额颞痴呆

一、流行病学额颞痴呆 (ｆｒｏｎｔｏｔｅｍｐｏｒａｌｄｅｍｅｎｔｉａ,ＦＴＤ)为一组临床综合征 ,1987年Ｇｕｓｔａｆｓｏｎ首先提出这一概念。一般认为ＦＴＤ为仅次于Ａｌｚｈｅｉｍｅｒ病 (ＡＤ)早老性痴呆 ,有时可与运动神经元病 (ＭＮＤ)、帕金森综合征并存。ＦＴＤ占痴呆的 10 0 %左右 ,占早老性痴呆的 2 5 0 % ,可见三种主要类型 :Ｐｉｃｋ病 (ＰｉＤ)、非特异性额叶变性、额叶变性合并脊髓前角神经元脱失[1] 。如未并存ＭＮＤ ,生前鉴别上述三型较为困难。近年来研究发现ＦＴＤ与染色体 17ｑ2 1相关[2 ] 、还与早老素 1(Ｌ113ｐ)…     

额颞痴呆

额颞痴呆(FTD)为一组临床综合征,1987年Gustafson首先提出这一概念,包括:Pick病、额颞叶变性(FTLD)、进行性失语(progressiveaphasia)、语义性痴呆(semanticdementia)。FTD早期有各种行为异常,易被误诊为Alzheimer病(AD)或精神分裂症、双相情感障碍等。FTD可合并运动神经元病(M     

Alzheimer病的分子遗传学进展

本对近年在阿尔采木氏病分子遗传学研究方面的进展作了一综述。     

神经遗传学研究进展:生理、病理与临床

随着遗传学理论和技术的日趋成熟,神经遗传学已发展成为神经科学领域中一门重要的分支学科。一方面,人们已不仅仅从形态、药理角度而更从基因水平、蛋白质水平来揭示神经细胞的结构和功能;另一方面,一些神经遗传病的病理机制在基因水平上得到了阐明,为这些疾病的临床诊治和预防提供了理论依据,一些非神经遗传病也成为神经遗传学研究的焦点。     

额颞叶痴呆的研究进展

额颞叶痴呆是一种原发性退行性痴呆,核心症状为缓慢发生、进行性加重的行为和语言障碍。本文就其分子生物学、神经病理、临床诊断、影像学及神经心理学等方面的研究进展进行综述。     

脑梗死的分子遗传学研究进展

脑梗死是一种严重影响人类健康的脑血管疾病,其分子遗传学研究对脑梗死的基因诊断和基因治疗以及对阐明血管性痴呆 (VaD)和Alzheimer病 (AD)的相互关系均有积极意义,值得我们重视。一、脑梗死的分子流行病学研究脑动脉粥样硬化与冠状动脉粥样硬化可能有许多共性,但是在基因     

伴有痴呆神经变性疾病的病理诊断

近年来,由于病理技术和免疫组织化学方法的不断完善和扩充,对伴有痴呆的神经变性疾病,有不少新的认识,从而发现了新的病种。本人在病理工作中遇到和学习的几个问题,结合文献复习概述如下。     

阿尔采木病分子遗传学研究进展

淀粉样前体蛋白（APP）、早老素－1（PS－1）和早老素－2基因突变引起的早发家族性阿尔采木病非常少见,ApoEε4等位基因与近半数的晚发AD有关联,其它一些基因虽有研究,但结果却不肯定。PS－1缺失可引起APP水解代谢紊乱,导致APP在神经元中沉积。     

肌萎缩侧索硬化-额颞痴呆:基因、分子标志物及代谢

肌萎缩侧索硬化(ALS)是累及脑和脊髓运动神经元的神经退行性疾病,认知功能障碍增加了其临床异质性,来自流行病学、临床、遗传、及代谢方面的证据表明其与额颞痴呆(FTD)属于同一疾病谱;ALS-FTD目前被认为是一种重要的痴呆综合征,对其诊断和治疗提出了挑战。本文主要围绕ALS-FTD的临床特征、常见致病基因、分子标志物及代谢特征作一综述。     

额颞叶痴呆和阿尔茨海默病的神经心理学特征比较

目的比较不同痴呆程度的额颞叶痴呆(FTD)和阿尔茨海默病(AD)患者神经心理学特征的差异。方法应用神经心理学量表评价27例FTD患者和36例AD患者的认知功能。结果无论何种痴呆程度,FTD组患者神经精神问卷(NPI)评分均显著高于AD组(P<0.05)。轻度AD组患者日常活动能力量表(ADL)评分略高于FTD组(P=0.046),中重度FTD组患者的简易精神状态检查量表(MMSE)评分(P=0.021)和画钟测验(CDT)评分(P=0.004)均低于AD组。在临床痴呆评定量表(CDR)各功能域评分中,轻度AD患者定向力(P=0.030)与工作和社会交往能力(P=0.039)评分高于FTD组,中重度FTD患者在CDR总分(P=0.011)和判断与解决问题的能力评分上高于AD(P=0.007)。结论临床工作中对痴呆患者进行全面的神经心理学检查有助于鉴别FTD和AD。     

The molecular genetics and neuropathology of frontotemporal lobar degeneration: recent developments

The past year has seen a number of significant advances in our understanding of the neuropathological and molecular genetic basis of frontotemporal lobar degeneration (FTLD). Whereas, in the past, most attention focused on FTLD associated with tau-based pathology and microtubule associated protein tau gene (MAPT) mutations, there has recently been greater attention paid to non-tau FTLD. FTLD with tau-negative, ubiquitinated inclusions (FTLD-U) is now recognized as the most common pathology associated with clinical FTLD. Mutations in the progranulin gene (PGRN) have been identified as the cause of FTLD-U linked to chromosome 17. A rapidly growing number of PGRN mutations have been identified, and to date, all appear to cause FTLD by reducing the amount of functional PGRN protein (haploinsufficiency). The neuropathology associated with each of the known non-MAPT FTLD genes and loci (PGRN, valosin-containing protein gene, CHMP2B and 9p), has been shown to be a specific subtype of FTLD-U. The ubiquitinated pathological protein in FTLD-U has been identified as TAR deoxyribonucleic acid-binding protein with M _r 43 kDa (TDP-43). Immunohistochemical and biochemical studies of TDP-43 have helped to clarify the relationship between different sub-types of FTLD-U and related conditions. It is anticipated that these discoveries will facilitate the development of new diagnostic tests and therapeutics.     

Cortical ubiquitin-positive inclusions in frontotemporal dementia without motor neuron disease: a quantitative immunocytochemical study

Ubiquitin-positive tau-negative inclusions were initially described in the rare form of frontotemporal dementia (FTD) associated with motor neuron disease. However, recent studies have indicated that these inclusions are also present in typical FTD, which is usually characterized by nonspecific histological changes. To examine the contribution of these inclusions to neuronal loss and to explore their relationship with disease duration, we performed a quantitative immunocytochemical analysis of 38 typical FTD cases. Relationships between neuron and ubiquitin inclusion densities as well as between duration of illness and neuropathological parameters was studied using linear regression in both univariate and multivariate models. Ubiquitin-positive tau-negative intracytoplasmic inclusions were present in 65.8% of cases in the dentate gyrus, 57.9% in temporal cortex and 31.6% in frontal cortex. The highest densities of ubiquitin-positive inclusions were consistently observed in the dentate gyrus, followed by the temporal and frontal cortex. There was no statistically significant relationship between neuron and ubiquitin-positive inclusion densities in any of the areas studied. In contrast, ubiquitin-positive inclusion densities in the dentate gyrus were negatively related to the duration of illness. Our data suggest that the development of ubiquitin-related pathology is the rule and not the exception in typical FTD, yet is not causally related to neuronal loss. They also reveal that the development of ubiquitin-positive inclusion densities in the dentate gyrus may be associated with a more aggressive form of the disease.     

Regional and cellular pathology in frontotemporal dementia: relationship to stage of disease in cases with and without Pick bodies

Frontotemporal dementia (FTD) is a prevalent neurodegenerative disease of heterogeneous histopathology. Neuropathological subtypes are identified on the basis of the presence or absence of tau- or ubiquitin-positive neuronal inclusions. Our recent work has established four disease stages that are independent of neuropathological subtype and reflect the clinical and degenerative progression observed in FTD. The variability in the extent of neuronal loss, astrogliosis, and microvacuolation are, therefore, more likely to reflect disease stage with potentially predictable differences between cases at early versus late disease stages. Understanding the variability in these parameters may assist in determining the importance of diverse disease subtypes in FTD. We examined 21 cases of sporadic, behavioural variant FTD and quantified the progression of histopathological change. The neuropathology of early disease was marked by severe astrogliosis of both the frontal and temporal cortices and neuronal loss, which was more evident in upper cortical layers of the frontal lobe. In late disease, neuronal loss was evident from both layer III and V in frontal and temporal cortices, and particularly the CA1 sector of the hippocampus. In addition, we compared the neuropathology of Picks disease, dementia lacking distinctive histopathology and FTD with motor neuron disease, and found no difference in these pathological subtypes on the basis of neuronal loss, astrogliosis or microvacuolation. These results show that the earliest cellular changes in FTD occur in glia, and that disease stage rather than FTD subtype determines the pattern and extent of neuronal degeneration.     

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer’s disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick’s disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family). Received: 8 November 1999 / Revised, accepted: 17 January 2000     

Subcortical neurofibrillary tangles and argyrophilic grains in a case of familial frontotemporal dementia with parkinsonism

A case of familial frontotemporal dementia with parkinsonism (FTDP) similar to progressive supranuclear palsy (PSP) was reported. A 58-year-old man developed personality change followed by parkinsonism and dementia. Three family members showed similar symptoms. Cerebral atrophy was marked on the anterior frontotemporal lobes. The substantia nigra, hippocampus, peri-aqueductal gray matter and pontine nucleus were affected with globose neurofibrillary tangles (NFT) and glial tangles. Argyrophilic grains were distributed in the CA1–CA2. NFT, glial tangles and argyrophilic grains expressed four-repeat microtubule-associated protein tau (MAPT). MAPT gene had no mutation. Familial occurrence of FTDP with PSP-like tauopathy is rare.     

A short neuropsychologic and cognitive evaluation of frontotemporal dementia

Objective

To elaborate a brief but efficient neuropsychological assessment of frontotemporal dementia (FTD), selecting the most specific and sensitive cognitive and behavioural items for distinguish between AD and FTD in the earlier dementia stages.

Methods

Retrospective study with three groups, 35 patients with FTD, 46 with AD and 36 normal subjects, were administered the MMSE, FAB, Tower of London and Stoop's test along with a 98 items behavioural and cognitive questionnaire. The most sensitive items were selected and validated internally for diagnosis by lineal discriminant analysis.

Results

From the 98 items in the questionnaire, 29 showed significant discriminatory power. Non-cognitive symptoms with higher odd-ratio for FTD compared to AD were impairment in social behaviour (disinhibition, aggressiveness), loss of insight and inappropriate acts. Language disorders, such as echolalia, verbal apraxia or aggramatism, dominate in the cognitive profile of FTD. FAB was confirmed as the best cognitive instrument to differentiate FTD and AD. A linear discriminant function with the combination of the FAB score and the items from our questionnaire with higher OR for FTD accurately classified 97% of individuals.

Conclusions

The neuropsychological tests allow the differentiation between FTD and AD. The combination of FAB test with the assessment of key behavioural and cognitive symptoms appears helpful in this distinction.     

Recent advances in defining the neuropathology of schizophrenia

The search for the defining neuropathology of schizophrenia continues to be one of the highest priority areas of research into this severely debilitating and common neuropsychiatric disorder. While lesions that are diagnostic of the disorder have not yet been identified, recent efforts employing molecule-specific probes and quantitative methods of analysis have enumerated many potentially important findings in the brains of patients with schizophrenia that warrant confirmation and elucidation. In this review, the major findings of six broad areas of neuropathological investigation are summarized and discussed. While substantial controversy exists in all areas, in sum: (1) diagnostic neuropathological investigations find only assorted and nonspecific abnormalities in the brains of schizophrenics that are likely to be representative of lesions found in age-compatible control groups; (2) morphometric studies of gross structures generally confirm the clinical in vivo neuroimaging findings of enlarged ventricles, decreased size of ventromedial temporal lobe structures, and decreased parahippocampal cortical thickness; (3) morphometric microscopy studies find frequent alterations in neuron density and decreased neuron size in limbic, temporal, and frontal regions; (4) investigations of connectivity are at an early stage but describe abnormal dendritic spine densities in the cortex, various changes in synaptic vesicle protein expression in limbic, temporal, and frontal cortices, and alterations in glutamatergic, catecholaminergic, and intrinsic innervation in anterior cingulate cortex – together, these findings suggest a “miswiring” in the schizophrenic brain; (5) investigations of aberrant neurodevelopment in schizophrenia describe abnormalities in cortical cytoarchitecture and several developmentally regulated proteins in the hippocampal region suggesting abnormal neuronal migration, differentiation, and/or cell pruning; and (6) studies of neurodegeneration and neural injury find a general lack of neurodegenerative disease lesions or ongoing astrocytosis that would indicate post-maturational neural injury. Received: 2 January 1996 / Revised: 15 March 1996 / Accepted: 29 March 1996     

Altered speech-related cortical network in frontotemporal dementia

BackgroundIn healthy subjects (HS), transcranial magnetic stimulation (TMS) demonstrated an increase in motor-evoked potential (MEP) amplitudes during specific linguistic tasks. This finding indicates functional connections between speech-related cortical areas and the dominant primary motor cortex (M1).ObjectiveTo investigate M1 function with TMS and the speech-related cortical network with neuroimaging measures in frontotemporal dementia (FTD), including the non-fluent variant of primary progressive aphasia (nfv-PPA) and the behavioral variant of FTD (bv-FTD).MethodsM1 excitability changes during specific linguistc tasks were examined using TMS in 24 patients (15 with nfv-PPA and 9 with bv-FTD) and in 18 age-matched HS. In the same patients neuroimaging was used to assess changes in specific white matter (WM) bundles and grey matter (GM) regions involved in language processing, with diffusion tensor imaging (DTI) and voxel-based morphometry (VBM).ResultsDuring the linguistic task, M1 excitability increased in HS, whereas in FTD patients it did not. M1 excitability changes were comparable in nfv-PPA and bv-FTD. DTI revealed decreased fractional anisotropy in the superior and inferior longitudinal and uncinate fasciculi. Moreover, VBM disclosed GM volume loss in the left frontal operculum though not in the parietal operculum or precentral gyrus. Furthermore, WM and GM changes were comparable in nfv-PPA and bv-FTD. There was no correlation between neurophysiological and neuroimaging changes in FTD. Atrophy in the left frontal operculum correlated with linguistic dysfunction, assessed by semantic and phonemic fluency tests.ConclusionWe provide converging neurophysiological and neuroimaging evidence of abnormal speech-related cortical network activation in FTD.     

Irisin levels are correlated with inflammatory markers in frontotemporal dementia

Irisin is a recently discovered adipomyokine involved in the regulation of glucose and lipid, which also exhibits anti-inflammatory and neuroprotective properties. Here we aimed to compare irisin peripheral levels between individuals with behavioral variant frontotemporal dementia (bvFTD) and cognitively healthy matched controls, in addition to investigating whether there is a correlation between irisin and pro-inflammatory cytokines (IL-6 and TNF) concentrations. Twenty-nine individuals participated in this study, being 18 patients with probable bvFTD and 11 controls. Irisin, IL-6 and TNF levels were measured in EDTA plasma through ELISA. There was no difference of the levels of irisin between the groups (p = 0.964). However, in the bvFTD, but not in control group, the levels of irisin were positively correlated with the concentration of IL-6 (r = 0.637, p = 0.006) and TNF (r = 0.517, p = 0.034). The results suggest that the production of irisin in bvFTD could be related to chronic inflammatory and neurodegenerative states in these patients.