Depression in late life, cognitive decline and white matter pathology in two clinico-pathologically investigated cases.

CASE REPORTS: We report two cases of late life depression who became progressively more resistant to treatment, developed cognitive impairment, and began to exhibit neurological abnormalities and evidence of vascular disease. A discussion of the clinical features of the cases is accompanied by reports of neuropathology and neuroimaging findings. Extensive white matter lesions were present on computed tomography in both patients, and basal ganglia infarcts were seen in one. Neuropathology revealed evidence of cerebral atrophy, demyelination and white matter lesions in addition to cerebrovascular and generalised vascular disease. Neither patient exhibited Alzheimer pathology outwith the norm for their age. We believe this to be the first report of neuropathological findings in depression with white matter changes. LITERATURE REVIEW: The pathological basis of white matter lesions and their relationship to depression, its age of onset and clinical features is addressed in relation to the cases described. Pathological investigation of white matter lesions has not previously been carried out in depression and hypotheses regarding their nature in this illness are based on extrapolation from research in a variety of other disorders. The association of depression with vascular risk factors is considered, as is the relationship between depression and cognitive deficits. There is a need for further investigation in this area.

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.

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.

EEG findings in dementia with Lewy bodies and Alzheimer's disease.

OBJECTIVES: To evaluate the role of the EEG in the diagnosis of dementia with Lewy bodies (DLB). METHODS: Standard EEG recordings from 14 patients with DLB confirmed at postmortem were examined and were compared with the records from 11 patients with Alzheimer's disease confirmed at postmortem RESULTS: Seventeen of the total of 19 records from the patients with DLB were abnormal. Thirteen showed loss of alpha activity as the dominant rhythm and half had slow wave transient activity in the temporal lobe areas. This slow wave transient activity correlated with a clinical history of loss of consciousness. The patients with Alzheimer's disease were less likely to show transient slow waves and tended to have less marked slowing of dominant rhythm. CONCLUSIONS: The greater slowing of the EEG in DLB than in Alzheimer's disease may be related to a greater loss of choline acetyltransferase found in DLB. Temporal slow wave transients may be a useful diagnostic feature in DLB and may help to explain the transient disturbance of consciousness which is characteristic of the disorder.

Do experienced diagnosticians agree about the diagnosis of dementia from survey data? The effects of informants' reports and interviewers' vignettes.

Dementia in community settings is often diagnosed by computerized algorithms. This study examines the extent to which independent diagnosticians agreed among themselves in diagnosing dementia, severity and type when presented with data obtained during a population-based incidence study of cognitive decline and dementia. Secondly, it examines how judgements, based initially on respondents' self-reports and cognitive performance, were affected first by informants' reports and then by short case-vignettes written by trained lay interviewers. Thirdly, it compares diagnosticians' diagnosis of dementia with the algorithmic diagnosis (AGECAT). The items presented were selected from two screening interviews at wave 1 and wave 2 separated by an interval of 2 years and from wave 2 assessment and informant interviews, and included medical, psychiatric and ADL items and interviewers' own observations. The sample (N = 42) was derived from the first year of the wave 2 assessments, potential dementia cases entering consecutively while presumed normals were selected randomly. Informants were available in 30. Agreement on diagnosis and type of dementia improved with increasing information, particularly from informants, but remained poor regarding severity. The number of cases of dementia, defined operationally, increased from 10 to 12 and uncertain cases fell from eight to six, but no respondent initially diagnosed as a dementia case was rediagnosed as a non-case, or vice versa. Dementia type changed from agreement about Alzheimer's disease to agreement about vascular dementia in one case. Operational and algorithmic diagnoses showed good agreement. Causes of disagreement, the role of vignettes and the relevance of the results for population surveys are discussed.

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.

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.

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.

Monoaminergic activities in Lewy body dementia: relation to hallucinosis and extrapyramidal features.

Serotonergic (5-HT) and dopaminergic activities have been examined in Lewy Body Dementia (LBD) and compared with Parkinson's disease (PD) and Alzheimer's disease (AD). In the neocortex the LBD subgroup experiencing hallucinations was distinguished from the other categories by an increase in the 5HIAA:5HT ratio measured in frontal cortex and by the serotonergic (5-HIAA or 5-HIAA:5-HT): cholinergic (choline acetyltransferase) ratio in frontal and temporal cortex. In the neostriatum (caudate nucleus), loss of dopamine and increased HVA:dopamine ratio correlated with the reduction in substantia nigra neurons in LBD but not PD, despite the greater loss of neurones and dopamine and the higher dopamine turnover ratio in PD. LBD patients experiencing severe Parkinsonism as a result of neuroleptic treatment tended to have lower neuron counts, in combination with higher turnover ratios, than the remainder. Qualitative differences between LBD and PD included decreased cortical 5-HT turnover in PD compared with the increase in LBD. There were no significant changes in any parameter in AD, with the exception of a reduction in temporal cortex 5HIAA. The results suggest that although the neurochemical pathology of LBD and PD involves similar systems, the nature of the derangements differs sufficiently between the diseases to account for differences in symptomatology.

Cholinergic transmitter and neurotrophic activities in Lewy body dementia: similarity to Parkinson's and distinction from Alzheimer disease.

Senile dementia of Lewy body type or Lewy body dementia (LBD), characterized neuropathologically by the presence of Lewy bodies in the brainstem and cortex, and in most cases neocortical senile plaques (but few or no tangles), bears a closer resemblance to Parkinson's (PD) than to Alzheimer disease (AD) in its cholinergic neurochemical pathology. Thus, reductions in the biochemical activity of choline acetyltransferase were generally more extensive in neo- as opposed to archicortical regions in LBD (especially hallucinating cases) and in PD, whereas muscarinic receptor binding was significantly increased in LBD and PD but not in AD. Nerve growth factor receptor (P75) assessed immunocytochemically in the archicortex were decreased in PD and, to a lesser extent, in LBD in conjunction with reductions of neuronal numbers in the nucleus of Meynert (Ch4), but were relatively spared in AD. These observations indicate that although AD is primarily associated with dysfunction of cholinergic axonal input to the cortex, LBD and PD are more likely to involve degeneration of the basal forebrain cholinergic system. Relevance of the findings in terms of aetiopathology and cholinergic treatment strategies is discussed.

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 Alzheimer's 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.

Gastrointestinal absorption of aluminium in Alzheimer's disease: response to aluminium citrate.

Alzheimer's disease (AD) has been linked to genetic defects on chromosome 21 in some families, but most elderly cases appear to be sporadic and may, at least in part, involve environmental risk factors. Several lines of evidence suggest that aluminium may be involved in the aetiology of AD. However, despite universal exposure to aluminium in the diet, only some people develop the disease. We have developed a test of aluminium absorption using an aluminium citrate drink, to examine the hypothesis that sufferers from AD show increased aluminium absorption. In a younger group of AD patients aluminium absorption was significantly raised compared with age-matched controls. Aluminium absorption increased with age in the control group but was not significantly raised in older AD patients when compared with age-matched controls.

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.

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.

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.

Reduced gastrointestinal absorption of calcium in dementia.

Several reports have suggested that the neurodegenerative change in Alzheimer-type dementia (ATD) may be related to alterations in calcium homoeostasis. The absorption of radiocalcium (45Ca) in 26 ATD subjects and 11 patients with multi-infarct dementia (MID) was compared to 24 normal age- and sex-matched controls. The absorption of radiocalcium was significantly lower in both ATD and MID when compared to controls. The reduced 45Ca absorption in ATD occurred in the presence of normal plasma concentrations of PTH and vitamin D metabolites and the serum concentrations of calcium and aluminium were in the normal range. The data suggest that the reduced uptake of radioactive calcium observed in ATD is a non-specific derangement.

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.

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.

Cholinergic and dopaminergic activities in senile dementia of Lewy body type.

Analyses of brain tissue in a recently identified group of elderly demented patients suggest a neurochemical basis for some of the clinical features. Senile dementia of the Lewy body type (SDLT) can be distinguished from classical Alzheimer disease (AD) clinically by its acute presentation with confusion frequently accompanied by visual hallucinations, and neuropathologically by the presence of Lewy bodies and senile plaques (but not generally neurofibrillary tangles) in the cerebral cortex. Reductions in the cortical cholinergic enzyme choline acetyltransferase were more pronounced in individuals with (80%) compared to those without (50%) hallucinations and correlated strongly with mental test scores in the group as a whole. In the caudate nucleus, dopamine levels were related to the number of neurons in the substantia nigra, there being a 40-60% loss of both in SDLT--probably accounting for mild extrapyramidal features in some of these cases--compared with an 80% loss in Parkinson disease and no change in AD. The cholinergic correlates of mental impairment in SDLT together with the relative absence of cortical neurofibrillary tangles and evidence for postsynaptic cholinergic receptor compensation raise the question of whether this type of dementia may be more amenable to cholinotherapy than classical AD.