DENNIS WILLIAM DICKSON

..The study investigates the effects of genetic factors on the pathology of Alzheimer's disease (AD) and Lewy body (LB) diseases, including Parkinson's disease and dementia with Lewy bodies...

..Such findings support a direct link between altered TDP-43 function and neurodegeneration...

..abstract:..

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..Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (PGRN) gene...

..Corpora amylacea tended to be more frequent in HSD than in FTLD-U, but there was no difference in frequency of argyrophilic grains...

..A specific molecular marker and a genetic locus for familial cases are not known...

..The findings suggest that iLBD is preclinical PD and that the lack of symptoms is due to subthreshold pathology...

..Proteolysis of tau may be critical to neurofibrillary degeneration, which correlates with dementia...

..A diagnostic algorithm is suggested for neuropathologic evaluation of neurodegenerative disorders. The importance of clinical information is emphasized in arriving at the most precise and meaningful neuropathologic diagnosis...

..It also reveals subclinical MND in a subset of cases of FTLD without clinical or pathologic evidence of MND...

..Imaging studies suggest that there may be sensitive and specific means to differentiate PSP from other parkinsonian disorders, but identification of a diagnostic biomarker is still elusive...

..The major neurodegenerative diseases can be classified into amyloidoses, tauopathies, alpha-synucleinopathies and TDP-43 proteinopathies...

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..These findings provide evidence that modifications of alpha-synuclein in MSA may be more widespread than obvious histopathology. Moreover, these alterations may constitute a biochemical signature for the synucleinopathies...

..Thus, MSA and LBD are both synucleinopathies, and they may comprise different poles of a disease spectrum that includes sporadic disorders as well as genetically determined disorders such as familial Lewy body Parkinsonism...

..Further clinicopathologic studies will refine our understanding of these disorders and open the possibility that common etiologic factors may be identified for these unusual sporadic tauopathies...

..This is contrasted with other Pick's disease subtypes, including Constantinidis' Type B (corticobasal degeneration) and Type C (dementia lacking distinctive histology)...

..Whether inclusion body formation is an adaptive response or is directly related to degeneration of neuronal and glial cells is a topic of current research...

..The anatomical distribution of tau pathology determines the clinical presentation of PSP and CBD, as well as PiD. The basis for this selective cortical vulnerability in FTLD-tau is unknown...

..In this situation, LBs may be unrelated to PD and more likely related to factors inherent to AD and the selective vulnerability of the amygdala to both Alzheimer and alpha-synuclein pathologies...

..Recently, a common genetic variant in the 3' untranslated region (3'UTR) of GRN (rs5848; c.*78C>T) located in a microRNA binding site regulated progranulin expression, and the T-allele was increased in FTLD-TDP compared to controls...

..This review highlights the range of clinical and pathologic presentations of PSP and its variants...

..Atrophy of anterior corpus callosum may be a potential neuroimaging marker to differentiate corticobasal degeneration from progressive supranuclear palsy in patients with Richardson syndrome...

..This study further expands the clinical and pathological spectrum of PGRN mutations, and suggests the diagnosis could be missed in some individuals with atypical presentations...

..The results add further evidence that PA is distinct from AD and indicate that decreased Abeta degradation by NEP is unlikely to contribute significantly to amyloid deposition in PA or, in many cases, of AD...

..To assess demographic and genetic determinants of Alzheimer type pathology in progressive supranuclear palsy (PSP)...

..Neither demographic variables nor cognitive measures had predictive value in determining which patients diagnosed with MCI will develop the neuropathologic features of AD...

..Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals...

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..We propose the term neurofilament inclusion body disease for this entity...

..This study reports clinical, genetic and neuropathologic investigations of Perry syndrome...

..The results suggest that tau in S2 represents an intermediate from which insoluble tau is derived, and that phosphorylation may play a role in filament formation and/or stabilization...

..These findings suggest advanced age and possibly MAPT H1 are risk factors for AGD, even in the setting of concurrent AD, in which neurofibrillary degeneration is associated with accumulation of both 3R and 4R tau...

..This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity...

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..An age-related decrease in MBP immunoreactivity was detected in NCI cases (r=0.71). These results support the hypothesis that white matter pathology may contribute to age-associated decline in cognition...

..These clinical and pathological findings suggest that PSP-PNLA should be considered a variant of PSP...

..On the other hand, there is no histopathologic feature or combination of features that is pathognomonic. Neuronal intranuclear inclusions are virtually always present, but they can be detected in PGRN(-) cases...

..It is unknown if loss of oligodendrocytes either through apoptosis or through the formation of intracellular tau lesions further contributes to the neurodegeneration seen in these mice...

..The progressive axonal pathology is most consistent with a dying-back process caused by abnormal accumulation of tau in upstream neurons, while vacuolar myelinopathy may be a secondary manifestation of neuroinflammation...

..This suggests that AGD is an independent disease process from AD...

..These results suggest that AGD, PSP and CBD are 4R tauopathies that share common pathologic, biochemical, and genetic characteristics...

..These results support the assertion that the H1/H1 genotype may contribute to the earlier occurrence of clinical symptoms...

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..Mutations in the progranulin gene (PGRN) have recently been identified as a cause of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in some families...

..05), suggesting that mechanisms of ischemic cell death may change with aging. In conclusion, aging alters mechanisms of ischemic cell death in CA1 neurons and ischemic tolerance mechanisms are blunted by aging...

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..p.L420R (g.1508T > G) is the mutation responsible for EOAD, seizures and CWP without SP in this family...

..Protein cross-linking and aggregation are important molecular processes in Alzheimer's disease (AD), and tissue transglutaminase (tTG) catalyzes protein cross-linking...

..These P301L transgenic mice exhibit many features common to human tauopathies, making them a valuable model to study the pathogenesis of these uncommon disorders...

..These findings extend previously described clinicopathological associations of FTLD-TDP subtypes and support the notion that FTLD-TDP subtypes may be distinct clinicopathologic disorders...

..We also identified a new family with the R406W mutation and pathology consistent with NFTD. This study validates the recently proposed diagnostic criteria and forms a framework for further refinement of this classification scheme...

..To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), with emphasis on the unique clinical features in this kindred...

..Additional clinicopathologic studies are warranted to address the role of other Lewy-related pathology, most notably Lewy neurites, in the cognitive impairment of DLB...

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..To enhance the sensitivity and specificity of the clinical diagnosis of progressive supranuclear palsy (PSP), neuroradiological parameters established in pathologically proven cases are needed...

..The present results suggest that tau may coaggregate with alpha-synuclein in LBs, especially in neuronal populations vulnerable to both NFTs and LBs...

..Unlike NFT, astrocytic degeneration does not seem to contribute to gliosis or neuronal loss in PSP, and its clinical significance remains unclear...

..Patients carrying an LRRK2 mutation display significant variability of clinical and pathologic phenotypes across and within affected families...

..Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies...

..We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals...

..Biochemically, TDP-43 proteinopathies are characterized by decreased solubility, hyperphosphorylation, and cleavage of TDP-43 into 25- and 35-kDa fragments, and by altered cellular localization...

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..To test for replication of the association between variants in the CLU, CR1, and PICALM genes with Alzheimer disease...

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..7; 95% confidence interval, 1.4-98.7; P=0.008). Our results suggest that tau genotype does not influence the disease course. However, it may predispose to a specific clinical sign in the early stage of FTDP-17...

..Immunohistochemistry for APP and alphaB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya...

..AGD is a common pathologic finding in subjects who have been diagnosed with amnestic MCI...

..42, P < 0.05). This study demonstrates that cardiac sympathetic degeneration and alpha-synuclein pathology is present in presymptomatic phase of PD, and that both increase with disease duration and severity...

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..0 (95% CI: 0.3-29, p=0.3). All three affected carriers were classified as diffuse Lewy body disease (n=3/50; 6%). Our study suggests glucosidase-beta variants have a limited role in susceptibility to Lewy body disease in North America...

..eight-vessel occlusion, respectively). Confocal microscopy verified that a subset of the bromedeoxyuridine-positive cells expressed nestin. In conclusion, severe ischemia elicits nestin expression in hippocampal progenitor cells in rats...

..These data establish that Abeta1-42 is essential for amyloid deposition in the parenchyma and also in vessels...

..05). Aging appears to delay caspase-3-dependent apoptotic cell death induced by global ischemia in the CA1 region of the hippocampus, consistent with an age-induced neuroprotective process...

..These finding extend prior research suggesting a cognitive profile that can aid in the clinical diagnosis of DLB. Early attention and visual perceptual disturbance suggests DLB, while early impairment in memory and naming suggests AD...

..2 years younger age at disease onset. In conclusion we show that the interaction of Lrrk1-Lrrk2 can form protein dimers and this interaction may influence the age of symptomatic manifestation in Lrrk2-parkinsonism patients...

..02). The difference in frequency of HpScl in FTLD-U compared to FTLD-MND is further evidence that they are separate clinicopathologic entities...

..Our findings suggest behavioural variant of frontotemporal dementia can therefore be subdivided into four different anatomical subtypes...

..Refining the classification of the degenerative aphasias and AOS may be necessary to improve our understanding of the relationships among behavioural, pathological and imaging correlations...

..The ability to detect the clinical signs of dementia and motor neuron disease in pathologically confirmed FTLD-MND has not been assessed...

..This provides further evidence in support of including RBD as one of the core diagnostic features of DLB...

..In subjects presenting with CBS, prominent temporoparietal, especially posterior temporal and inferior parietal, atrophy may be a clue to the presence of underlying AD pathology...

..There are no reports on the possible association of rapid eye movement sleep without atonia and RBD with any familial tauopathy...

..Despite this selection bias, the retrospective data collection, and the small sample size, we made several observations that illustrate the difficulty in achieving an accurate antemortem diagnosis of parkinsonism...

..The definitive diagnosis of FTDP-17 requires a set of clinical and pathological features combined with a molecular genetic analysis. Currently, there is no known effective treatment for FTDP-17...

..To determine the rates of cerebral atrophy and ventricular expansion in six patients with autopsy confirmed progressive supranuclear palsy (PSP) and multiple antemortem volumetric head MRI scans...

..This model will provide an important tool for understanding the early events leading to the development of tau pathology and a model for analysis of potential therapeutic targets for sporadic tauopathies...

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..To test the hypothesis that beta-amyloid (Abeta) burden is associated with rates of brain atrophy...

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..No patient experienced visual hallucinations. If confirmed by a prospective study, the absence of visual hallucinations may help to distinguish corticobasal syndrome from other parkinsonian syndromes...

..To determine the neuropathologic correlates of antemortem hydrogen 1 ((1)H) magnetic resonance (MR) spectroscopy metabolite measurements in subjects with Alzheimer disease (AD)-type pathology...

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