Daniel I. Kaufer

Diagnosis and management of dementia with Lewy bodies Third report of the DLB consortium

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Assessing the Impact of Neuropsychiatric Symptoms in Alzheimer's Disease: The Neuropsychiatric Inventory Caregiver Distress Scale

OBJECTIVES: To develop an adjunct scale to the Neuropsychiatric Inventory (NPI) for assessing the impact of neuropsychiatric symptoms in Alzheimers disease (AD) patients on caregiver distress.

Diagnosis and management of dementia with Lewy bodies Fourth consensus report of the DLB Consortium

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Cognitive correlates of cortical cholinergic denervation in Parkinson's disease and parkinsonian dementia.

AbstractWe recently reported findings that loss of cortical acetylcholinesterase (AChE) activity is greater in parkinsonian dementia than in Alzheimer’s disease (AD). In this study we determined cognitive correlates of in vivo cortical AChE activity in patients with parkinsonian dementia (PDem, n = 11), Parkinson’s disease without dementia (PD, n = 13), and in normal controls (NC, n = 14) using N–[11C]methyl–piperidin–4–yl propionate ([11C]PMP) AChE positron emission tomography (PET). Cortical AChE activity was significantly reduced in the PDem (–20.9%) and PD (–12.7 %) subjects (P < 0.001) when compared with the control subjects. Analysis of the cognitive data within the patient groups demonstrated that scores on the WAIS-III Digit Span, a test of working memory and attention, had most robust correlation with cortical AChE activity (R = 0.61, p < 0.005). There were also significant correlations between cortical AChE activity and other tests of attentional and executive functions, such as the Trail Making and Stroop Color Word tests. There was no significant correlation between cortical AChE activity and duration of motor disease (R = –0.01, ns) or severity of parkinsonian motor symptoms (R = 0.14, ns). We conclude that cortical cholinergic denervation in PD and parkinsonian dementia is associated with decreased performance on tests of attentional and executive functioning.

Neuropsychiatric aspects of Alzheimer's disease: The cholinergic hypothesis revisited

Altered cholinergic function is a prominent feature of AD.The neuropsychological impairments of AD are attributed, at least partially, to the cholinergic disturbance, and current approaches to treatment of the cognitive abnormalities attempt to enhance cholinergic function. Behavioral changes are common in AD and include psychosis, agitation, depression, anxiety, personality alterations, and neurovegetative changes. The contribution of the cholinergic deficiency to the behavioral alterations has been little explored, but neurochemical, neuroanatomic, pharmacologic, and clinical observations suggest that the cholinergic deficiency contributes importantly to the neuropsychiatric dimension of AD. Investigation of the role of cholinergic dysfunction in the behavioral changes of AD will improve understanding of the pathophysiologic basis of these abnormalities and may lead to new types of therapy for the neuropsychiatric disturbances associated with this common dementing disorder. NEUROLOGY 1996;47: 876-883

Dementia with Lewy bodies: Reliability and validity of clinical and pathologic criteria

Clinical criteria for dementia with Lewy bodies (DLB) have been proposed, but their formulation, reliability, and validity require further study.Pathologic criteria for DLB are also undergoing evolution. Two studies were conducted with the goal of identifying the components of these evolving criteria that may benefit from further refinement; one study evaluated the components of the clinical criteria and another study operationalized the pathologic criteria for DLB. Twenty-four patients with a premorbid diagnosis of probable or possible Alzheimers disease (AD) (n = 18), Parkinsons disease (PD) (n = 5), or progressive supranuclear palsy (PSP) (n = 1) were studied. Inter-rater reliability and validity of the clinical criteria were determined by a retrospective chart review, done by five neurologists, and a blinded pathologic evaluation. The Consortium on dementia with Lewy bodies (CDLB) pathologic criteria were operationalized to compare past criteria and test the validity of the evolving clinical criteria on the dementia patients. Three or more cortical fields (at 250x magnification) with many (four or more) Lewy bodies (LBs) on ubiquitin immunoreactive sections were required to meet the CDLB neocortical score of >6. Fifteen of the AD patients had at least one LB in a cortical section, four had many LBs, while three had no LBs; all patients with movement disorder had at least one LB in a cortical section. The sensitivity/specificity ratio of the CDLB probable DLB clinical criteria based upon many LBs being present was 75%/79%. Reformulated clinical criteria that require the presence of extrapyramidal signs significantly predicted those patients with many LBs versus those with few or no LBs (chi squared = 5.48, p = 0.02) and increased clinical specificity to 100%. This preliminary study identifies components of the evolving clinical and pathologic criteria for DLB that require further refinement. NEUROLOGY 1996;47: 1403-1409

Accuracy of four clinical diagnostic criteria for the diagnosis of neurodegenerative dementias

Objective: To evaluate the inter-rater reliability and validity of clinical diagnostic criteria for neurodegenerative dementias. Background: Inter-rater accuracy of the diagnosis of AD has been explored, but there are few accuracy studies for progressive supranuclear palsy (PSP) and frontotemporal lobe dementia (FTD). Furthermore, there have been no simultaneous accuracy studies in a mixed sample of patients with cortical and subcortical neurodegenerative processes. Methods: Four experienced clinicians reviewed first-visit clinical data abstracted from the records of 40 pathologically diagnosed demented subjects. They were asked to apply the NINCDS-ADRDA criteria for AD, the NINDS-SPSP clinical criteria for PSP, the Lund and Manchester criteria for FTD, and the Consensus Guidelines for the Clinical Diagnosis of Dementia with Lewy Bodies (DLB). Results: The generalized κ for AD was 0.73, for PSP 0.82, for FTD 0.75, and for DLB 0.37. The κ pool test showed a statistically significant difference between DLB and the other disease processes, and no differences were observed among AD, FTD, and PSP. The mean sensitivity for AD was 95%, for PSP 75%, for FTD 97%, and for DLB 34%. The mean specificity for AD was 79%, for PSP 98.5%, for FTD 97%, and for DLB 94%. Conclusions: We found improved inter-rater reliability for the diagnosis of AD among clinicians compared with earlier studies. Similarly, there was a near-perfect and substantial inter-rater agreement for the diagnosis of PSP and FTD. The sensitivity for the diagnosis of AD was high, although clinicians overdiagnosed this condition. However, there was a reasonable accuracy for the diagnosis of PSP and FTD. Heterogeneity of the clinical presentation of DLB significantly affected inter-rater agreement and accuracy. The use of multiple diagnostic criteria for cortical and subcortical dementia increases the level of clinical diagnostic accuracy.

Research evaluation and diagnosis of probable Alzheimer's disease over the last two decades: I.

Objective: To describe the experience of a research clinic diagnosing AD during the last two decades, with special emphasis on patients who meet the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for probable AD, their patterns of clinical presentation, and neuropathologic outcomes. Background: Probable AD has a heterogeneous clinical presentation, and can occur in the context of complicating factors. There are few reports, and none with this large of a sample, about the pattern of presentation, the nature of comorbidities, and the sensitivity and specificity of diagnosis. Results: The AD Research Center of Pittsburgh examined 1139 patients with probable AD between April 1983 and February 2000. Of these 1139 probable AD patients, 29 (2.5%) had slow progression, 27 (2%) had rapid progression, 70 (6%) had an atypical presentation, and 85 (7%) had coexistent cerebrovascular disease. Confluent periventricular white matter lesions were found in 348 (30.5%) patients with probable AD. The overall sensitivity for the diagnosis of AD was 97% and the specificity 80%. However, the accuracy for the diagnosis of AD varied over the years: from 1983 to 1989, the sensitivity was 94% and specificity 52%, and from 1990 to 2000, the sensitivity was 98% and specificity 88%. Conclusion: Although the diagnosis of probable AD has been used to indicate the presence of a homogeneous clinical entity, these patients can vary in presentation, onset, or clinical course. This finding is of particular importance for the understanding of the pathophysiologic basis of the disease, and for the better identification of responders to dementia treatments. Although the sensitivity for the diagnosis of AD remained above 90% over the last two decades, the specificity increased, reflecting progressive improvement in the diagnosis of other dementing disorders.

Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer’s disease

Objectives: To determine in vivo cortical acetylcholinesterase (AChE) activity and cognitive effects in subjects with mild Alzheimer’s disease (AD, n = 14) prior to and after 12 weeks of donepezil therapy. Methods: Cognitive and N-[11C]methyl-piperidin-4-yl propionate ([11C]PMP) AChE positron emission tomography (PET) assessments before and after donepezil therapy. Results: Analysis of the PET data revealed mean (temporal, parietal, and frontal) cortical donepezil induced AChE inhibition of 19.1% (SD 9.4%) (t = −7.9; p<0.0001). Enzyme inhibition was most robust in the anterior cingulate cortex (24.2% (6.9%), t = −14.1; p<0.0001). Donepezil induced cortical inhibition of AChE activity correlated with changes in the Stroop Color Word interference scores (R2 = 0.59, p<0.01), but not with primary memory test scores. Analysis of the Stroop test data indicated that subjects with AChE inhibition greater than the median value (>22.2%) had improved scores on the Stroop Color Word Test compared with subjects with less inhibition who had stable to worsening scores (t = −2.7; p<0.05). Conclusions: Donepezil induced inhibition of cortical AChE enzyme activity is modest in patients with mild AD. The degree of cortical enzyme inhibition correlates with changes in executive and attentional functions.

Dementia with Lewy bodies Response of delirium-like features to donepezil

Dementia with Lewy bodies (DLB) is a clinicopathologically heterogeneous dementia with features that overlap Alzheimers disease (AD) and Parkinsons disease (PD).1-3 DLB is defined pathologically by the presence of cortical Lewy bodies, although most cases have concomitant histopathologic markers of AD (primarily amyloid plaques). Autopsy studies have observed cortical Lewy bodies in 10 to 30% of all dementia cases, making DLB the second most common form of dementia behind AD. Consensus guidelines for the clinical diagnosis of DLB highlight three core features: fluctuating attention, recurrent visual hallucinations, and parkinsonian motor features.3 Fluctuating attention confusional state and may be associated with hypersomnolence. Visual hallucinations in DLB are often florid, whereas extrapyramidal features are typically less severe than they are in PD and may include prominent gait disturbance.2 The combination of psychosis and extrapyramidal features can be problematic because DLB patients may be exquisitely sensitive to the side effects of antipsychotic agents. Preliminary observations suggest that DLB patients may particularly benefit …