Robert H. Perry

Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB) Report of the consortium on DLB international workshop

Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimers disease (AD).The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinsons disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification. NEUROLOGY 1996;47: 1113-1124

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.

Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia.

Necropsy brain tissue from normal (control) patients and patients with depression and dementia was examined for activities of various cholinergic components, and these related to the degree of senile plaque formation and extent of intellectual impairment. Choline acetyltransferase and acetylcholinesterase activities decreased significantly as the mean plaque count rose, and in depressed and demented subjects the reduction in choline acetyltransferase activity correlated with the extent of intellectual impairment as measured by a memory information test; muscarinic cholinergic receptor binding activity remained unchanged with increasing senile plaque formation but butyrylcholinesterase activity increased. The results suggest a close relation between changes in the cholinergic system and Alzheimers dementia, but the precise role of the system in this disease remains to be elucidated.

High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease

Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% ± 9.3%; individuals with Parkinson disease, 52.3% ± 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease.

Neurotransmitter enzyme abnormalities in senile dementia ☆: Choline acetyltransferase and glutamic acid decarboxylase activities in necropsy brain tissue

Reductions in 2 neurotransmitter synthesizing enzymes in brain, glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT), have been found in dementias of different origins, including senile dementia (Alzheimer type). Significant reductions in cerebral GAD have also been found in depression (unipolar). The GAD reductions did not generally appear to be localised in any specific region of the brain examined. However, the reduction of CAT in the hippocampus, relative to reductions in other areas examined, was substantially greater in the brains with Alzheimer-type changes. GAD and CAT activities in normal brains were examined for the effects of some variable factors inherent in necropsy biochemical measurements. These factors included: (i) age; (ii) agonal status; (iii) time of death, and (iv) delay in tissue sampling; and GAD was found to be significantly influenced by (ii), (iii) and (iv) and CAT by (i), (iii) and (iv). None of these factors accounted for the total alterations in the enzyme activities of the mentally abnormal brains. The results indicate that reductions in cerebral GAD require to be interpreted with caution in view of the sensitivity of this enzyme to premortem status but that reductions in cerebral CAT may be a more reliable index of pathological change in senile (Alzheimer-type) dementia.

Senile dementia of Lewy body type: A clinically and neuropathologically distinct form of Lewy body dementia in the elderly

A dementing syndrome has been identified in a group of psychiatric cases aged 71-90 years, presenting initially with a subacute/acute confusional state, often fluctuating and associated with visual hallucinations and behavioural disturbances. Clinically, these cases did not meet criteria for a diagnosis of Alzheimers disease, and many were assigned to the multiinfarct dementia group, although no significant ischaemic lesions were evident at autopsy. Mild extrapyramidal features were apparent in a number of cases but the characteristic clinical triad of Parkinsons disease, i.e., tremor, rigidity, and akinesia, was absent. Detailed neuropathological examination revealed Lewy body formation and selective neuronal loss in brain stem and other subcortical nuclei, accompanied by Lewy body formation in neo- and limbic cortex, at densities well below those previously reported in diffuse Lewy body disease. A variable degree of senile degenerative change was present; numerous senile plaques and minimal neurofibrillary tangles in most cases. Neither the clinical nor the neuropathological features of this group are typical of Parkinsons or Alzheimers disease, but suggest a distinct neurodegenerative disorder, part of the Lewy body disease spectrum, in which mental symptoms predominate over motor disabilities and lead to eventual psychogeriatric hospital admission. In a sequential series of autopsies conducted on clinically assessed demented patients, neuropathological analysis has indicated that such cases may comprise up to 20% of a hospitalized population of demented old people over the age of 70 years, an observation clearly relevant to the diagnosis and management of dementia in the elderly.

D2 dopamine receptor gene (DRD2) Taq1 A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele.

The relationship between a dopamine D2 receptor genetic polymorphism at the Taq1 A locus and the level of D2 receptor binding was investigated in normal, middle aged to elderly subjects with no psychiatric or neurological disorders. D2 receptor binding was measured by autoradiography in the caudate, putamen and nucleus accumbens, using the specific D2 receptor ligand [3H]-raclopride. In a sample of 44 individuals, only one was homozygous for the A1 allele, 25 were homozygous for A2 and 18 were heterozygotes. The presence of one or two A1 alleles was associated with reduced D2 receptor binding in all areas of the striatum, reaching statistical significance in the ventral caudate and putamen (p = 0.01 and p = 0.044, respectively). This reduction was more marked in males than females, particularly in the putamen. A genetic predisposition to lower D2 receptor expression may increase susceptibility to neuroleptic medication or clinical symptoms that are associated with diseases involving dopaminergic pathology.

Neuroleptic sensitivity in patients with senile dementia of Lewy body type.

OBJECTIVE--To determine the outcome of administration of neuroleptics to patients with senile dementia of Lewy body type confirmed at necropsy. DESIGN--Retrospective analysis of clinical notes blind to neuropathological diagnosis. SETTING--Specialist psychogeriatric assessment units referring cases for necropsy to a teaching hospital neuropathology service. PATIENTS--41 elderly patients with diagnosis of either Alzheimer type dementia (n = 21) or Lewy body type dementia (n = 20) confirmed at necropsy. MAIN OUTCOME MEASURES--Clinical state including extrapyramidal features before and after neuroleptic treatment and survival analysis of patients showing severe neuroleptic sensitivity compared with the remainder in the group. RESULTS--16 (80%) patients with Lewy body type dementia received neuroleptics, 13 (81%) of whom reacted adversely; in seven (54%) the reactions were severe. Survival analysis showed an increased mortality in the year after presentation to psychiatric services compared with patients with mild or no neuroleptic sensitivity (hazard ratio 2.70 (95% confidence interval 2.50-8.99); (chi 2 = 2.68, p = 0.05). By contrast, only one (7%) of 14 patients with Alzheimer type dementia given neuroleptics showed severe neuroleptic sensitivity. CONCLUSIONS--Severe, and often fatal, neuroleptic sensitivity may occur in elderly patients with confusion, dementia, or behavioural disturbance. Its occurrence may indicate senile dementia of Lewy body type and this feature has been included in clinical diagnostic criteria for this type of dementia.

Cholinergic correlates of cognitive impairment in Parkinson's disease: comparisons with Alzheimer's disease.

Dementia in Parkinsons disease has previously been attributed to the presence in the cerebral cortex of Alzheimer-type neuropathological abnormalities. New evidence suggests, however, that dementia in this disease usually occurs in the absence of substantial Alzheimer-type changes in the cortex and may be related to abnormalities in the cortical cholinergic system. Thus, in Parkinsonian patients with dementia there were extensive reductions of choline acetyltransferase and less extensive reductions of acetylcholinesterase in all four cortical lobes. Choline acetyltransferase reductions in temporal neocortex correlated with the degree of mental impairment assessed by a test of memory and information but not with the extent of plaque or tangle formation. In Parkinsons but not Alzheimers disease the decrease in neocortical (particularly temporal) choline acetyltransferase correlated with the number of neurons in the nucleus of Meynert suggesting that primary degeneration of these cholinergic neurons may be related, directly or indirectly, to declining cognitive function in Parkinsons disease.

A harmonized classification system for FTLD-TDP pathology

In 2006, two papers were published, each describing pathological heterogeneity in cases of frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) [7, 11]. In both studies, large series of cases were evaluated and the investigators felt that they could recognize three distinct histological patterns, based on the morphology and anatomical distribution of ubiquitin immunoreactive neuronal inclusions. The findings of Sampathu et al. were further supported by differential labelling of the pathology, using a panel of novel monoclonal antibodies; whereas, Mackenzie et al. found relatively specific clinicopathological correlations. Most importantly, the pathological features that defined the subtypes in these two studies were almost identical, providing powerful validation of the results. However, because the studies were conducted simultaneously and independently, the numbering of the subtypes, used in the respective papers, did not match (Table 1). Table 1 Proposed new classification system for FTLD-TDP pathology, compared with existing systems Shortly thereafter, further work by one of the two groups led to the identification of the transactive response DNA-binding protein with Mr 43 kD (TDP-43) as the ubiquitinated pathological protein in most cases of FTLD-U as well as the majority of sporadic amyotrophic lateral sclerosis (ALS) and some familial ALS [10]. It was subsequently confirmed that most FTLD-U cases had TDP-43 pathology and that the same pathological patterns could be recognized based on the results of TDP-43 immunohistochemistry (IHC) [1, 2]. By this time, a fourth FTLD-U subtype had been described, specifically associated with the familial syndrome of inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) caused by mutations in the valosin-containing protein (VCP) gene [4], and this was also shown to have TDP-43 pathology [9]. As a result, cases of FTLD with TDP-43 pathology are now designated as FTLD-TDP and the term FTLD-U is no longer recommended [8]. The two classification systems for FTLD-U/FTLD-TDP have now gained wide acceptance and have repeatedly been validated by the discovery of additional clinical, genetic and pathological correlations. However, the continued use of two discordant numbering systems proves to be an ongoing source of confusion within the field. Previous attempts, by other groups of authors, to promote one classification over the other have not been successful. To resolve this issue, the principal authors of the original two papers are now proposing a new classification for FTLD-TDP pathology, the sole purpose of which is to provide a single harmonized system that replaces the two currently in use. In developing this new classification, the following principles were adhered to: (1) different pathological subtypes are designated by letters to help distinguish this from the pre-existing number-based systems, (2) the order of subtypes should not exactly match either of the previous systems to avoid any apparent bias, and (3) the order of the subtypes should be based on their relative frequency, with “A” being the most common. The result is summarized in Table 1. Type A is equivalent to type 1 of Mackenzie et al. and type 3 of Sampathu et al., being characterized by numerous short dystrophic neurites (DN) and crescentic or oval neuronal cytoplasmic inclusions (NCI), concentrated primarily in neocortical layer 2. Moderate numbers of lentiform neuronal intranuclear inclusions (NII) are also a common but inconsistent feature of this subtype. Type B matches Mackenzie et al. type 3 and Sampathu et al. type 2, with moderate numbers of NCI, throughout all cortical layers, but very few DN. Type C is the same as Mackenzie et al. type 2 and Sampathu et al. type 1, having a predominance of elongated DN in upper cortical layers, with very few NCI. Finally, Type D refers to the pathology associated with IBMPFD caused by VCP mutations, characterized by numerous short DN and frequent lentiform NII. Based on the results of more recent studies, there are a number of other modifications that we could have considered incorporating into this new system. Additional pathological subtypes could be added; for instance, to describe the TDP-43 pathology that is found in the mesial temporal lobe in a high proportion of cases of Alzheimer’s disease and most other common neurodegenerative conditions [3]. The pathological criteria for each of the subtypes could be expanded to include characteristic findings in subcortical regions [5, 6]. The description of the pathological features could be modified to take into account the greater sensitivity and specificity of TDP-43 IHC, which may demonstrate additional findings, not recognized with the ubiquitin immunostaining techniques upon which the original classifications were based (such as neuronal “pre-inclusions”) [2]. Although these and other recent findings represent important advances in our understanding of FTLD-TDP, most have not yet been broadly replicated or completely defined. Therefore, in order to make the transition to a new classification as simple and widely acceptable as possible and, most importantly, to allow for direct translation with the currently existing systems, we are not proposing any other significant changes, beyond the coding of the subtypes. In summary, we believed that adoption of a single harmonized system for the classification of FTLD-TDP neuropathology would greatly improve communication within the rapidly advancing field of FTLD diagnosis and research. Future attempts to resolve any outstanding issues related to the practical implementation and interpretation of FTLD pathological classification should also benefit. As indicated by their inclusion as co-authors on this paper, this proposal has received the unanimous support of all of the neuropathologists involved in the original two studies [7, 11].