The neuropathology and cerebrovascular mechanisms of dementia

The prevalence of dementia is increasing in our aging population at an alarming rate. Because of the heterogeneity of clinical presentation and complexity of disease neuropathology, dementia classifications remain controversial. Recently, the National Plan to address Alzheimer’s Disease prioritized Alzheimer’s disease-related dementias to include: Alzheimer’s disease, dementia with Lewy bodies, frontotemporal dementia, vascular dementia, and mixed dementias. While each of these dementing conditions has their unique pathologic signature, one common etiology shared among all these conditions is cerebrovascular dysfunction at some point during the disease process. The goal of this comprehensive review is to summarize the current findings in the field and address the important contributions of cerebrovascular, physiologic, and cellular alterations to cognitive impairment in these human dementias. Specifically, evidence will be presented in support of small-vessel disease as an underlying neuropathologic hallmark of various dementias, while controversial findings will also be highlighted. Finally, the molecular mechanisms shared among all dementia types including hypoxia, oxidative stress, mitochondrial bioenergetics, neuroinflammation, neurodegeneration, and blood–brain barrier permeability responsible for disease etiology and progression will be discussed.     

The neuropathology of chromosome 17-linked dementia

We recently described a family with chromosome 17-linked dementia, characterized clinically by disinhibition-dementia parkinsonism-amyotrophy complex. We report now the neuropathology of 6 affected family members. This included semiquantitative scoring of neuronal loss, gliosis, and spongiosis and immunocytochemical and ultrastructural characterization of neuronal and glial inclusions. The changes consisted of circumscribed neuronal loss, gliosis, and spongiosis of limbic neocortical areas and frontal, temporal, and occipital association areas. Similar changes were present in subcortical nuclei, most severe in the substantia nigra, but also involved the ventral striatum and amygdala. The hippocampus was spared except for degeneration of the afferent perforant tract, secondary to entorhinal nerve cell loss. Hgyrophilic neuronal inclusions, with a characteristic immunocytochemical profile, were found in brainstem nuclei, hypothalamus, and basal ganglia. Ultrastructurally, in 3 patients these inclusions showed hitherto undescribed abnormally assembled filaments. Glial cytoplasmic inclusions were widespread in white matter structures. Immunocytochemistry failed to demonstrate the protease-resistant prion protein. The pathology appears to be unique, involving various cortical and subcortical structures, and is consistent with the clinical findings of Kliiver-Bucy-like syndrome, parkinsonism, and frontal lobe dementia. For this entity we suggest the term “chromosome 17- linked dementia”.     

额颞痴呆的神经病理及分子遗传学研究进展

额颞痴呆(frontotemporal dementia,FTD)或额颞叶变性(frontotemporal lobardegeneration,FTLD)是一组以进行性行为异常、人格改变、语言障碍,而早期记忆相对保留为特征的临床综合征.     

Limbic neuropathology in idiopathic Parkinson's disease with concomitant dementia

To study pathological background of dementia in idiopathic Parkinson's disease (PD), 41 autopsy brains (31 cases with and 10 cases without dementia) were investigated. The severity of degenerative changes was evaluated in selected limbic regions (trans- and entorhinal cortex, hippocampus, and amygdala). The densities of Lewy bodies (LBs), Lewy neurites (LNs), neurofibrillary tangles (NFTs), and amyloid neuritic plaques (NPs) were determined on immunohistochemically stained sections using antibodies against alpha-synuclein, tau-protein, and amyloid-beta. Precisely defined modern criteria for selecting study cohort (Newcastle, CERAD and Braak et al.) ensured homogeneity of the study sample and reliability of the results. Comparisons between the cases of Parkinson's disease with dementia (PDD) and those without (PD-only) revealed that the former were characterised by significantly higher densities of LBs and LNs in transentorhinal and entorhinal cortices as well as in the CA2-3 region of the hippocampus and cortical complex of amygdala. In the PDD sub-set we found statistically significant correlation of LBs with LNs counts in CA2-3 region of hippocampus as well as of LBs counts in transentorhinal cortex with LNs counts in CA2-3 hippocampal region. The relationship was also observed between LBs counts in CA2-3 region of the hippocampus and LNs counts in cortical complex of amygdala. Our studies suggest that dementia in PD may be associated with the presence of degenerative changes of PD-type in leading limbic structures, without co-existent Alzheimer's disease (AD). They also imply that LBs and LNs may appear to be morphological hallmarks of the pathological process associated with dementia in PD. LBs and LNs distribution pattern and correlations of LBs with LNs counts in limbic regions observed in our study suggest the cumulative patomechanism of changes dependent on transsynaptic alpha-syn pathology and indicate the spread of the pathological process via axonal transport. The coexistence of the small number of changes of AD-type may exacerbate cognitive deficits in PDD.     

Clock drawing in dementia: its reliability and relation to the neuropsychological measures]

To examine the reliability and validity of clock drawing (CD) for evaluating dementia patients in Japan, we investigated the CD performance and its relation to several neuropsychological tests in 150 demented patients including 105 patients with Alzheimer disease and 30 age- and education-matched non-demented subjects (16 patients with mild cognitive impairment and 14 normals). Patients were also evaluated using the Mini-mental State Exam (MMSE), Wechsler Memory Scale (WMS), Kohs Block Design, and word fluency. CD was scored using the Shulman method. CD scores showed a high interrater reliability (r = 0.97). CD by non-demented subjects was essentially normal. As a screening test for Alzheimer disease (AD, mean MMSE = 18.0), CD had a sensitivity of 57.1% and a specificity of 96.7%. However, four of eight AD patients who showed normal MMSE score (> or = 24) drew abnormal clocks. CD scores in dementia were significantly correlated with performance on the Block Design (r = 0.68), MMSE (r = 0.56), and the Mental Control subtest in the WMS (r = 0.58). Stepwise regression analysis revealed that performance on the MMSE and the Block Design explain 53.8% of the variance in the CD scores. These findings indicate that low CD score by the Shulman method may be reflective of a constructional disability and general severity of dementia. CD is not so sensitive as the result of the original report when the patient group includes milder cases of AD. CD is, however, an efficient screening test for detecting and following the patients with dementia, especially combined with the MMSE.     

A reassessment of the neuropathology of frontotemporal dementia linked to chromosome 3

ABSTRACT: A large Danish family has previously been reported in which autosomal dominant frontotemporal dementia (FTD) is genetically linked to chromosome 3 (FTD-3). A mutation was recently identified in the CHMP2B gene that is probably responsible for causing disease in this family. Because of its neuropathologic findings, FTD-3 was originally categorized as a subtype of frontotemporal lobar degeneration, termed "dementia lacking distinctive histopathology." We now report a reevaluation of the neuropathologic changes in this family. Postmortem material from 4 affected family members was available for examination. Gross examination revealed generalized cortical atrophy that was most severe in frontal and temporal cortices. Microscopy showed loss of cortical neurons, microvacuolation of layer II, mild gliosis, and demyelination of the deep white matter. Results of immunohistochemical staining for alpha-synuclein, prion protein, neurofilament, and tau protein were unremarkable. Variable numbers of small, round, ubiquitin-positive cytoplasmic inclusions were present in the dentate granule layer of the hippocampus in all 4 cases. Rare ubiquitin-positive inclusions were also found in frontal and temporal cortical neurons. These inclusions were also positive for p62 but not for TDP-43. The finding of ubiquitin- and p62-positive, TDP-43-negative cytoplasmic inclusions in the hippocampus and neocortex suggests reclassification of the neuropathology of FTD-3 as a unique subtype of frontotemporal lobar degeneration with ubiquitin-positive inclusions that are TDP-43-negative.     

The behavioral variant of frontotemporal dementia: linking neuropathology to social cognition

The behavioral variant of frontotemporal dementia (bvFTD) is one of the most frequent neurodegenerative disorders with a presenile onset. It is characterized by a long phase of subclinical behavioral changes and social conduct disorders, associated with a progressive modification of personality. Recently, an international consortium of experts developed revised guidelines for its clinical diagnosis, which highlight the supportive role of biomarkers in the diagnostic process. According to new criteria, bvFTD can be classified in “possible” (requiring three of six specific clinical features), “probable” (in the presence of functional disability and typical neuroimaging features), and “with definite frontotemporal lobar degeneration” (requiring the presence of a known causal mutation or a histopathological confirmation). Familial aggregation is frequently reported in bvFTD and frontotemporal lobar degeneration in general, with an autosomal dominant transmission in about 10 % cases. The aim of this paper is to review and discuss recent advances in the knowledge of clinical, neuropsychological, and imaging features of bvFTD. We also briefly summarize the available genetic information about the frontotemporal lobar degeneration spectrum.     

痴呆患者的攻击行为与抑郁的关系

目的了解痴呆病人攻击行为与抑郁等相关因素的关系.方法对78例住院痴呆病人进行资料分析,评价工具主要采用Cornell痴呆抑郁量表、简易智力状态检查(MMSE)、日常生活能力量表(BEHAVE-AD)、Cohen-Mansfieid激越问卷(CMAI)、汉密顿抑郁量表(HAMD)、总体退化量表(GDS).结果抑郁组与非抑郁组的攻击行为比较有显著性差异(P＜0.01),抑郁与攻击行为相关(P＜0.01).结论攻击行为与抑郁症状、病程长、文化程度高、丧偶、日常生活能力差等相关.     

Awareness in dementia: ethical and legal issues in relation to people with dementia

Our improved understanding of the experience of people with dementia provides a new impetus to address legal and ethical issues. This paper explores emerging issues in relation to awareness in dementia and its impact on legal and ethical matters. The different approaches and principles demonstrated in relation to ethical issues are discussed, with an exploration of the concepts of beneficence, non-maleficence, autonomy, and paternalism. Application of these concepts is discussed in relation to advance directives, capacity, and decision making, participation in research and treatment, including informed consent, and truth telling. The tensions that exist between the imperatives of doing no harm and of maintaining autonomy in addressing legal and ethical issues are highlighted, and attention drawn to the manner in which the attribution of unawareness is used to justify withholding autonomy. The review emphasizes the importance of considering competency and awareness as being multi-faceted, to be understood in the context of social interaction.     

The heterogeneity of frontotemporal dementia with regard to initial symptoms, qEEG and neuropathology

OBJECTIVES/METHODS: Ten patients with neuropathologically verified frontotemporal dementia (FTD) were analysed for neuropathological features in relation to first presenting and dominating symptoms, age at onset and duration of dementia, as well as to EEG/quantitative EEG. RESULTS: Cases with a late onset (> 65 years) initially presented language disturbances, while the early onset group (< 65 years) showed predominantly behavioural symptoms and mood alterations as early features. The late onset group presented combined cortical-subcortical degeneration including white matter pathology, while early onset cases showed pathology predominantly in the cortex. EEG was normal in the late onset group, while it was mildly and variably abnormal in those with early onset. CONCLUSIONS: Within this small sample of clinical and neuropathological FTD, cases with late vs early onset differed with respect to initial symptoms, EEG findings and regional distribution of brain pathology.     

Accent processing in dementia

Accented speech conveys important nonverbal information about the speaker as well as presenting the brain with the problem of decoding a non-canonical auditory signal. The processing of non-native accents has seldom been studied in neurodegenerative disease and its brain basis remains poorly understood. Here we investigated the processing of non-native international and regional accents of English in cohorts of patients with Alzheimer's disease (AD; n=20) and progressive nonfluent aphasia (PNFA; n=6) in relation to healthy older control subjects (n=35). A novel battery was designed to assess accent comprehension and recognition and all subjects had a general neuropsychological assessment. Neuroanatomical associations of accent processing performance were assessed using voxel-based morphometry on MR brain images within the larger AD group. Compared with healthy controls, both the AD and PNFA groups showed deficits of non-native accent recognition and the PNFA group showed reduced comprehension of words spoken in international accents compared with a Southern English accent. At individual subject level deficits were observed more consistently in the PNFA group, and the disease groups showed different patterns of accent comprehension impairment (generally more marked for sentences in AD and for single words in PNFA). Within the AD group, grey matter associations of accent comprehension and recognition were identified in the anterior superior temporal lobe. The findings suggest that accent processing deficits may constitute signatures of neurodegenerative disease with potentially broader implications for understanding how these diseases affect vocal communication under challenging listening conditions.     

Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia

OBJECTIVES: To assess the diagnostic specificity of MRI-defined hippocampal atrophy for AD among individuals with a variety of pathologically confirmed conditions associated with dementia as well as changes attributable to typical aging, and to measure correlations among premortem MRI measurements of hippocampal atrophy, mental status examination performance, and the pathologic stage of AD. METHODS: An unselected series of 67 individuals participating in the Mayo Alzheimer's Disease Research Center/Alzheimer's Disease Patient Registry who had undergone a standardized antemortem MRI study and also postmortem examination were identified. Hippocampal volumes were measured from antemortem MRI. Each postmortem specimen was assigned a pathologic diagnosis and in addition, the severity of AD pathology was staged using the method of Braak and Braak. RESULTS: Individuals with an isolated pathologic diagnosis of AD, hippocampal sclerosis, frontotemporal degeneration, and neurofibrillary tangle--only degeneration usually had substantial hippocampal atrophy, while those with changes of typical aging did not. Among all 67 subjects, correlations (all p < 0.001) were observed between hippocampal volume and Braak and Braak stage (r = -0.39), between hippocampal volume and Mini-Mental State Examination (MMSE) score (r = 0.60), and between MMSE score and Braak and Braak stage (r = -0.41). CONCLUSIONS: Hippocampal atrophy, while not specific for AD, was a fairly sensitive marker of the pathologic AD stage (particularly among subjects with isolated AD pathology [r = -0.63, p = 0.001]) and consequent cognitive status.     

Anterior type dementia from the viewpoint of neuropathology]

Anterior type dementia is characterized by primary degeneration in the anterior brain region and represents pick symptom. Anterior type dementia includes several pathological disease entities, almost of them usually exhibit variation of atrophic brain regions in greater or lesser degree. This variation of each disease cause confusion, namely, the same clinical manifestations occur even if it is a different disease and diversely, different clinical manifestations can occur even if it is the same disease entity. This is the reason why discrepancy between clinical diagnosis and pathology diagnosis occurs sometimes in anterior type dementia. For reasonable clinical diagnosis, anterior type dementia, separate from neuropathological diseases entity, should be deal with clinical symptom-complex, which consists of frontotemporal dementia (FTD) progressive nonfluent aphasia (PA) and semantic dementia (SD). FTD, PA and SD have, though broadly, corresponding responsible brain lesion respectively.     

Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations

Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease of bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in the valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene superfamily. The neuropathology associated with sporadic FTD is heterogeneous and includes tauopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). However, there is limited information on the neuropathology in IBMPFD. We performed a detailed, systematic analysis of the neuropathologic changes in 8 patients with VCP mutations. A novel pattern of ubiquitin pathology was identified in IBMPFD that was distinct from sporadic and familial FTLD-U without VCP gene mutations. This was characterized by ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. In contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and there was no biochemical alteration in the VCP protein. VCP is associated with a variety of cellular activities, including regulation of the ubiquitin-proteasome system. Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways.