: These findings support the usefulness of memory and other cognitive test score patterns as in distinguishing AD from DLB, particularly in mild to moderately demented populations that may not present with hallmark symptomology.     

Young adult-form of dementia with neurofibrillary changes and lewy bodies

Summary Alzheimer's neurofibrillary tangles, Lewy bodies and chromatolytic neurons were found in the brain at autopsy of a 28-year-old male with pyramidal and extrapyramidal signs, and severe dementia of 7-year duration prior to his death. Review of histological material showed generalized changes involving both cortical and subcortical structures. These changes were characterized by the presence of neurofibrillary tangles, Lewy bodies and chromatolytic neurons. Neuritic plaques were not found. There was also loss of neurons and gliosis in the prefrontal cortex, hippocampus, amygdaloid nucleus, basal ganglia, midbrain and pons. There were spongiform changes due to loss of neurons. Myelin stain showed pallor of myelin in long tracts and in subcortical regions. The neurofibrillary tangles were mostly composed of Alzheimer's paired helical filaments (PHF). PHF were immunostained with both polyclonal and monoclonal antibodies to PHF and the microtubule-associated protein tau. Some Lewy bodies were immunolabelled with monoclonal antibodies to PHF. To the best of our knowledge it is the first reported case of a young adult-form of dementia with extensive formation of neurofibrillary changes and Lewy bodies.Supported in part by grants from the NIH NS18105 and POINS04220     

Cerebrospinal fluid and plasma biomarkers for dementia with lewy bodies

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in the elderly. DLB is clinically characterized by fluctuating cognitive dysfunction, visual hallucinations, and parkinsonism. It is sometimes difficult to clinically diagnose patients with DLB because of the overlap of the clinical and pathological findings of this disease with those of Alzheimer's disease. Precise clinical diagnosis is important for determining the drug therapy appropriate for improving DLB symptoms. Biomarkers that enable more accurate diagnosis of DLB and reflect its complex clinical progression are highly desired. Cognitive impairment frequently occurs in patients with Parkinson's disease (PD). The common pathological features of DLB and PD are Lewy bodies and Lewy neurites, both of which are composed of α-synuclein. DLB and PD are now considered to belong to a common spectrum of disorders designated as Lewy body disease (LBD). We have previously reported that the α-synuclein levels in cerebrospinal fluid (CSF) are significantly lower in patients with DLB than in patients with other types of dementia. However, the significance of quantifying the CSF α-synuclein levels as a biomarker for DLB has been a matter of debate because the results for these levels have been inconsistent among different studies. Similar inconsistency has been observed in studies on the plasma α-synuclein levels in patients with LBD. Here, we review the recent progress on biomarkers of LBD, especially in DLB, and discuss their application to clinical diagnosis.     

Neuropsychiatric symptoms in mild dementia with lewy bodies and Alzheimer's disease

Background/Aims: To compare neuropsychiatric symptoms in patients with Alzheimer's disease (AD) and dementia with Lewy bodies(DLB). Methods: Neuropsychiatric symptoms and caregiver distress were assessed using the Neuropsychiatric Inventory (NPI) in mild DLB (n = 57) and AD (n = 126), and compared across the two groups using non-parametric tests. Results: The DLB patients had a higher NPI totalscore (median 24 vs. 11.5, p < 0.005), more numerous symptoms (median 5 vs. 4, p = 0.001) and more clinically significant symptoms (3 vs. 1, p = 0.001). They also had higher item hallucinations (6 vs. 2, p < 0.005) and apathy (7 vs. 5, p = 0.002) subscores. Caregivers scored higher on the NPI total caregiver distress scale (12.5 vs. 6, p = 0.003). Conclusions: In mild dementia, DLB patients have more neuropsychiatric symptoms and more associated caregiver distress compared with AD.     

Cerebrospinal fluid markers in dementia with lewy bodies compared with Alzheimer disease

BACKGROUND: Most patients with dementia with Lewy bodies (DLB) exhibit diffuse plaque-only pathology with rare neocortical neurofibrillary tangles (NFTs), as opposed to the widespread cortical neurofibrillary-tau involvement in Alzheimer disease (AD). Another pathological difference is the astrocytic and microglial inflammatory responses, including release of interleukins (ILs), around the neuritic plaques and NFTs in AD brains that are absent or much lower in DLB. We analyzed cerebrospinal fluid (CSF) markers that reflect the pathological differences between AD and DLB. OBJECTIVE: To determine CSF concentrations of tau, beta-amyloid, IL-1beta, and IL-6 as potential diagnostic clues to distinguish between AD and DLB. METHODS: We measured total tau, beta-amyloid1-42, IL-1beta, and IL-6 levels in CSF samples of 33 patients with probable AD without parkinsonism, 25 patients with all the core features of DLB, and 46 age-matched controls. RESULTS: Patients with AD had significantly higher levels of tau protein than patients with DLB and controls (P<.001). The most efficient cutoff value provided 76% specificity to distinguish AD and DLB cases. Patients with AD and DLB had lower, but not significantly so, beta-amyloid levels than controls. The combination of tau and beta-amyloid levels provided the best sensitivity (84%) and specificity (79%) to differentiate AD vs controls but was worse than tau values alone in discriminating between AD and DLB. Beta-amyloid levels had the best correlation with disease progression in both AD and DLB (P =.01). There were no significant differences in IL-1beta levels among patients with AD, patients with DLB, and controls. Patients with AD and DLB showed slightly, but not significantly, higher IL-6 levels than controls. CONCLUSIONS: The tau levels in CSF may contribute to the clinical distinction between AD and DLB. Beta-amyloid CSF levels are similar in both dementia disorders and reflect disease progression better than tau levels. Interleukin CSF concentrations do not distinguish between AD and DLB.     

路易体痴呆与帕金森病痴呆的神经心理学特征比较

目的　比较路易体痴呆（DLB）和帕金森病痴呆（PDD）患者神经心理学特征的差异。方法　采用简易精神状态检查量表（Mini-mental State Examination,MMSE）、画钟测验（Clock-drawing Test,CDT）、神经精神问卷（Neuropsychiatric Inventory,NPI）、日常活动能力量表（Activities of Daily Living Scale,ADL）、汉密尔顿抑郁量表（Hamilton Depression Scale,HAMD）17项版本、临床痴呆评定量表（Clinical Dementia Rate,CDR）评估 20例DLB患者和56例 PDD患者的认知功能,并比较不同痴呆阶段的两组患者神经心理学差异。结果　60%的 DLB患者存在症状的波动,多于PDD患者（ 19.6%）（P=0.001）。中重度痴呆阶段, DLB 组NPI评分高于 PDD组（P＜ 0.05）。轻度痴呆阶段, PDD患者在 CDR的家庭生活和个人业余爱好域评分高于 DLB患者（ P=0.039）。中重度痴呆阶段, DLB组记忆力（P=0.018）和定向力评分（P=0.010）以及 CDR总体得分（P=0.028）高于 PDD组。结论　临床工作中结合病史并对痴呆患者进行全面的神经心理学检查有助于鉴别 DLB和PDD。     

Efficacy of olanzapine in the treatment of psychosis in dementia with lewy bodies

OBJECTIVE: This study sought to determine whether patients with dementia with Lewy bodies (DLB) and psychosis responded to treatment with olanzapine. METHODS: This was a post hoc analysis of a subgroup of patients with DLB included in a larger double-blind, placebo-controlled, randomized parallel group trial of olanzapine for the treatment of psychosis in patients with Alzheimer's disease. Patients meeting the consensus criteria for DLB and exhibiting parkinsonism and visual hallucinations were selected from the initial study. Psychosis was assessed with the Neuropsychiatric Inventory/Nursing Home (NPI-NH) version and the Brief Psychiatric Rating Scale (BPRS). Extrapyramidal symptoms were evaluated with the Simpson-Angus scale. RESULTS: Twenty-nine patients met the criteria for DLB; 10 were randomized to placebo, 5 received 5 mg of olanzapine, 7 received 10 mg of olanzapine and 7 received 15 mg of olanzapine. Patients with DLB treated with 5 mg of olanzapine showed significant reductions in delusions and hallucinations. Patients treated with 10 mg showed a significant reduction in the NPI-NH delusion subscale score. No significant differences were found between the 15-mg group and the placebo group. Confirmatory findings emerged from an analysis of the BPRS. Caregivers reported decreased disruptions in their occupational routines for the group receiving 5 or 10 mg of olanzapine. There was no significant exacerbation of parkinsonian symptoms in any study group, no decrement in Mini-Mental State Examination scores in any of the treatment groups, and symptoms suggestive of anticholinergic toxicity did not differ among treatment groups. CONCLUSIONS: This preliminary analysis suggests that olanzapine (5 or 10 mg) reduces psychosis in patients with DLB without worsening parkinsonism.     

A multiparametric MRI study of structural brain damage in dementia with lewy bodies: A comparison with Alzheimer's disease

IntroductionDifferential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is crucial for an adequate patients' management but might be challenging. We investigated with advanced MRI techniques gray (GM) and white matter (WM) damage in DLB patients compared to those with AD.Methods24 DLB patients, 26 age- and disease severity-matched AD patients, and 20 age and sex-matched controls performed clinical and neuropsychological assessment, and brain structural and diffusion-tensor MRI. We measured GM atrophy using voxel-based morphometry, WM hyperintensities (WMH) using a local thresholding segmentation technique, and normal-appearing WM (NAWM) damage using tract-based spatial statistic.ResultsDLB and AD patients exhibited mild-to-moderate-stage dementia. Compared to controls, GM damage was diffuse in AD, while limited to bilateral thalamus and temporal regions in DLB. Compared to DLB, AD patients exhibited GM atrophy in bilateral fronto-temporal and occipital regions. DLB and AD patients showed higher WMH load than controls, with no differences among each other. WMH in DLB were diffuse with relative prevalence in posterior parietal-occipital regions. Compared to controls, both DLB and AD patients showed reduced microstructural integrity of the main supratentorial and infratentorial NAWM tracts. AD patients exhibited greater posterior NAWM damage than DLB.ConclusionsDLB showed prominent WM degeneration compared to the limited GM atrophy, while in AD both tissue compartments were severely involved. In DLB, NAWM microstructural degeneration was independent of WMH, thus revealing two possible underlying processes. Different pathophysiological mechanisms are likely to drive GM and WM damage distribution in DLB and AD.