Neuropathological substrates and structural changes in late-life depression: the impact of vascular burden

A first episode of depression after 65 years of age has long been associated with both severe macrovascular and small microvascular pathology. Among the three more frequent forms of depression in old age, post-stroke depression has been associated with an abrupt damage of cortical circuits involved in monoamine production and mood regulation. Late-onset depression (LOD) in the absence of stroke has been related to lacunes and white matter lesions that invade both the neocortex and subcortical nuclei. Recurrent late-life depression is thought to induce neuronal loss in the hippocampal formation and white matter lesions that affect limbic pathways. Despite an impressive number of magnetic resonance imaging (MRI) studies in this field, the presence of a causal relationship between structural changes in the human brain and LOD is still controversial. The present article provides a critical overview of the contribution of neuropathology in post-stroke, late-onset, and late-life recurrent depression. Recent autopsy findings challenge the role of stroke location in the occurrence of post-stroke depression by pointing to the deleterious effect of subcortical lacunes. Despite the lines of evidences supporting the association between MRI-assessed white matter changes and mood dysregulation, lacunes, periventricular and deep white matter demyelination are all unrelated to the occurrence of LOD. In the same line, neuropathological data show that early-onset depression is not associated with an acceleration of aging-related neurodegenerative changes in the human brain. However, they also provide data in favor of the neurotoxic theory of depression by showing that neuronal loss occurs in the hippocampus of chronically depressed patients. These three paradigms are discussed in the light of the complex relationships between psychosocial determinants and biological vulnerability in affective disorders.     

Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia

Summary The acetylcholine (ACh) and choline (Ch) concentrations in the cerebrospinal fluid were investigated in patients with vascular dementia of the Binswanger type (VDBT) or multiple small infarct type (MSID) as compared with patients with Alzheimer-type dementia (ATD). The ACh concentration in patients with ATD was found to be significantly lower than in controls (73%, p < 0.0001), and showed a significant positive correlation with dementia scale scores (r_s=0.63, p < 0.03). The Ch concentration in the CSF of ATD patients was approximately the same as in controls. In VDBT/MSID patients, the ACh concentration was significantly lower than in controls (p < 0.001), also showing a significant positive correlation with dementia scale scores (r_s=0.62, p < 0.02), but was significantly higher than in ATD patients (p < 0.001). Moreover, the Ch concentration in VDBT/MSID patients was significantly higher than in controls (p < 0.001) or ATD patients (p < 0.001). These results suggest that simultaneous determination of ACh and Ch concentrations in CSF may be useful for differentiating VDBT/MSID from ATD and that increasing the ACh level using cholinergic agents may be a beneficial therapeutic strategy for the treatment of ATD as well as VDBT/MSIT, and is worthy of further investigation.     

Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies

OBJECTIVE: This investigation was undertaken to clarify the neuropathological substrates of key psychiatric symptoms in dementia with Lewy bodies. METHOD: The authors studied 112 autopsy-confirmed cases of dementia with Lewy bodies in patients who had had annual standardized clinical evaluations until their death. The relationships of persistent psychiatric symptoms (visual hallucinations, delusions, depression) to plaques (Consortium to Establish a Registry for Alzheimer's Disease protocol), tangles (Braak staging), and Lewy bodies (consensus Lewy body staging) were evaluated. In addition, symptom frequency and persistent symptoms were compared in the patients with Lewy body dementia and 90 patients with autopsy-confirmed Alzheimer's disease studied prospectively during life. RESULTS: The main neuropathological correlate of persistent visual hallucinations was the presence of less severe tangle pathology, but there was no significant association between tangle pathology and persistent delusions. Lewy body staging was associated with the presence of persistent visual hallucinations and persistent delusions. All baseline psychiatric features were significantly more frequent in dementia with Lewy bodies than in Alzheimer's disease, as were persistent visual hallucinations, but patients who had dementia with Lewy bodies and severe tangle pathology had a clinical symptom profile more similar to that of Alzheimer's disease patients and were less likely to have neocortical Lewy bodies. CONCLUSIONS: The modest proportion of patients with Lewy body dementia and more severe tangle pathology resembled Alzheimer's disease patients clinically. Unlike Alzheimer's disease, dementia with Lewy bodies showed a significant inverse association between tangle burden and psychosis.     

Neuropathological assessment of the lesions of significance in vascular dementia

OBJECTIVES—To better define the neuropathology ofvascular dementia.
METHODS—The neuropathological findings in 18 elderly, undemented subjects free of cerebrovascular disease werecompared with 19 elderly undemented subjects who had cerebrovasculardisease (many of whom had had a "stroke") and 24 elderly dementedsubjects who had cerebrovascular disease, but no other pathology toaccount for dementia. Cases in all groups were selected for absence orno more than very mild Alzheimer type pathology.
RESULTS—Microvascular brain damage in the form ofsevere cribriform change and associated subcortical white matter damageand microinfarction were correlated with a history of dementia. Severecribriform change was much more common and microinfarction somewhatmore common in the demented group with vascular disease than theundemented group with vascular disease (P=0.0006 and P=0.031respectively). Other findings of note were that congophilic angiopathyhad a greater prevalence in the vascular dementia group than thecontrol group, single cerebral infarcts were more common in the group who were undemented with vascular disease than in the group with dementia and vascular disease (P=0.0028), and the last group lacked evidence of macroscopic infarction more often than the first (P=0.034). There was a non-significant trend for the ratio ofinfarcted:uninfarcted tissue in one cerebral hemisphere to be higher inthe group with dementia and vascular disease than in the group withvascular disease but no dementia.
CONCLUSIONS—Microvascular disease, not macroscopicinfarction, was the chief substrate of vascular dementia in this seriesof cases.

     

Neuropeptides in psychiatric diseases: an overview with a particular focus on depression and anxiety disorders

This paper aimed at reviewing the involvement of neuropeptides in various psychiatric diseases, particularly in depression, and anxiety disorders. General features of neuropeptides are first described, including the history of their discovery, their definition, classification, biosynthesis, transport, release, inactivation, as well as their interaction with specific neuronal receptors. The differences with classical neurotransmitters are mentioned, as well as the different patterns of co-transmission. Finally, different mechanisms, both at the cellular and at the systemic level, are proposed that may explain the involvement of these molecules in various psychiatric diseases. Indeed, at the cellular level, a neuropeptide can be involved in a psychiatric disease, either because it is co-localized with a classical neurotransmitter involved in a disease, or because the neuropeptide-containing neuron projects on a target neuron involved in the disease. At the systemic level, a neuropeptide can play a direct role in the expression of a symptom of the disease. This is illustrated by different examples.     

Caudate nucleus volumes in stroke and vascular dementia

We aimed to assess the volume of the nucleus caudatus as a neuroanatomical substrate of fronto-subcortical circuits, in stroke patients with/without dementia, and the relationship to potential determinants of neural circuit integrity such as white matter hyperintensities (WMH) and stroke volume. Stroke only (Stroke) (n = 19) and stroke with Vascular Dementia (VaD) (n = 16) and healthy control (n = 20) subjects, matched on demographic variables, underwent extensive neuropsychiatric assessments and manual MRI-based volumetric measurements for intracranial area (ICA), stroke volume, and bilateral caudate volume. WMH on MRI were quantified using an automated algorithm. Multivariate analysis of covariance (controlling for age and ICA), revealed that across the three groups, caudate volumes were significantly different. There was a significant difference in bilateral caudate nucleus volume between subjects by diagnosis (Stroke, VaD, control). The control group was largest in overall mean volume of the diagnostic groups, followed by the Stroke group (86% of controls), and finally, the VaD group (72%). There was a partial correlation between total caudate volume and the total volume of deep WMH including periventricular regions and brainstem, controlling for ICA; and for total stroke volume. Stroke patients with VaD have smaller caudate nuclei compared to those without dementia and healthy controls, with the stroke-only patients being intermediate in their caudate volume status. There was preliminary evidence of negative correlation of caudate volume with volume of deep WMH and total stroke volume, suggesting cerebrovascular disease contributes to caudate atrophy,which, in turn may disrupt fronto-subcortical circuits.     

Medial temporal lobe width on CT scanning in Alzheimer's disease: comparison with vascular dementia, depression and dementia with Lewy bodies

A simple linear measurement of the minimum width of the medial temporal lobe (MTL) on angled CT scans has been suggested as an accurate ante-mortem marker for Alzheimer's disease (AD). To determine the clinical utility and specificity of this finding, we performed angled CT scans with 5-mm slices in 116 subjects referred to a geographically based Old Age Psychiatry service in Newcastle. Diagnoses were of NINCDS/ADRDA AD (n = 69, 36 probable and 33 possible). NINDS/AIREN vascular dementia (VaD, n = 25), consensus criteria for dementia with Lewy bodies (DLB, n = 9) and DSM-IV criteria for major depression (n = 13). Subjects were well matched for age. Minimum MTL width was significantly greater in depressed subjects (13.7 mm) compared to those with dementia, though no differences were seen within the dementia groups (AD 10.8, VaD 10.4, and DLB 10.9 mm). An MTL width below 11.5 mm had a sensitivity of 54% (56/103) and a specificity of 77% (10/13) for distinguishing dementia from depression. We conclude that a single cross-sectional measurement of MTL width on CT does not help differentiate between different types of dementia, though it may provide some supportive evidence when distinguishing depression from dementia.     

阿尔茨海默病和血管性痴呆的颅脑核磁共振定量研究

目的测量阿尔茨海默病（AD）、血管性痴呆（VD）患者颅脑MRI片上的海马结构（HF）、胼胝体（CC）、侧脑室（LV）、外侧裂（SL）、白质疏松（LA）体积，建立判别函数，进行判别分析，提高区分AD组、VD组与老年健康对照组（NC）间的准确性。方法应用GE Signa 1．5T超导磁共振成像系统，对AD组、VD组、NC组各20例进行颅脑扫描，根据体视学的卡瓦列里原理，构建测试网格，对HF、CC、LV、SL、LA体积进行测量，建立判别函数，进行判别分析。结果AD组、VD组HF、CC体积均显著小于NC组，LV、SL、LA体积显著大于NC组；AD组的HF、LA体积均显著小于VD组。Fisher判别函数示判别总符合率为83.3％，AD组为95％，VD组为75％，NC组为80％。结论测量颅脑MRI的HF、CC、LV、SL、LA体积，建立判别函数，对AD、VD患者的临床诊断及鉴别诊断可能有一定的指导意义。     

Cognitive profiles in degenerative dementia without evidence of small vessel pathology and small vessel vascular dementia

Although a large number of studies have examined possible differences in cognitive performance between Alzheimer’s disease (AD) and vascular dementia (VaD), the data in the literature are conflicting. The aims of this study were to analyze the neuropsychological pattern of subjects affected by degenerative dementia without evidence of small vessel pathology (DD) and small vessel VaD subjects in the early stages and to investigate differences in the progression of cognitive impairment. Seventy-five patients with probable VaD and 75 patients with probable DD were included. All the subjects underwent a standard neuropsychological evaluation, including the following test: Visual Search, Attentional matrices, Story Recall, Raven’s Coloured Progressive Matrices, Phonological and Semantic Verbal Fluency, Token, and Copying Drawings. The severity of cognitive impairment was stratified according to the MMSE score. Fifteen subjects with probable DD and 10 subjects with probable VaD underwent a 12-month cognitive re-evaluation. No significant difference was found between DD and VaD subjects in any of the neuropsychological tests except Story Recall in the mild cognitive impairment (P < 0.001). The re-test value was significantly worse than the baseline value in the MMSE (P = 0.037), Corsi (P = 0.041), Story Recall (P = 0.032), Phonological Verbal Fluency (P = 0.02), and Copying Drawings (P = 0.043) in DD patients and in the Visual Search test (P = 0.036) in VaD subjects. These results suggest that a neuropsychological evaluation might help to differentiate degenerative dementia without evidence of small vessel pathology from small vessel VaD in the early stages of these diseases.     

Experiences with depression in a dementia clinic

Of 317 consecutive cases seen in a dementia clinic, 19 (6%) had little or no objective evidence of cognitive impairment on clinical examination and extensive neuropsychological testing. Of the remaining 298 cases, 192 (64%) were diagnosed as probable or possible Alzheimer's disease (AD). Of the 19 nondemented cases, 8 (42%) were thought to have cognitive difficulty due to depression. In the AD group, only 4 cases (2%) were thought to be depressed and only 2 of the 4 met DSM-III-R criteria for major depression. There was no relationship between Hamilton Rating Scale for Depression scores and either cognitive or behavioral measurements of dementia severity, suggesting that the difference between the two groups was not due to underreporting by AD patients. The authors concluded that a tertiary care setting, depression is a common cause of cognitive complaints in persons without organic disease and a rare cause of excess morbidity in AD.     

Prevalence of Alzheimer's disease, vascular dementia and dementia with Lewy bodies in a Japanese population

We studied the prevalence of dementing disorders in a rural town of Japan (Amino-cho), using a door-to-door two-phase design. Of the 170 persons screened as having cognitive impairment, 142 cases were diagnosed as having dementia. The prevalence (cases/100 aged 65 years older) was 3.8 for all types of dementia, 2.1 for Alzheimer's disease (AD), 1.0 for vascular dementia (VD) and 0.7 for other types of dementia. Among other types of dementia, there were four male patients with dementia with Lewy bodies (prevalence: 0.1), but no patients with frontotemporal lobar degeneration. The overall prevalence was higher in women for AD, while that of VD was the same in both sexes. With results similar to many previous studies in Western countries and some recent surveys in Japan, the present sudy clearly showed that AD is more prevalent than VD.     

The Japanese language and psychotherapy, with a particular focus on the handling of "contradictions"]

Verbalization, a technique used in analytic psychotherapy, plays a variety of roles including "naming", "uncovering", "clarifying", "weaving a story", and "thinking about the story". When we apply this technique in Japanese, however, resistance to such verbalization is liable to occur. Japanese is often said to be an "ambiguous" language. However, the only reason the Japanese language sounds ambiguous is because Japanese people use it ambiguously. One of the reasons for Japanese people's psychology of placing importance on polysemy and ambiguity is that it is unreasonable to impose an artificially-coined word on another person, and try to make him or her "share it" or "understand it". As a term that opposes "words" in Japanese, there is "jo" (affect) or "kanjo" (emotion) ; and the so-called non-verbal exchange that is emphasized in the Japanese language includes physical contact (such as touching) and interplay of the emotions. Structures that emphasize duality-such as "tatemae to honne," or what one says and what one really means, and "giri to ninjo," or duty and feeling-are internalized in the character of the Japanese people. This is reflected in daily context by the pattern of conflict that Japanese people share: namely, verbal versus nonverbal exchanges. In this paper, the author discusses how the contradictions and discrepancies seen in such exchanges originate from mother-child relationships, and proposes that therapeutic relations be used as an opportunity to deal with such contradictions and ambiguities. In particular, the author quotes from "Yuzuru (The Crane Wife)" and other Japanese folktales, and points out that, to deal with individual tragedies, like the heroine of "Yuzuru" who leaves her husband after he discovers her true nature, the therapist must recognize the existence of such contradictions in himself/herself. For example, contradictions such as a therapist being possibly ill despite appearing healthy, is liable to become a key target of patient scrutiny for testing the therapeutic objective.     

Association of depression with Alzheimer's disease and vascular dementia in an elderly Arab population of Wadi-Ara, Israel

OBJECTIVES: Because dementia and depression share common risk factors, we investigated risk factors for depression in Arab subjects with Alzheimer's disease (AD) and vascular dementia (VaD). METHODS: In a cross-sectional population-based study, we conducted a door-to-door survey of all adults over age 60 in an Arab community of rural Israel. We conducted interviews, gave questionnaires, and collected DNA blood specimens for determination of ApoE genotype. RESULTS: Of the 823 individuals in this naturalistic sample, 168 had dementia of Alzheimer's type (DAT) and 49 had VaD. Vascular risk factors, including the ApoE-epsilon4 allele, were more prevalent among VaD than DAT subjects. Depressive symptoms were present in 57% of DAT patients and 86% of VaD patients. Depressed DAT individuals had a greater history of ischemic cardiovascular or cerebrovascular (CV/CBV) disease than non-depressed DAT subjects, but depressed DAT subjects were less likely to have the ApoE-epsilon4 allele. Within the VaD group, there was no difference in the distribution of cardiovascular risk factors in individuals with and without depressive symptoms, and ApoE-epsilon4 was more prevalent among subjects with depressive symptoms. CONCLUSIONS: Depressive symptomatology is prevalent among subjects with dementias in this Arab community. History of CV/CBV is associated with the presence of depressive symptoms in DAT. Further studies are needed to clarify the role of ApoE in depression onset in different ethnic groups with DAT.     

Quantifying fluctuation in dementia with Lewy bodies, Alzheimer's disease, and vascular dementia

BACKGROUND: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in the major dementias, particularly dementia with Lewy bodies (DLB), where it is one of three core clinical diagnostic features. OBJECTIVES: To examine the frequency, characteristics, and diagnostic utility of FC in dementia using clinical, attentional, and EEG markers. Method:- A total of 155 subjects (61 with AD, 37 with DLB, 22 with vascular dementia [VaD], 35 elderly controls) received clinical evaluation for FC using a semiquantified measure applied by experienced clinicians and 90-second cognitive choice reaction time (CRT) and vigilance reaction time (VIGRT) trials. Forty subjects also received an evaluation of mean EEG frequency across 90 seconds. RESULTS: Patients with DLB had a greater prevalence and severity of FC than did patients with AD or VaD rated using clinical, attentional, and EEG measures. The 90-second cognitive and EEG trials demonstrated that FC occurs on a second-to-second basis in patients with DLB. Patients with VaD had a higher prevalence of FC than did those with AD, although the profile of FC was different from that expressed by DLB cases. Optimal cutoff values on the clinical scale achieved good discrimination between the dementia groups (sensitivity 81%, specificity 92%, DLB versus AD; sensitivity 81%, specificity 82%, DLB versus VaD; sensitivity 64%, specificity 77%, VaD versus AD). CONCLUSION: Standardized assessment methods demonstrate that FC is significantly more common and severe in DLB than in other major dementias. The periodicity of FC is different in DLB and VaD cases, with important implications for the underlying causal mechanisms and for differential diagnosis.     

Cerebral amyloid angiopathy and cortical microinfarcts as putative substrates of vascular dementia

BACKGROUND AND PURPOSE: Vascular dementia (VaD) has occasionally been associated with cerebral amyloid angiopathy (CAA), but the prevalence and significance of this counterintuitive relationship are poorly known. Therefore, we investigated the presence and characteristics of CAA in brains of VaD cases. METHODS: We examined temporal and parietal regions of the cerebral cortex of 26 consecutive VaD cases from the Lund Longitudinal Dementia Study. We carried out immunohistochemistry and routine stainings, determined Apolipoprotein E (ApoE) genotypes, and obtained clinical characteristics on the studied group for retrospective analysis. RESULTS: CAA was marked in eight out of 26 cases, and correlated strongly with the presence of cortical microinfarcts, both in the temporal lobe and in the parietal lobe. Based on comparisons with eight age-matched VaD cases without CAA, the clinical records suggested that VaD cases with CAA as a group exhibited less pronounced neurological symptoms. A clear contribution of the ApoE genotype could not be identified. CONCLUSIONS: Based on a combination of the clinical and pathological data, we suggest that microinfarcts in the cerebral cortex associated with severe CAA may be the primary pathological substrate in a significant proportion of VaD cases. Future studies should be undertaken to confirm or dismiss the hypothesis that these cases exhibit a different symptom profile than VaD cases without CAA.     

Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia

The authors determined rates of brain atrophy, as assessed by the boundary shift integral on serial MRI, in patients with dementia with Lewy Bodies (DLB, n = 10), AD (n = 9), vascular dementia (VaD, n = 9), and age-matched controls (n = 20). Mean % +/- SD atrophy rates per year were as follows: DLB, 1.4 +/- 1.1; AD, 2.0 +/- 0.9; VaD, 1.9 +/- 1.1; and controls, 0.5 +/- 0.7. Dementia subjects had higher rates than controls (p < 0.001), but there were no significant differences between the three dementia groups. The authors found accelerating atrophy with increasing severity of cognitive impairment, further emphasizing the need for early diagnosis and intervention in dementia.     

CT measurement of medial temporal lobe atrophy in Alzheimer's disease, vascular dementia, depression and paraphrenia

OBJECTIVE: Measurement of medial temporal lobe atrophy (MTL) by computerised tomography (CT) may be a useful adjunct to the diagnosis of AD. The aim of this study was to assess the sensitivity, specificity, predictive values and diagnostic accuracy of CT measurement of MTL thickness for patients with probable AD, compared with a 'diseased' control group, and to correlate the measure with neuropsychological test scores. DESIGN: Cross-sectional. METHODS: One hundred subjects were prospectively recruited: 60 with probable AD (mean age 73.7 years, mean Mini-Mental State Examination [MMSE] 19.6), 17 with probable vascular dementia (VaD) (mean age 77.9 years, mean MMSE 20.9), 14 with depression (mean age 73.2 years, mean MMSE 25.7) and nine with paraphrenia (mean age 74 years, mean MMSE 25.4). Axial and temporal lobe-oriented CT brain was performed and the minimum MTL thickness was measured electronically. RESULTS: The mean minimum MTL thickness was significantly smaller in AD subjects compared to VaD (p<0.0001) and psychiatric subjects (p<0.0001). For the clinical diagnosis of probable AD, the sensitivity of the measure was 0.75, specificity 0.9, and diagnostic accuracy 0.81. For the mildest cases of AD (CDR 0.5), the sensitivity of the measure was 0.61, specificity 0.91, and diagnostic accuracy 0.81. No significant correlations with neuropsychological test scores were found. CONCLUSIONS: Temporal lobe-oriented CT imaging is a non-invasive test with good discrimination for AD. Potential uses of this technique include as an aid to diagnosis and possibly as a means of monitoring disease progression.