Use-dependent behavioral and neurochemical asymmetry in MPTP mice

Folic acid is believed to play a role in protection from oxidant stress. Low levels of folic acid had been found in serum from patients with Alzheimer disease (AD). Folate concentration was evaluated in sera from 136 patients with cortical dementia [AD, n = 108; frontotemporal dementia (FTD), n = 28], 57 patients with subcortical dementia [Lewy body disease (LBD), n = 9; corticobasal degeneration (CBD), n = 5; progressive supranuclear palsy (PSP), n = 6; Parkinson disease with dementia (PD-Dem), n = 37], and 76 nondemented, healthy age-matched people. Serum folic acid levels were decreased in patients with AD and FTD as compared with either controls or patients with subcortical dementia (3.60 ± 2.22 and 5.37 ± 2.92 μg/L versus 6.87 ± 3.50 μg/L, respectively; P < 0.01). A tendency towards decreased folate concentration was found in LBD and CBD, but not to a significant extent. The highest proportion of folate-deficient patients was found in CBD, FTD and AD (respectively, 60, 48.2 and 46.3% versus 7.9% in controls; P < 0.001). Folate deficiency characterizes FTD as well as AD. These differences observed among different clinical dementing syndromes may be related to neocortical damage.     

Voxel-based morphometry in autopsy proven PSP and CBD

The aim of this study was to compare the patterns of grey and white matter atrophy on MRI in autopsy confirmed progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and to determine whether the patterns vary depending on the clinical syndrome. Voxel-based morphometry was used to compare patterns of atrophy in 13 PSP and 11 CBD subjects and 24 controls. PSP and CBD subjects were also subdivided into those with a dominant dementia or extrapyramidal syndrome. PSP subjects showed brainstem atrophy with involvement of the cortex and underlying white matter. Frontoparietal grey and subcortical grey matter atrophy occurred in CBD. When subdivided, PSP subjects with an extrapyramidal syndrome had more brainstem atrophy and less cortical atrophy than CBD subjects with an extrapyramidal syndrome. PSP subjects with a dementia syndrome had more subcortical white matter atrophy than CBD subjects with a dementia syndrome. These results show regional differences between PSP and CBD that are useful in predicting the underlying pathology, and help to shed light on the in vivo distribution of regional atrophy in PSP and CBD.     

Microtubule-associated protein tau genetic variations are uncommon cause of frontotemporal dementia in south India

Microtubule-associated protein tau (MAPT) positive neuropathology is the characteristic feature of majority of frontotemporal dementia (FTD) cases, which is due to the mutations or haplotypic variations in the gene encoding MAPT (MAPT). The present study was aimed at determining the frequency of genetic variations in MAPT in a south Indian FTD cohort. The frequency of mutations were determined in 116 FTD, 8 progressive supranuclear palsy (PSP) and 3 corticobasal syndrome (CBS) patients and haplotype diversity were analyzed in a study cohort comprising 116 FTD, 8 PSP, 3 CBS, 194 other dementia groups, 78 mild cognitive impairment (MCI) and 130 cognitively normal individuals and report no pathogenic mutations in FTD/PSP/CBS or haplotypic association with disease risk in FTD or other dementia patients. These findings suggest that there may be other genetic or epigenetic factors contributing to the pathogenesis of FTD in the south Indian population.     

进行性核上性麻痹和皮质基底节变性的胶质细胞病变的观察

目的 观察进行性核上性麻痹和皮质基底节变性胶质细胞变性特征,探讨不同类型胶质细胞变性的病理意义。方法 对具有详细临床资料和病理确诊的2例进行性核上性麻痹和3例皮质基底节变性的脑标本进行了Gallyas—Braak银染色和tau蛋白免疫组织化学链霉素抗生物素蛋白-过氧化物酶法染色,并以5例阿尔茨海默病,4例帕金森病和6例无神经疾病史的同龄老年人脑标本作对照。结果 Gallyas-Braak银染色显示进行性核上性麻痹和皮质基底节变性的脑组织内存在广泛分布的两种形态胶质细胞变性,即呈菊花团或蜘蛛网样形态的葱状星形细胞和位于核周线圈样或逗点样形状的线团样少突胶质细胞变性。葱状星形细胞主要见于额顶叶皮层,基底节和脑干灰质区,而线团样少突胶质细胞则主要分布于基底节,脑干和小脑白质束内。星形细胞斑是由粗短的突起样结构呈放射状排列形成,仅见于皮质基底节变性的额、顶叶皮层和纹状体区。这3种类型胶质细胞变性的tau蛋白免疫组织化学染色均为阳性。所有对照病例脑组织内未见上述形态的胶质细胞变性改变。结论 葱状星形细胞和线团样少突胶质细胞变性是进行性核上性麻痹和皮质基底节变性的共同的组织学改变特征之一;星形细胞斑是皮质基底节变性相对特异性的病理标志。     

The differentiation of semantic dementia and frontal lobe dementia (temporal and frontal variants of frontotemporal dementia) from early Alzheimer's disease: a comparative neuropsychological study

The authors compared age-matched groups of patients with the frontal and temporal lobe variants of frontotemporal dementia (FTD; dementia of frontal type [DFT] and semantic dementia), early Alzheimer's disease (AD), and normal controls (n = 9 per group) on a comprehensive neuropsychological battery. A distinct profile emerged for each group: Those with AD showed a severe deficit in episodic memory with more subtle, but significant, impairments in semantic memory and visuospatial skills; patients with semantic dementia showed the previously documented picture of isolated, but profound, semantic memory breakdown with anomia and surface dyslexia but were indistinguishable from the AD group on a test of story recall; and the DFT group were the least impaired and showed mild deficits in episodic memory and verbal fluency but normal semantic memory. The frontal and temporal presentations of FTD are clearly separable from each other and from early AD.     

Cerebral metabolic patterns at early stages of frontotemporal dementia and semantic dementia. A PET study

OBJECTIVE: To determine the patterns of cerebral glucose metabolism in frontotemporal dementia (FTD) and semantic dementia (SD). METHODS: 25 patients with mild FTD and 9 patients with mild SD as well as 15 healthy age-matched control subjects underwent 18F-FDG- positron emission tomography. Patient scans were compared with control scans using SPM-99. RESULTS: As compared with healthy control subjects patients with FTD showed an extensive symmetrical hypometabolism of the frontal lobes (height threshold P <0.01) which spared the motor cortex. Patients with SD showed a hypometabolism in the whole left temporal lobe and in the right temporal pole. CONCLUSIONS: In the clinical syndromes of FTD and SD two distinct patterns of cerebral metabolism were identified. FTD was associated with frontal hypometabolism, whereas in SD cerebral glucose metabolism was exclusively reduced in the temporal lobes. Our findings are consistent with the notion that FTD and SD begin as strictly lobar neuronal degenerations and that a spread of pathological changes is not seen until more advanced stages.     

Cerebral glucose metabolism in corticobasal degeneration comparison with progressive supranuclear palsy using statistical mapping analysis

This study measured the cerebral glucose metabolism in patients suffering from corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). The aim was to determine if there is a different metabolic pattern using (18)F-labeled 2-deoxyglucose ((18)F-FDG) positron emission tomography (PET). The regional cerebral glucose metabolism was examined in 8 patients diagnosed clinically with CBD (mean age 69.6 +/- 7.8 years; male/female: 5/3), 8 patients with probable PSP (mean age 67.8 +/- 4.5 years; male/female: 4/4) and 22 healthy controls. The regional cerebral glucose metabolism between the three groups was compared using statistical parametric mapping (SPM) with a voxel-by-voxel approach (p < 0.001, 200-voxel level). Compared with the normal controls, asymmetry in the regional glucose metabolism was observed in the parietal, frontal and cingulate in the CBD patients. In the PSP patients, the glucose metabolism was lower in the orbitofrontal, middle frontal, cingulate, thalamus and mid-brain than their age matched normal controls. A comparison of the two patient groups demonstrated relative hypometabolism in the thalamus, the mid-brain in the PSP patients and the parietal lobe in CBD patients. These results suggest that when making a differential diagnosis of CBD and PSP, voxel-based analysis of the (18)F-FDG PET images using a SPM might be a useful tool in clinical examinations.     

Verb production in the nonfluent and semantic variants of primary progressive aphasia: The influence of lexical and semantic factors

Differential patterns of impairment with respect to noun and verb production have been observed in the nonfluent and semantic variants of primary progressive aphasia. However, the factors influencing this discrepancy remain unclear. The present study evaluates verb retrieval in primary progressive aphasia using a naming task and a story completion task. Findings indicate that patients with the semantic variant are influenced by familiarity, frequency, and age of acquisition in both object and action naming, whereas patients with the nonfluent variant are not. Surprisingly, there were no differences in either group between object and action naming, presumably because the lists were well matched on pertinent variables. In the story completion task, greater impairment in semantically heavier than in semantically lighter verbs was observed for the semantic variant, and grammaticality and verb tense agreement was significantly lower in the nonfluent variant. The present findings suggest that lexicosemantic attributes affect verb production in the semantic variant, whereas both lexicosemantic and syntactic attributes affect verb production in the nonfluent variant.     

Regions of neural dysfunction associated with impaired naming of actions and objects in acute stroke

The proposal that there are distinct neural regions devoted to the representation or processing of names of objects versus actions has received support from a variety of sources. However, there have been conflicting results regarding the localisation of the postulated mechanisms that are more crucial for one category or the other. There is also controversy as to whether the separation of mechanisms devoted to object versus action naming arises at the level of lexical-semantics or at the level of accessing lexical representations for output. We addressed these issues by testing oral naming and word comprehension of object and action names in 33 right-handed patients with acute left-hemisphere stroke, and by obtaining magnetic resonance (MR) perfusion-weighted and diffusion-weighted imaging of each patient at the same time. We identified regions of abnormal blood flow or infarction associated with impaired naming (with and without impaired word comprehension) of objects, of actions, or of both, using Fisher Exact tests. We found both neural regions shared by networks underlying naming of actions and networks underlying naming of objects, and other neural regions that were crucial to only one network or the other. One of the shared components (in the left superior temporal gyrus) was also essential to comprehension of action and object names (as tested by word/picture verification). These results converge with evidence from chronic lesion studies and functional imaging studies, indicating that some components of the neural networks for accessing lexical representations for output are more important for object names (e.g., left temporal cortex) and others more important for action names (e.g., left posterior frontal cortex).     

Regions of neural dysfunction associated with impaired naming of actions and objects in acute stroke

The proposal that there are distinct neural regions devoted to the representation or processing of names of objects versus actions has received support from a variety of sources. However, there have been conflicting results regarding the localisation of the postulated mechanisms that are more crucial for one category or the other. There is also controversy as to whether the separation of mechanisms devoted to object versus action naming arises at the level of lexical-semantics or at the level of accessing lexical representations for output. We addressed these issues by testing oral naming and word comprehension of object and action names in 33 right-handed patients with acute left-hemisphere stroke, and by obtaining magnetic resonance (MR) perfusion-weighted and diffusion-weighted imaging of each patient at the same time. We identified regions of abnormal blood flow or infarction associated with impaired naming (with and without impaired word comprehension) of objects, of actions, or of both, using Fisher Exact tests. We found both neural regions shared by networks underlying naming of actions and networks underlying naming of objects, and other neural regions that were crucial to only one network or the other. One of the shared components (in the left superior temporal gyrus) was also essential to comprehension of action and object names (as tested by word/picture verification). These results converge with evidence from chronic lesion studies and functional imaging studies, indicating that some components of the neural networks for accessing lexical representations for output are more important for object names (e.g., left temporal cortex) and others more important for action names (e.g., left posterior frontal cortex).     

Semantic categorisation of novel objects in frontotemporal dementia

Impaired semantic memory is ubiquitous in frontotemporal dementia (FTD), including patients with semantic dementia (SD), progressive nonfluent aphasia (PNFA) and nonaphasic FTD patients with a deficit in executive and social functioning (EXEC/SOC). One hypothesis attributes this to the degradation of specific categories of knowledge in semantic memory. This study explores the alternate hypothesis that impaired semantic memory in FTD can also reflect limitations in the categorisation processes that determine object meaning. Patients were taught a novel semantic category under two conditions: rule-based categorisation, where executive resources support the evaluation of specific features to determine category membership; and similarity-based categorisation, where category membership is determined by the overall resemblance of an item to a prototype or recalled exemplars. In the first experiment, patients learned a novel category composed of highly salient features. For SD patients, we found category membership judgment profiles following rule-based and similarity-based training that resembled the performance of control subjects. Categorisation was impaired following rule-based training in PNFA and EXEC/SOC patients. In the second experiment, we modified the category so that membership was determined by less salient features, thus increasing the burden on executive resources. Under these circumstances, SD patients' categorisation profiles continued to resemble those of control subjects, PNFA patients' category judgments were governed by feature salience, and EXEC/SOC patients' judgments were limited by impaired executive resources. These observations suggest that the semantic memory deficit in SD largely reflects degraded feature knowledge for familiar objects, while impaired semantic memory in PNFA and in EXEC/SOC patients largely reflects a deficit in the processes associated with semantic categorisation.     

Semantic categorisation of novel objects in frontotemporal dementia

Impaired semantic memory is ubiquitous in frontotemporal dementia (FTD), including patients with semantic dementia (SD), progressive nonfluent aphasia (PNFA) and nonaphasic FTD patients with a deficit in executive and social functioning (EXEC/SOC). One hypothesis attributes this to the degradation of specific categories of knowledge in semantic memory. This study explores the alternate hypothesis that impaired semantic memory in FTD can also reflect limitations in the categorisation processes that determine object meaning. Patients were taught a novel semantic category under two conditions: rule-based categorisation, where executive resources support the evaluation of specific features to determine category membership; and similarity-based categorisation, where category membership is determined by the overall resemblance of an item to a prototype or recalled exemplars. In the first experiment, patients learned a novel category composed of highly salient features. For SD patients, we found category membership judgment profiles following rule-based and similarity-based training that resembled the performance of control subjects. Categorisation was impaired following rule-based training in PNFA and EXEC/SOC patients. In the second experiment, we modified the category so that membership was determined by less salient features, thus increasing the burden on executive resources. Under these circumstances, SD patients' categorisation profiles continued to resemble those of control subjects, PNFA patients' category judgments were governed by feature salience, and EXEC/SOC patients' judgments were limited by impaired executive resources. These observations suggest that the semantic memory deficit in SD largely reflects degraded feature knowledge for familiar objects, while impaired semantic memory in PNFA and in EXEC/SOC patients largely reflects a deficit in the processes associated with semantic categorisation.     

Quantitative neurohistological features of frontotemporal degeneration

Frontotemporal degeneration (FTD) is a neurodegenerative condition that has been principally associated with frontal lobe dementia. In this study, we compared neuropathological abnormalities in frontal, hippocampal, and calcarine cortices from patients assigned a diagnosis of FTD, normal elderly and Alzheimer’s disease (AD). Densities of Nissl-stained neurons and lesions which were immunolabeled for tau, β-amyloid (Aβ), - and β-synuclein, ubiquitin, glial fibrillary acidic protein (GFAP) and CD68 antigen were determined using computer-assisted, non-biased quantitative microscopy. We found that FTD frontal and hippocampal regions exhibited marked neuron loss, abundant ubiquitin-immunoreactive (ir) dystrophic neurites, GFAP-ir astrocytes, and CD68-ir microglia, while calcarine cortex was spared. No - or β-synuclein-ir lesions were observed, and neither the density of tau-ir neurofibrillary tangles nor that of Aβ-ir plaques in FTD exceeded normal controls. In addition, there were no neuropathological differences between FTD subjects who presented clinically with a frontal lobe dementia versus an AD-like dementia. These findings indicate that FTD is a category of neurodegnerative dementias with varying clinical presentations that is characterized by the progressive degeneration of select populations of cortical neurons. The molecular neurodegenerative mechanisms that lead to FTD remain to be elucidated.     

Semantic memory in Alzheimer's disease and the frontotemporal dementias: a longitudinal study of 236 patients

Using semantic dementia (SD) as a reference point, the authors assessed semantic memory in four other neurodegenerative disorders: progressive nonfluent aphasia (PNFA), frontal variant frontotemporal dementia (fvFTD), Alzheimer's disease (AD), and posterior cortical atrophy (PCA). Individuals with SD were more impaired than other groups on semantic measures and showed a characteristic pattern across tasks: category fluency (CF) worse than letter fluency (LF), naming worse than comprehension, and visual and verbal comprehension equally affected, suggesting disruption to an amodal semantic system. Individuals with AD demonstrated a similar pattern to a milder degree. Although PNFA, fvFTD, and PCA groups had abnormal scores (relative to controls) on most semantic measures, their differing patterns across measures indicate that the apparent semantic impairment in these conditions is largely secondary to other factors.     

Quantitative proteomics identifies surfactant-resistant alpha-synuclein in cerebral cortex of Parkinsonism-dementia complex of Guam but not Alzheimer's disease or progressive supranuclear palsy

Parkinsonism-dementia complex (PDC) remains a significant health burden to the Chamorro population. We tested the hypothesis that quantitative proteomics might provide fresh insight into this enigmatic illness by analyzing proteins resistant to surfactant extraction from patients with Alzheimer's disease (AD) or PDC and their matched controls using isobaric tags for relative and absolute quantification. In addition to the expected increase in abnormal frontal cortical Abeta peptides, tau, ubiquitin, and apolipoprotein E in AD, and tau in PDC, we identified alpha-synuclein (SNCA) as a major abnormal protein in PDC but not AD. We confirmed our isobaric tags for relative and absolute quantification findings by enzyme-linked immunosorbent assay in frontal and temporal cortices. We extended our assays to include a limited number of cases of progressive supranuclear palsy (PSP) and dementia with Lewy bodies; we observed increased abnormal tau but not SNCA in PSP, and abnormal SNCA in dementia with Lewy bodies that was quantitatively similar to PDC. Finally, soluble Abeta oligomers were selectively increased in AD but not PDC or PSP. These results show that frontal and temporal cortex in PDC is distinguished from AD and PSP by its accumulation of abnormal SNCA and suggest that PDC be considered a synucleinopathy as well as a tauopathy.     

C9orf72 repeat expansions are restricted to the ALS-FTD spectrum

Expansion of a GGGGCC repeat (RE) in the C9orf72 gene has been recently reported as the main genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Given the growing evidence of genetic and clinicopathologic overlap among ALS, FTD, and other neurodegenerative diseases, we investigated the occurrence of RE in a subset of 9 patients with ALS-plus syndromes, including Parkinson's disease (PD), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy. We identified RE in 2 ALS-plus individuals (22.2%) displaying PSP and CBS features. On the basis of this finding, we extended our analysis to a cohort composed of 190 PD, 103 CBS, 107 PSP, and 177 Alzheimer's disease cases. We did not identify any RE in these patients, indicating that C9orf72 is in all probability not involved in the pathogenesis of these disorders. However, the high frequency of C9orf72 RE in patients with ALS-plus syndromes suggests that, similar to ALS-FTD patients, individuals with combined motor neuron and extrapyramidal features should be screened for RE, independent of their family history.     

Contribution of the astrocytic tau pathology to synapse loss in progressive supranuclear palsy and corticobasal degeneration

Primary 4‐repeat tauopathies with frontotemporal lobar degeneration (FTLD) like Progressive Supranuclear Palsy (PSP) or Corticobasal Degeneration (CBD) show diverse cellular pathology in various brain regions. Besides shared characteristics of neuronal and oligodendroglial cytoplasmic inclusions of accumulated hyperphosphorylated tau protein (pTau), astrocytes in PSP and CBD contain pathognomonic pTau aggregates — hence, lending the designation tufted astrocytes (TA) or astrocytic plaques (AP), respectively. pTau toxicity is most commonly assigned to neurons, whereas the implications of astrocytic pTau for maintaining neurotransmission within the tripartite synapse of human brains is not well understood. We performed immunofluorescent synapse labeling and automated puncta quantification in the medial frontal gyrus (MFG) and striatal regions from PSP and CBD postmortem samples to capture morphometric synaptic alterations. This approach indicated general synaptic losses of both, excitatory and inhibitory bipartite synapses in the frontal cortex of PSP cases, whereas in CBD lower synapse densities were only related to astrocytic plaques. In contrast to tufted astrocytes in PSP, affected astrocytes in CBD could not preserve synaptic integrity within their spatial domains, when compared to non‐affected internal astrocytes or astrocytes in healthy controls. These findings suggest a pTau pathology‐associated role of astrocytes in maintaining connections within neuronal circuits, considered as the microscopic substrate of cognitive dysfunction in CBD. By contrasting astrocytic‐synaptic associations in both diseases, we hereby highlight astrocytic pTau as an important subject of prospective research and as a potential cellular target for therapeutic approaches in the primary tauopathies PSP and CBD.     

The MRI pattern of frontal and temporal brain atrophy in fronto-temporal dementia

OBJECTIVE: To compare patterns of brain atrophy in fronto-temporal dementia (FTD) and Alzheimer's disease (AD) since atrophy in individual areas may not be sufficiently specific as diagnostic marker. METHODS: Frontal, temporal and hippocampal atrophy was measured from MRI of 10 FTD patients, 27 AD, and 27 controls. Corrected atrophy and asymmetry were computed (W-scores). RESULTS: FTD had mild atrophy in the hippocampus (average W-score=-1.3), severe in the frontal (W-score=-2.4) and very severe in the temporal lobes (W-score=-2.9). AD had moderate atrophy in the hippocampus and temporal lobes (W-score=-1.8 and -1.9, respectively), and very mild frontal atrophy (W-score=-0.9). Atrophy was more asymmetrical in FTD (left more atrophic) than in AD patients, particularly in the temporal lobes. A discriminant function including the asymmetry values of frontal and temporal regions could separate FTD from AD with 90% sensitivity and 93% specificity. CONCLUSIONS: FTD is characterized by a specific pattern of atrophy, more useful than atrophy of single regions in the differential diagnosis.     

The extended haplotype of the microtubule associated protein tau gene is not associated with Pick's disease

Pick's disease (PiD) is a rare neurodegenerative condition and is a member of a heterogeneous group of disorders known as tauopathies, so-called because of the predominantly neuronal aberrant tau accumulations found in these diseases. The tauopathy, familial frontotemporal dementia (FTD), is caused by mutations in the tau gene. Moreover, progressive supranuclear palsy (PSP) is associated with the tau H1 haplotype. In certain familial forms of FTD and in PSP the microtubule-binding four repeat tau isoform principally accumulates in neuropathological lesions. However, in PiD three repeat tau accumulations are found. We therefore investigated whether either the tau H1 or H2 haplotype was associated with PiD. Our results indicate a slight increase in H2H2 frequency in Pick's cases which is not statistically significant.     

H1 haplotype of the MAPT gene is associated with lower regional gray matter volume in healthy carriers

The microtubule-associated protein Tau (MAPT) gene codes for the protein Tau that is involved in the pathogenesis of neurodegenerative diseases. Recent studies have detected an over-representation of the H1 haplotype of the MAPT gene in neurodegenerative disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD) and Parkinson's disease (PD), whereas the H2 haplotype has been found to be related to familial FTD. We aimed to investigate the association between MAPT haplotype status and brain morphology in healthy adults. A total of 150 healthy subjects underwent 3D high-resolution magnetic resonance (MR). MR images were processed following an optimized protocol to perform the Voxel-based morphometry (VBM) comparisons of the gray matter (GM) in H1 carriers (n=141) in contrast to H2H2 homozygous (n=9), and H1H1 homozygous (n=85) in contrast to H2 carriers (n=65). The threshold for statistical significance was 0.005 uncorrected. Opposite comparisons were also carried out. The groups had similar demographic and cognitive features. Compared with H2H2, the H1 carriers showed up to 19% smaller GM volume in the head of the right caudate nucleus, in the right middle frontal gyrus, in the left insula and orbito-frontal cortex, and in the inferior temporal and inferior cerebellar lobes, bilaterally. Compared with all H2 carriers, H1H1 displayed lower GM in the same regions, but the effect was smaller (5%), possibly due to a dilution effect by H1 in the H2 carriers group. The data suggest that H1 haplotype is associated with a particular cerebral morphology that may increase the susceptibility of the healthy carriers to develop neurodegenerative diseases such as sporadic tauopathies.