CYP2D6 is associated with Parkinson's disease but not with dementia with Lewy Bodies or Alzheimer's disease.

The similarities between the clinical and pathological findings of dementia with Lewy Bodies (DLB) with Alzheimer's disease and Parkinson's disease are complex, and their significance for pathogenesis is unresolved. It is likely that DLB shares common disease determinants with both Alzheimer's disease and Parkinson's disease. Clinically DLB shows the presence of dementia similar, though not identical, to that found in Alzheimer's disease. A parkinsonian movement disorder is present in a proportion of DLB cases. Pathologically DLB shows senile plaques, as with Alzheimer's disease, and also substantia nigra neurone loss and Lewy bodies, as with Parkinson's disease. At a genetic level, DLB shows an elevated Apolipoprotein E epsilon4 frequency as described in Alzheimer's disease, but this is absent in Parkinson's disease. An elevated frequency of the CYP2D6*4 allele has been found in Parkinson's disease and we have therefore genotyped a large series of clinically and neuropathologically confirmed cases of DLB, Alzheimer's disease, Parkinson's disease and age-matched control individuals for the CYP2D6*4 allele. Whilst an elevated frequency of the CYP2D6*4 allele was found in Parkinson's disease, no such elevations were found in DLB or Alzheimer's disease. Stratification of the CYP2D6*4 allele with respect to the Apolipoprotein E epsilon4 also did not show any significant associations with the CYP2D6*4 allele. The CYP2D6*4 allele is not a major genetic determinant of DLB and the results place DLB with Alzheimer's disease rather than Parkinson's disease on a genetic level.

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.

Cortical concentrations of corticotropin-releasing hormone and its receptor in Alzheimer type dementia and major depression.

Corticotropin-releasing hormone-immunoreactivity (CRH-IR) and CRH receptors (binding capacity and affinity) were measured in postmortem cortical areas from depressed subjects, two groups of senile dementia of the Alzheimer type (SDAT), and age-, sex-, and postmortem-delay-matched controls. No difference in CRH-IR and CRH receptor status between depressed subjects and controls was noted. CRH-IR was decreased in all cortical areas in SDAT, with a corresponding increase in CRH receptor binding capacity (with no change in affinity) in occipital cortex. No effects of postmortem delay were seen. It is suggested that the increase in CRH receptor numbers in SDAT is related to the degree of distribution of pathological involvement in specific regions.

Cortisol, ACTH, and dexamethasone concentrations in a psychogeriatric population.

Cortisol and adrenocorticotrophic hormone (ACTH) were measured at 2 time points before the administration of 1 mg of dexamethasone (day 1) and 1 time point on the following day (day 2). Thirteen severely depressed elderly patients, 15 patients with Alzheimer-type dementia (ATD), and 16 normal controls were studied. Cortisol was markedly elevated in depressed patients compared with the other subjects in day 1 samples. Following dexamethasone, both the depressed and ATD patients showed a similar elevation of cortisol compared with controls. ACTH concentrations were not significantly different between the groups before dexamethasone, but were significantly higher in both depressed and ATD patients after dexamethasone. More depressed patients than ATD patients exhibited hypersecretion of ACTH after dexamethasone. This implies that ACTH is less responsive to glucocorticoid feedback in elderly depressed patients, which may be a factor in causing hypercortisolemia.

Neocortical concentrations of neuropeptides in senile dementia of the Alzheimer and Lewy body type: comparison with Parkinson's disease and severity correlations.

Corticotropin releasing hormone (CRH), somatostatin (SRIF), and arginine vasopressin (AVP) concentrations were estimated using radioimmunoassay in the temporal and occipital cortices in postmortem brain from patients clinically and neuropathologically diagnosed as senile dementia of the Lewy body type (SDLT), senile dementia of the Alzheimer type (SDAT), and Parkinson's disease (PD) and from neurologically normal controls. The concentration of temporal and occipital neocortical CRH was diminished in both SDAT and SDLT compared to control values, whereas SRIF was reduced only in temporal cortex in both these conditions. In contrast, the concentrations of both CRH and SRIF were unaltered in PD. The concentrations of AVP in SDLT, SDAT, and PD were similar to those found in the control groups. The decrement in SRIF, but not CRH, was found to be correlated with some indices of severity of illness in SDAT; a similar but nonsignificant trend for SRIF was observed in SDLT.

An evaluation of the predictive validity and inter-rater reliability of clinical diagnostic criteria for senile dementia of Lewy body type.

Several recent autopsy studies suggest that senile dementia of Lewy body type (SDLT) may be the second most common neuropathologic cause of dementia in the elderly, accounting for 7 to 30% of all cases. Operational criteria for the antemortem clinical diagnosis of SDLT have already been proposed by our group. The performance of these is now examined by randomizing the case notes from a new series of SDLT, Alzheimer, and multi-infarct dementia patients for psychiatric assessment by four raters of varying clinical experience and blind to pathologic diagnosis. Using the SDLT criteria, the two most experienced raters agreed in 94% of cases (kappa = 0.87), with the least experienced rater agreeing in 78% (kappa = 0.50). Diagnostic specificity for SDLT was uniformly high (90.0 to 97.0%), with a mean sensitivity of detection of 74%, and was greater by the experienced (90.0%) than the least experienced (55%) clinician. The antemortem identification of SDLT patients can therefore be achieved with a high degree of diagnostic specificity using such operationalized criteria, although there remains a minority of patients who present with either "typical" Alzheimer-type symptoms or with paranoid or delusional symptoms in the absence of substantial cognitive impairment. Sensitivity to neuroleptics may be a useful diagnostic pointer in these patients.

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.

Amnesia and memory for modality information.

In this study, lists of words were used in a mixed-modality fashion (some read aloud by the subject, others read only by the experimenter). They were presented in this format to both Korsakoff amnesics and matched controls, with subjects only told to remember the words themselves. Controls and amnesics were matched on item-memory (forced-choice recognition) by using longer lists, tested at longer delays, for the controls. Despite this, however, the controls performed significantly better than the amnesics at modality-identification judgements about the items chosen during recognition. Whether the reported result reflects the memory deficit which causes amnesia, or whether it is more properly attributed to additional (frontal lobe) pathology present in only certain amnesics, is discussed.

The performance of amnesic subjects on tests of experimental amnesia in animals: delayed matching-to-sample and concurrent learning.

A group of amnesic Korsakoff subjects and a group of alcoholic controls were trained on a test of visual recognition, delayed matching-to-sample with trial unique stimuli. This test was modelled on comparable tasks used in the development of animal models of human amnesia. It was found that the Korsakoff subjects were severely impaired when the task difficulty was increased by lengthening the retention delay beyond 10 sec or by increasing the number of items intervening between sample presentation and test. The amnesic subjects were also impaired on the acquisition of a set of concurrent visual discriminations. These results bear clear similarities to those obtained from experimental amnesic syndromes in monkeys.

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 Parkinson's 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 Parkinson's 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 Alzheimer's 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 Alzheimer's disease but not Lewy body dementia. In temporal neocortex there were reductions in Alzheimer's 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 Parkinson's disease and Lewy body dementia, amyloid plaques and tangles in subicular and entorhinal areas in Alzheimer's disease. Loss or down-regulation of the receptor may precede neurodegeneration.

Guanine nucleotide modulation of muscarinic cholinergic receptor binding in postmortem human brain--a preliminary study in Alzheimer's disease.

The coupling of cortical muscarinic receptors to guanosine triphosphate (GTP) binding proteins, as defined by changes in agonist affinity states of the receptor in the presence of magnesium ions (Mg2+) and a GTP analogue has been investigated using carbachol in competition experiments with either N-methylscopolamine (NMS) or pirenzepine (PZ). The stability of the system with regard to autopsy delay and freezing was first established in membrane preparations from mouse brain. Applying the same methods to human autopsy tissue from the parietal cortex of Alzheimer's diseased cases and controls, matched for age and postmortem delay, there was no significant difference in the detectable coupling of the total (NMS-labelled) muscarinic receptor population. However, coupling of the 'M1' muscarinic receptor subtype, selectively labelled by PZ, appeared to be more labile than that of the receptor population as a whole and the modulation of this subtype by the GTP analogue was significantly attenuated in Alzheimer's disease.

Extensive loss of choline acetyltransferase activity is not reflected by neuronal loss in the nucleus of Meynert in Alzheimer's disease.

Choline acetyltransferase activity in discrete tissue punches from the nucleus of Meynert and in tissue from the temporal cortex was reduced by at least 90% and 75%, respectively, in 5 out of 6 elderly cases of Alzheimer's disease compared with 5 normal cases. In contrast, estimates of neurone density in these same cases revealed that there was only, on average, a 33% neurone loss in the nucleus of Meynert in Alzheimer's disease. These observations suggest that a key pathological change in Alzheimer's disease may be the 'down regulation' of transmitter-specific enzyme production in cholinergic neurones, and that neurone loss itself may be a secondary feature of the disease.

Cortical serotonin-S2 receptor binding abnormalities in patients with Alzheimer's disease: comparisons with Parkinson's disease.

Reductions in the numbers of binding sites for the serotonergic S2-receptor antagonist, ketanserin, are, as previously reported, evident in Alzheimer's disease. New findings indicate that these sites are not affected in the cortex of patients with Parkinson's disease despite the presence of cognitive impairment. In contrast S1-receptor binding sites were reduced to a small but significant extent in both Alzheimer's and Parkinson's disease with cognitive deficit. The S2-receptor binding loss was not related to the cholinergic deficit (decreased choline acetyltransferase) common to both disorders nor to the presence of cortical senile plaques but did relate to the extent of cortical neurofibrillary tangle formation, evident in Alzheimer's but not generally in Parkinson's disease. These observations suggest that S2- but not S1-receptor binding abnormalities may reflect an important intrinsic cortical involvement specifically associated with the Alzheimer disease process.

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 Parkinson's 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 Parkinson's disease. These observations, together with major differences in the neuropathology of the nucleus in SDAT and Parkinson's disease (neurofibrillary tangle and Lewy body formation, respectively) suggest that the involvement of the cholinergic system may differ in the two disease processes.

Korsakoff amnesics are poor at judging the sequence of two tones.

Alcoholic amnesics were given a test of temporal sequencing ability devised by Efron which has practically no memory component. These amnesics were very impaired on the task. However, the extent of this impairment did not relate to the magnitude of their "target memory" deficit nor did it relate to the ability to make temporal judgements from memory. Two other groups of amnesics (3 post-encephalitis and 4 with ruptured aneurysms of the anterior communicating artery) did not show impairments on the sequencing task. Data from the amnesic patient N.A. (who was unimpaired on the task), three other amnesics (who showed a tendency to be poor at the task) and two frontally damaged patients (one of whom performed especially badly on the sequencing task but had no obvious memory difficulties) were also presented. It is argued that deficits in temporal discrimination may not be found in all amnesics but, when they are observed, are an incidental feature related to additional (possibly cortical damage. Implications of the results for the view that amnesia results from a deficit in the use of contextual information (including temporal information) are considered.

Studies on the serotonin uptake binding site in major depressive disorder and control post-mortem brain: neurochemical and clinical correlates.

Serotonin (5-hydroxytryptamine; 5HT) uptake sites have been measured using the selective high affinity uptake inhibitor 3H-citalopram in post-mortem frontal cortex from depressed and matched control subjects. The lateralization of these sites was assessed in neurologically normal brain. A lower concentration of 3H-citalopram binding was found in brains from depressed subjects. A nonsignificant trend toward a greater attenuation of 5HT uptake sites was observed in brains of bipolar cases in the depressed state. No effect of antidepressant treatment or of the age at onset of illness was noted. No difference in the binding capacity of the 5HT uptake site was noted between hemispheres of normal brains.

The clinical diagnosis and misdiagnosis of senile dementia of Lewy body type (SDLT).

BACKGROUND: Current clinical classifications do not contain specific diagnostic categories for patients with senile dementia of the Lewy body type (SDLT), recently proposed as the second commonest neuropathological cause of dementia in the elderly. This study determines how existing clinical diagnosis systems label SDLT patients and suggests how such patients may be identified. METHOD: A range of clinical diagnostic criteria for dementia were applied to case notes of autopsy-confirmed SDLT (n = 20), dementia of Alzheimer type (DAT; n = 21) and multi-infarct dementia (MID; n = 9) patients who had received psychogeriatric assessment. The predictive validity of each set of clinical criteria was calculated against the external criterion of neuropathological diagnosis. RESULTS: Many SDLT patients erroneously met criteria for MID (35% with Hachinski scores > or = 7) or for DAT (15% by NINCDS 'probable AD', 35% by DSM-III-R DAT and 50% by NINCDS 'possible AD'). Up to 85% of SDLT cases could be correctly identified using recently published specific criteria. CONCLUSIONS: SDLT usually has a discernible clinical syndrome and existing clinical classifications may need revision to diagnose correctly such patients.