Progressive aphasia in a patient with Pick's disease: a neuropsychological, radiologic, and anatomic study

Although Pick's disease is generally considered as a dementia characterized by signs of frontal lobe dysfunction, it can present with selective language defects rather than with cognitive decline. In this study, we report prospective and serial clinical, neuropsychological, and neuroradiologic observations in a 59-year-old man whose prominent disturbance was in the retrieval and learning of names denoting concrete entities and actions. Postmortem study confirmed the diagnosis of Pick's disease and revealed that neuronal loss and gliosis were most prominent in left anterior temporal cortices. The findings are in keeping with evidence that the left anterior temporal cortices and interconnected hippocampal system are critically involved in the learning and retrieval of verbal lexical items. The evidence from this patient, along with similar evidence from the literature we reviewed, suggests that when patients present with a progressive aphasia characterized by anomia, Pick's disease should be considered as the probable diagnosis.     

Astrocytic straight tubules in the brain of a patient with Pick's disease

This report concerns an immunohistochemical and ultrastructural study of cerebral astrocytes in a patient with Pick's disease of 20 years' duration. The autopsied brain was prominently small (710 g) with marked fronto-temporal lobar atrophy. Histological examination demonstrated profound neuronal loss and spongy changes with tau-positive Pick bodies in the frontal and temporal cortex. In addition, many glial cells in the temporal lobe white matter contained round to oval, argentophilic and slightly hematoxinophilic cytoplasmic inclusions that were also immunolabeled with the anti-tau antibody. On electron microscopy, the glial inclusions were observed in the perikarya of astrocytes that were recognized as such from intracytoplasmic glial filaments and the presence of gap junctions. The inclusions were free in the cytoplasm, without a limiting membrane, and mainly comprised irregular aggregations of bundles of about 15-nm straight tubules, which were indistinguishable from those of intraneuronal Pick bodies. Furthermore, various patterns of accumulation of the same straight tubules were frequently noted in perivascular astrocytic processes carrying a basal lamina. These findings indicate that in Pick's disease astrocytes are also affected by a similar insult to that which affects neurons.     

Immunocytochemical and ultrastructural studies of Pick's disease

Cerebral cortical changes in 10 cases with Pick's disease were studied immunocytochemically and ultrastructurally. All cases contained Pick's argentophilic bodies and ballooned neurons. The antibodies against phosphorylated tau proteins that intensely stained all Pick bodies recognized numerous neuronal processes around Pick body-bearing cells and focal portions in the perikarya of ballooned neurons. Monoclonal and polyclonal anti-ubiquitin antibodies stained not only some Pick bodies with variable intensity, but also the perikarya of all ballooned neurons. Ultrastructurally, Pick bodies consisted of accumulation of randomly oriented, approximately 15-nm straight filaments and paired twisted profiles with a minimal diameter of 13 nm, maximal diameter of 26 nm, and twist periodicity of 120 nm. These Pick body-type filaments were also observed in the perikarya of ballooned neurons and neuronal processes around Pick body-bearing cells. Our studies demonstrate, for the first time, the characteristic pathological feature of neuropil in Pick's disease. Pick body-bearing cells and ballooned neurons show unique immunocytochemical and ultrastructural properties that may be a clue to the pathogenesis of Pick's disease.     

脑节细胞胶质瘤27例临床分析

目的 研究颅内节细胞胶质瘤(GGs)的临床、影像和病理学特征.方法 回顾性分析2001-2005年于复旦大学华山医院神经外科接受手术治疗的27例患者的临床、影像和病理资料及术后随访.结果 20例手术全切,7例未完全切除.病理结果示25例为低级别,2例为间变性,胶质和神经元成分共存为其典型特征.平均随访(27.3±18)个月,均未复发.8例术前癫痫发作的患者5例术后完全控制,2例缓解,1例仍有较频繁发作.结论 节细胞胶质瘤多属良性,术后患者预后良好.术中应尽可能全切,低级别肿瘤术后可以不进行辅助治疗.     

Kennedy病的临床、病理及AR基因分析一例

目的探讨Kennedy病(KD)的临床、病理及基因特点。方法对1例KD患者进行临床、电生理和病理检查。抽取该患者及4位家族成员外周静脉血并抽提其基因组DNA,采用PCR-DNA直接测序的方法进行AR基因分析。结果该患者临床表现为缓慢进行性四肢无力,伴有延髓麻痹、肌肉萎缩、肌束跳动、感觉障碍和男性乳房发育;血脂、肌酶升高;肌电图提示前角细胞损害,周围神经感觉及运动传导速度减慢;肌肉病理可见萎缩的肌纤维及肥大固缩的细胞核;AR基因分析发现患者第一外显子CAG重复突变,重复次数为43次,4位家族成员为19～23次。结论该例为散发性KD患者;KD临床表现不典型,肌电图和病理检查提示神经源性损害,确诊需行AR基因分析。     

Cognitive dysfunctions and pathological gambling in patients with Parkinson's disease

The purpose of this study was to investigate the neuropsychological correlates of pathological gambling (PG) in Parkinson's disease (PD). Fifteen patients with PD affected by PG (identified based on DSM‐IV criteria; PD+PG) without clinically evident dementia were compared with 15 nondemented patients with PD not affected by PG (PD?PG). Two groups of patients with PD were matched for age, length of education, and gender. Clinical and neuropsychiatric features were assessed; several cognitive domains, mainly related to executive functions, were explored by means of standardized neuropsychological tasks. PD+PG and PD?PG did not differ on clinical and neuropsychiatric aspects. PD+PG patients performed significantly worse than PD?PG patients on cognitive tasks that evaluated visuo‐spatial long‐term memory and several frontal lobe functions. After Bonferroni correction, differences remained significant on the Frontal Assessment Battery (FAB) (P = 0.001), on phonological fluency task (P = 0.003), and on the Trail Making Test, part B minus part A (P = 0.002). Logistic regression analysis demonstrated that low scores on the FAB were the only independent predictor of PG (odds ratio, 27.9; 95% CI: 2.82–277.95, P = 0.004). The results indicate an association between PG and frontal lobe dysfunctions in nondemented patients with PD. Low scores on the FAB indicate patients with PD at high risk for PG. © 2009 Movement Disorder Society     

Argyrophilic grain disease mimicking temporal Pick's disease: a clinical, radiological, and pathological study of an autopsy case with a clinical course of 15 years

This report concerns an autopsy case of argyrophilic grain disease (AGD) mimicking temporal Pick's disease. The patient was a Japanese woman without hereditary burden who was 89 years old at the time of death. She developed memory impairment and began wandering at the age of 74, followed by prominent character changes about 6 years after disease onset. A neurological examination 5 months before her death revealed poor rapport, unconcern, severe dementia, and double incontinence, without aphasia or muscle rigidity. Serial neuroradiological examination revealed progressive enlargement of the bilateral inferior horns of the lateral ventricle, reflecting progressive atrophy of the medial temporal lobes. Macroscopically, neuropathological examination showed circumscribed atrophy of the bilateral amygdalae, hippocampi, parahippocampal gyri, and lateral occipitotemporal gyri. Histologically, there was neuronal loss in the areas mentioned above, the caudate nucleus, putamen, thalamus, substantia nigra, and locus ceruleus, with ballooned neurons in the cerebral cortex and amygdala. Numerous argyrophilic grains with coiled bodies were present not only in the limbic system, but also in the affected cerebrum. Rare neurofibrillary changes were present in the limbic areas, consistent with Braak stage II, with no senile plaques. Based on these findings and a review of the literature, we note that AGD is clinicopathologically similar not only to mesolimbocortical dementia, but also to atypical senile dementia of Alzheimer type. This report may contribute to the elucidation of the clinicopathological hallmarks of AGD.     

阿尔茨海默病神经影像学研究进展

阿尔茨海默病(Alzheimer Disease,AD),又称老年性痴呆,是一种病因复杂、隐匿起病的神经退行性疾病,主要临床表现为记忆障碍,同时伴有人格改变及思维语言障碍等神经精神症状,AD的特征性病理改变为β淀粉样蛋白(Aβ)沉积和神经元纤维缠结,以及神经元丢失伴胶质细胞增生等,这些病理改变破坏了大脑结构和功能.AD发病率高,平均生存周期只有5.5年.随着我国人口老龄化的快速发展,AD患者数量逐年增加,给家庭及社会带来越来越沉重的负担,因此,对AD做出早期诊断变得尤为重要.然而,AD起病隐匿,早期的临床表现并不突出,且实验室检查也缺乏足够的特异性,早期容易被漏诊和误诊,当临床医生做出明确诊断时,多数患者已处于AD的中晚期,这在一定程度上延误了AD的治疗,因此,对AD进行早期诊断,尽早进行治疗具有非常重要的意义.近年来,随着影像学技术的不断发展,为AD的早期诊断提供重要的影像学依据.现分别从结构性磁共振(sMRI)、静息态功能磁共振成像(Rs-fMRI)、磁共振弥散张量成像(DTI)、正电子发射计算机断层显像(PET)等几个方面,阐述影像学技术在AD早期诊断的研究进展.     

Sporadic Pick's disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter

Pick's disease is characterized neuropathologically by distinct tau-immunoreactive intraneuronal inclusions known as Pick bodies and by insoluble tau proteins with predominantly three microtubule-binding repeat tau isoforms. However, recent immunohistochemical studies showed that the antibody specific for exon 10, which encodes the fourth microtubule-binding repeat, detected other tau lesions in Pick's disease. To better define the spectrum of tau pathology in Pick's disease, we used biochemical, immunohistochemical, and ultrastructural techniques to analyze the tau isoform composition in 14 Pick's disease brains. Western blot analysis showed that both three and four microtubule-binding repeat pathological tau isoforms are present in gray and white matter of various brain regions. Using phosphorylation-dependent anti-tau antibodies, we show that major tau phosphoepitopes are present in sarcosyl-insoluble gray and white matter regions of Pick's disease brains. Also, for the first time to our knowledge, we demonstrated that isoforms with four microtubule-binding repeat tau isoforms are present in Pick bodies from selected brains. Isolated tau filaments were straight or twisted and formed by three microtubule-binding repeat or four microtubule-binding repeat tau isoforms. Major tau phosphorylation-dependent and exon 10-specific epitopes were present in filaments. Therefore, Pick's disease is characterized by an accumulations of Pick bodies in the hippocampal region and cortex as well as the presence of three and four microtubule-binding repeat tau pathology in both cortical gray and white matter that distinguish this tauopathy from other neurodegenerative disorders.     

Cognitive and neuroimaging profile of a Brazilian family with CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease leading to small infarcts and subcortical vascular dementia. This study presents results from the neuropsychological and neuroimaging evaluation of functionally autonomous individuals of a Brazilian family with CADASIL. The causal mutation was confirmed in four family members. Seven individuals from two generations were evaluated using the CERAD battery and additional neuropsychological tests and were submitted (6 individuals) to magnetic resonance imaging (MRI) of the brain with specific protocols for white matter lesion quantification. Apraxic changes and fast progression over nine months (neuropsychological reevaluation of 6 individuals) were found in many individuals. The MRI study suggests greater involvement of frontal lobes in more severely affected individuals. Even functionally independent individuals may exhibit significant neuropsychological and neuroimaging changes. Apraxia, little commented on in literature, and rapidly progressive cognitive changes were found in this group.     

Depression,anxiety, and apathy in Parkinson's disease: insights from neuroimaging studies

Depression, anxiety and apathy are common mood disturbances in Parkinson's disease (PD) but their pathophysiology is unclear. Advanced neuroimaging has been increasingly used to unravel neural substrates linked to these disturbances. A systematic review is provided of neuroimaging findings in depression, anxiety and apathy in PD. A PubMed, MEDLINE and EMBASE search of peer‐reviewed original research articles on these mood disturbances in PD identified 38 studies on depression, eight on anxiety and 14 on apathy in PD. Most of the imaging studies used either position emission tomography or single‐photon emission computed tomography techniques. These studies generally suggest increased neural activity in the prefrontal regions and decreased functional connectivity between the prefrontal?limbic networks in depressed patients. Functional imaging studies revealed an inverse correlation between dopaminergic density in the caudate and putamen with the severity of anxiety in PD. There was no consistent correlation between dopaminergic density of thalamus and anxiety. Studies demonstrated both positive and inverse correlations between apathy and metabolism or activity in the striatum, amygdalar, prefrontal, temporal and parietal regions. The clinical variability of study subjects and differences in image pre‐processing and analytical strategies may contribute to discrepant findings in these studies. Both nigrostriatal and extra‐nigrostriatal pathways (in particular the frontal region and its connecting areas) are affected in mood disorders in PD. Identifying the relative contributions of these neural pathways in PD patients with overlapping motor and mood symptoms could provide new pathophysiological clues for the development of better therapeutic targets for affected patients.     

Cytoskeleton derangement in brain of patients with Down syndrome, Alzheimer's disease and Pick's disease

Although cytoskeleton derangement has been reported in brain of patients with neurodegenerative disorders, basic information on integral constituents forming this network including stoichiometric composition is missing. It was therefore the aim of the study to qualitatively and quantitatively evaluate individual proteins of the three major classes representing the cytoskeleton of human brain. Cytoskeleton proteins beta-actin (betaA), alpha-actinin (Act), tubulin beta-III (betaIII), microtubule associated protein 1 (MAP1), neurofilaments NF-L, NF-M and NF-H and neuron specific enolase (NSE), a marker for neuronal density, were determined by immunoblotting. Brain samples (frontal cortex) of controls (CO), patients with Down Syndrome (DS), Alzheimer's disease (AD) and Pick's disease (PD) were used for the study. In DS brain betaIII, NF-H and NF-M, in AD brain NF-M and NF-H and in PD brain NF-L, NF-M and NF-H were significantly reduced. Stoichiometry of cytoskeleton proteins in control brain revealed the following relations: betaA:Act:betaIII:MAP1:NF-L:NF-M:NF-H = 1.0:0.8:3.8:2.4:3.2:2.2. This stoichiometrical ratios were aberrant in DS, AD and PD with the main outcome that ratios of members of the neurocytoskeleton (betaIII, NF's) in relation to betaA were remarkably decreased. This finding confirms data of decreased neuronal density using NSE in DS and AD. We propose stoichiometry of cytoskeleton elements in normal brain and confirm and extend knowledge on cytoskeleton defects in neurodegenerative diseases. The finding of significantly decreased individual elements may well lead to or represent disassembly of the neurocytoskeleton observed in neurodegenerative diseases.     

Genetic aspects of Alzheimer's disease, Pick's disease, and other dementias

Although genetic testing is available for some degenerative diseases, in most types of dementia, both genetic and environmental factors are involved. Overall, dementing diseases can be either sporadic or inherited, and in general, the earlier the onset, the more likely a disease is to be inherited. Before genetic testing is performed, the ethical issues, such as the effect the tests might have on asymptomatic children, should be considered. The ethical use of DNA samples in research is another genetic testing issue to be considered.     

A comparison of histological and immunohistochemical methods for quantifying the pathological lesions of Pick's disease

Counts of Pick bodies (PB), Pick cells (PC), senile plaques (SP) and neurofibrillary tangles (NFT) were made in the frontal and temporal cortex from patients with Pick's disease (PD). Lesions were stained histologically with hematoxylin and eosin (HE) and the Bielschowsky silver impregnation method and labeled immunohistochemically with antibodies raised to ubiquitin and tau. The greatest numbers of PB were revealed by immunohistochemistry. Counts of PB revealed by ubiquitin and tau were highly positively correlated which suggested that the two antibodies recognized virtually identical populations of PB. The greatest numbers of PC were revealed by HE followed by the anti-ubiquitin antibody. However, the correlation between counts was poor, suggesting that HE and ubiquitin revealed different populations of PC. The greatest numbers of SP and NFT were revealed by the Bielschowsky method indicating the presence of Alzheimer-type lesions not revealed by the immunohistochemistry. In addition, more NFT were revealed by the anti-ubiquitin compared with the anti-tau antibody. The data suggested that in PD: (i) the anti-ubiquitin and anti-tau antibodies were equally effective at labeling PB; (ii) both HE and anti-ubiquitin should be used to quantitate PC; and (iii) the Bielschowsky method should be used to quantitate SP and NFT.     

Pick's disease with compound intraneuronal inclusion bodies

Summary This report presents findings from an unusual case of Pick's disease that was characterized by unique compound inclusion bodies consisting of a small eosinophilic core within the hematoxylinophilic Pick bodies. These structures are compared to other inclusions observed in Pick's disease and motor neuron disease.

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Zusammenfassung Diese Mitteilung betrifft Befunde eines ungewöhnlichen Falles von Pickscher Krankheit, der durch unikale Einschlußkörperchen mit kleinem eosinophilen Zentrum innerhalb der hämatoxylinophilen Pick bodies (Silberkugeln) gekennzeichnet war. Diese Gebilde werden mit anderen Einschlüssen verglichen, die man bei der Pickschen Krankheit und bei Erkrankungen des motorischen Neurons findet.