Andrew Fairbairn

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.

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.

Prospective validation of Consensus criteria for the diagnosis of dementia with Lewy bodies

Objective: To determine the validity of a clinical diagnosis of probable or possible dementia with Lewy bodies (DLB) made using International Consensus criteria. Background: Validation studies based on retrospective chart reviews of autopsy-confirmed cases have suggested that diagnostic specificity for DLB is acceptable but case detection rates as low as 0.22 have been suggested. Methods: We evaluated the first 50 cases reaching neuropathologic autopsy in a cohort to which Consensus clinical diagnostic criteria for DLB, National Institute for Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for AD, and National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences criteria for vascular dementia (VaD) had been prospectively applied. Results: Twenty-six clinical diagnoses of DLB, 19 of AD, and 5 of VaD were made. At autopsy, 29 DLB cases, 15 AD, 5 VaD, and 1 progressive supranuclear palsy were identified. The sensitivity and specificity of a clinical diagnosis of probable DLB in this sample were 0.83 and 0.95. Of the five cases receiving a false-negative diagnosis of DLB, significant fluctuation was present in four but visual hallucinations and spontaneous motor features of parkinsonism were generally absent. Thirty-one percent of the DLB cases had additional vascular pathology and in two cases this contributed to a misdiagnosis of VaD. No correlations were found between the distribution of Lewy bodies and clinical features. Conclusion: The Consensus criteria for DLB performed as well in this prospective study as those for AD and VaD, with a diagnostic sensitivity substantially higher than that reported by previous retrospective studies. DLB occurs in the absence of extrapyramidal features and in the presence of comorbid cerebrovascular disease. Fluctuation is an important diagnostic indicator, reliable measures of which need to be developed further.

Pathological changes in the nucleus of meynert in Alzheimer's and Parkinson's diseases ☆

Combined neuropathological and neurochemical assessment of the nucleus of Meynert in senile dementia of Alzheimer type (SDAT) have demonstrated that the cholinergic biochemical activity, choline acetyltransferase, is more extensively reduced in the nucleus (over 90%) than the loss of putative cholinergic perikarya (35%). Acetylcholinesterase histochemical activity was however substantially retained in individual neurones in the nucleus although virtually absent from the neocortex in SDAT. These abnormalities are consistent with a primary degeneration of cholinergic axons projecting to the cortex and secondary loss of perikarya from the subcortical nucleus. In contrast, preliminary observations on cases of Parkinsons disease suggest that the neuronal loss from the nucleus of Meynert may be greater in this disease than in SDAT, and previous studies have not consistently demonstrated a reduction in cortical choline acetyltransferase activities in Parkinsons disease. These observations, together with major differences in the neuropathology of the nucleus in SDAT and Parkinsons disease (neurofibrillary tangle and Lewy body formation, respectively) suggest that the involvement of the cholinergic system may differ in the two disease processes.

Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia and Alzheimer's disease: Possible index of early neuropathology

High-affinity nicotine binding, considered to primarily reflect the presence of CNS alpha 4 beta 2 nicotinic receptor subunits, was examined autoradiographically in brain regions most severely affected by Alzheimer and Parkinson types of pathology. In the midbrain, the high density of binding associated with the pars compacta of the substantia nigra was extensively reduced (65-75%, particularly in the lateral portion) in both Lewy body dementia and Parkinsons disease. Since loss of dopaminergic neurons in Lewy body dementia was only moderate (40%), loss or down-regulation of the nicotinic receptor may precede degeneration of dopaminergic neurons in this region. In the dorsolateral tegmentum, where diffuse cholinergic perikarya are located, nicotine binding was highly significantly decreased in both Lewy body dementia and Parkinsons disease with almost no overlap between the normal and disease groups, indicative of a major pathological involvement in or around the pedunculopontine cholinergic neurons. In the hippocampus, binding was decreased around the granular layer in Lewy body dementia and Alzheimers disease, although unchanged in the stratum lacunosum moleculare, where binding was relatively higher. Dense bands of receptor binding in the presubiculum and parahippocampal gyrus--areas of highest binding in human cortex--were diminished in Alzheimers disease but not Lewy body dementia. In temporal neocortex there were reductions in Alzheimers disease throughout the cortical layers but in Lewy body dementia only in lower layers, in which Lewy bodies are concentrated. Abnormalities of the nicotinic receptor in the diseases examined appear to be closely associated with primary histopathological changes: dopaminergic cell loss in Parkinsons disease and Lewy body dementia, amyloid plaques and tangles in subicular and entorhinal areas in Alzheimers disease. Loss or down-regulation of the receptor may precede neurodegeneration.

Operational criteria for senile dementia of Lewy body type (SDLT)

Recent reports have suggested that brain stem and cortical Lewy body formation may identify a neurodegenerative disorder in elderly demented individuals which accounts for up to 20% of cases of senile dementia coming to autopsy. Retrospective analysis of case notes of 21 autopsy patients with neuropathologically proven senile dementia of Lewy body type (SDLT) and 37 cases with neuropathologically proven Alzheimers disease (AD) identified a characteristic clinical syndrome in SDLT. Fluctuating cognitive impairment; psychotic features including visual and auditory hallucinations, and paranoid delusions; depressive symptoms; falling and unexplained losses of consciousness were all seen significantly more often than in AD. Over half of the SDLT patients in this series who were given neuroleptics in standard dose showed acute and often irreversible adverse reactions indicative of a neuroleptic sensitivity syndrome. The survival time of drug treated patients was reduced by 50%. Operational criteria to aid in the clinical distinction between SDLT and AD patients are proposed and hypotheses regarding possible aetiology and treatment discussed.

Prevalence and pharmacological management of behavioural and psychological symptoms amongst dementia sufferers living in care environments

Behavioural and psychological symptoms in dementia (BPSD) are a common reason for placement in long term care and are often associated with indiscriminate prescription of psychotropic medication.

5HT2 receptor changes in major depression

The 5HT2 receptor has been studied using quantitative tritium film autoradiography in the postmortem frontal cortex of 15 cases suffering from major depression and controls, matched for age, gender, postmortem delay, and storage time. In unmedicated depressives there was a significant increase in 5HT2 receptor binding over matched control values. Antidepressant-treated depressives dying while depressed had 5HT2 receptor densities not significantly different from control values. Depressives dying euthymic, (i.e., recovered) showed a marked reduction in 5HT2 receptor binding when compared with controls. A tentative hierarchy of 5HT2 receptors in affective states is proposed.

Molecular forms of acetylcholinesterase in senile dementia of Alzheimer type: Selective loss of the intermediate (10S) form

Using density gradient centrifugation, three molecular forms of acetylcholinesterase have been distinguished in both normal and senile dementia of Alzheimer-type (SDAT) postmortem neocortex. Whilst the levels of the light and heavy forms were unaltered in SDAT there was a selective and extensive loss of the intermediate form. This form is predominantly hydrophobic and its loss from the cerebral cortex in SDAT may reflect degeneration of cholinergic axonal processes. This is the first report of an altered distribution of acetylcholinesterase molecular forms in a disease of the central nervous system.