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1.
Zhonghua Nei Ke Za Zhi ; 58(12): 905-907, 2019 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-31775454

RESUMO

The clinical and imaging data in 6 patients with corticobasal syndrome were retrospectively analyzed. Six patients presented asymmetric clinical symptoms, including 5 with cognitive impairment, 6 with emotional disorders, 2 with cortical sensory deficit, 5 with lalopathy, and 4 with apraxia. All patients developed limb dystonia and limb or trunk stiffness, 4 with tumble, 4 with bradykinesia, and 2 with tremor. Brain magnetic resonance imaging (MRI) showed that 4 patients had unilateral cerebral atrophy and 2 had mild atrophy of bilateral hippocampus. Localized low glucose metabolism in the unilateral cerebral lobe was seen in four patients by positron emission computed tomography (PET) examination, suggesting that PET is helpful for the diagnosis of corticobasal syndrome.


Assuntos
Córtex Cerebral/diagnóstico por imagem , Degeneração Lobar Frontotemporal/diagnóstico , Imagem por Ressonância Magnética , Doenças Neurodegenerativas/diagnóstico , Neuroimagem , Tomografia por Emissão de Pósitrons , Doenças dos Gânglios da Base/diagnóstico , Doenças dos Gânglios da Base/patologia , Encéfalo/diagnóstico por imagem , Degeneração Lobar Frontotemporal/patologia , Humanos , Doenças Neurodegenerativas/patologia , Estudos Retrospectivos , Síndrome
2.
Front Biosci (Landmark Ed) ; 24: 1241-1258, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136977

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that is characterized by the progressive degeneration of both upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord. Recent advances in human genetics have identified more than 30 ALS-causing genes or genetic loci that include the fused in sarcoma (FUS) gene. In addition, a set of studies suggested a mutual relationship between cancer and ALS. The hpo gene, Drosophila MST was newly identified as a novel genetic modifier of the cabeza (caz), Drosophila FUS. The Hippo pathway negatively regulates the control of organ growth and tumor suppression. Moreover, the p53 tumor suppressor was found to genetically interact with caz. Frontotemporal lobar degeneration (FTLD) is characterized by the degeneration of neurons in the frontal and temporal lobes, and consists of a spectrum with ALS. Fusion protein nucleophosmin-human myeloid leukemia factor 1 (NPM-hMLF1), which is associated with the pathologies of myelodysplastic syndrome and acute myeloid leukemia, was recently shown to suppress defects in the Drosophila FTLD model expressing the human FUS gene. Further studies in the field are expected to elucidate epidemiological, genetic, and histopathological links between cancer and ALS/FTLD, and will lead to the development of therapeutic strategies. We herein summarize previous and current findings that support mutual links between cancer and ALS/FTLD.


Assuntos
Esclerose Amiotrófica Lateral/genética , Degeneração Lobar Frontotemporal/genética , Neurônios Motores/metabolismo , Neoplasias/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Degeneração Lobar Frontotemporal/patologia , Humanos , Neurônios Motores/patologia , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/genética , Proteína FUS de Ligação a RNA/genética
3.
PLoS Genet ; 15(5): e1007947, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31100073

RESUMO

Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases.


Assuntos
Proteases Dependentes de ATP/genética , Esclerose Amiotrófica Lateral/genética , Proteínas de Ligação a DNA/genética , Degeneração Lobar Frontotemporal/genética , Proteínas Mitocondriais/genética , Proteinopatias TDP-43/genética , Resposta a Proteínas não Dobradas , Proteases Dependentes de ATP/metabolismo , Trifosfato de Adenosina/biossíntese , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Drosophila melanogaster , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Regulação da Expressão Gênica , Células HEK293 , Humanos , Potencial da Membrana Mitocondrial/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Mutação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Proteinopatias TDP-43/metabolismo , Proteinopatias TDP-43/patologia
4.
Molecules ; 24(8)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022909

RESUMO

Fused in sarcoma (FUS) is a DNA/RNA binding protein that is involved in RNA metabolism and DNA repair. Numerous reports have demonstrated by pathological and genetic analysis that FUS is associated with a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and polyglutamine diseases. Traditionally, the fibrillar aggregation of FUS was considered to be the cause of those diseases, especially via its prion-like domains (PrLDs), which are rich in glutamine and asparagine residues. Lately, a nonfibrillar self-assembling phenomenon, liquid-liquid phase separation (LLPS), was observed in FUS, and studies of its functions, mechanism, and mutual transformation with pathogenic amyloid have been emerging. This review summarizes recent studies on FUS self-assembling, including both aggregation and LLPS as well as their relationship with the pathology of ALS, FTLD, and other neurodegenerative diseases.


Assuntos
Doenças Neurodegenerativas/genética , Agregação Patológica de Proteínas/genética , Proteína FUS de Ligação a RNA/química , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Asparagina/química , Asparagina/genética , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Proteínas Ligadas por GPI/química , Proteínas Ligadas por GPI/genética , Humanos , Doenças Neurodegenerativas/patologia , Peptídeos/química , Peptídeos/genética , Príons/química , Príons/genética , Agregação Patológica de Proteínas/patologia , Domínios Proteicos/genética , Proteína FUS de Ligação a RNA/genética
5.
Neurology ; 92(21): e2472-e2482, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31019099

RESUMO

OBJECTIVE: To investigate the prevalence of clinically relevant multiple system atrophy (MSA) and Lewy body disease (LBD) pathologies in a large frontotemporal lobar degeneration (FTLD) cohort to determine if concomitant pathologies underlie the heterogeneity of clinical features. METHODS: All prospectively followed FTLD-tau and FTLD-TDP cases held by the Sydney Brain Bank (n = 126) were screened for coexisting MSA and LBD (Braak ≥ stage IV) pathology. Relevant clinical (including family history) and genetic associations were determined. RESULTS: MSA pathology was not identified in this series. Of the FTLD cohort, 9 cases had coexisting LBD ≥ Braak stage IV and were associated with different FTLD subtypes including Pick disease (n = 2), corticobasal degeneration (n = 2), progressive supranuclear palsy (n = 2), and TDP type A (n = 3). All FTLD-TDP cases with coexisting LBD had mutations in progranulin (n = 2) or an abnormal repeat expansion in C9orf72 (n = 1). All FTLD-tau cases with coexisting LBD were sporadic. The H1H1 MAPT haplotype was found in all cases that could be genotyped (n = 6 of 9). Seven cases presented with a predominant dementia disorder, 3 of which developed parkinsonism. Two cases presented with a movement disorder and developed dementia in their disease course. The age at symptom onset (62 ± 11 years) and disease duration (8 ± 5 years) in FTLD cases with coexisting LBD did not differ from pure FTLD or pure LBD cases in the brain bank. CONCLUSION: Coexisting LBD in FTLD comprises a small proportion of cases but has implications for clinical and neuropathologic diagnoses and the identification of biomarkers.


Assuntos
Degeneração Lobar Frontotemporal/epidemiologia , Doença por Corpos de Lewy/epidemiologia , Atrofia de Múltiplos Sistemas/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Encéfalo/patologia , Proteína C9orf72/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Degeneração Lobar Frontotemporal/fisiopatologia , Humanos , Doença por Corpos de Lewy/genética , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/fisiopatologia , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/genética , Atrofia de Múltiplos Sistemas/patologia , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Prevalência , Progranulinas/genética , alfa-Sinucleína/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
6.
Medicine (Baltimore) ; 98(16): e15292, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31008977

RESUMO

RATIONALE: Brain atrophy coupled with impaired cognition may be a sign of dementia. However, growing evidence indicates that schizoaffective disorder (SAD) and type 2 diabetes mellitus (T2DM) play roles in the processes of frontotemporal atrophy and cognitive decline. Few cases of frontotemporal atrophy and impaired cognition have been reported in young adult patients with SAD and T2DM. PATIENT CONCERNS: A 34-year-old man was admitted for his 19th rehospitalization due to auditory verbal hallucinations (AVHs), delusions of persecution, mania, and fluctuating blood sugar levels. After admission, a brain computed tomography (CT) scan revealed that the patient's frontotemporal atrophy, which was first found in 2014, had gradually degenerated over time. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) revealed cognitive impairments. Based on the clinical assessment, his cognition and social function impairments were determined to mainly result from SAD and T2DM because the clinical characteristics and course of the disease did not coincide with the features of progressive aggravation of dementia. DIAGNOSES: Diagnoses include the following: SAD-mania and T2DM. INTERVENTIONS: Paliperidone and sodium valproate coupled with quetiapine add-on treatment were prescribed for the patient. OUTCOMES: The therapeutic strategy had a limited effect on the patient. LESSONS: Early onset of SAD and T2DM, as well as irregular treatment, resulting in brain atrophy coupled with cognitive impairments, may be the main causes of the patient's treatment resistance and poor outcome. The risks and benefits of treatment strategies should be individually assessed. Further neuroimaging, pertinent biomarkers, and genetic tests along with long-term follow-up are needed for precise evaluation of the patient's condition.


Assuntos
Transtornos Cognitivos/complicações , Disfunção Cognitiva/etiologia , Diabetes Mellitus Tipo 2/complicações , Degeneração Lobar Frontotemporal/etiologia , Transtornos Psicóticos/complicações , Adulto , Disfunção Cognitiva/diagnóstico por imagem , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Degeneração Lobar Frontotemporal/patologia , Humanos , Masculino , Neuroimagem , Tomografia Computadorizada por Raios X
7.
Brain ; 142(4): 1121-1133, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30906945

RESUMO

Cortical mean diffusivity has been proposed as a novel biomarker for the study of the cortical microstructure in Alzheimer's disease. In this multicentre study, we aimed to assess the cortical microstructural changes in the behavioural variant of frontotemporal dementia (bvFTD); and to correlate cortical mean diffusivity with clinical measures of disease severity and CSF biomarkers (neurofilament light and the soluble fraction beta of the amyloid precursor protein). We included 148 participants with a 3 T MRI and appropriate structural and diffusion weighted imaging sequences: 70 patients with bvFTD and 78 age-matched cognitively healthy controls. The modified frontotemporal lobar degeneration clinical dementia rating was obtained as a measure of disease severity. A subset of patients also underwent a lumbar puncture for CSF biomarker analysis. Two independent raters blind to the clinical data determined the presence of significant frontotemporal atrophy to dichotomize the participants into possible or probable bvFTD. Cortical thickness and cortical mean diffusivity were computed using a surface-based approach. We compared cortical thickness and cortical mean diffusivity between bvFTD (both using the whole sample and probable and possible bvFTD subgroups) and controls. Then we computed the Cohen's d effect size for both cortical thickness and cortical mean diffusivity. We also performed correlation analyses with the modified frontotemporal lobar degeneration clinical dementia rating score and CSF neuronal biomarkers. The cortical mean diffusivity maps, in the whole cohort and in the probable bvFTD subgroup, showed widespread areas with increased cortical mean diffusivity that partially overlapped with cortical thickness, but further expanded to other bvFTD-related regions. In the possible bvFTD subgroup, we found increased cortical mean diffusivity in frontotemporal regions, but only minimal loss of cortical thickness. The effect sizes of cortical mean diffusivity were notably higher than the effect sizes of cortical thickness in the areas that are typically involved in bvFTD. In the whole bvFTD group, both cortical mean diffusivity and cortical thickness correlated with measures of disease severity and CSF biomarkers. However, the areas of correlation with cortical mean diffusivity were more extensive. In the possible bvFTD subgroup, only cortical mean diffusivity correlated with the modified frontotemporal lobar degeneration clinical dementia rating. Our data suggest that cortical mean diffusivity could be a sensitive biomarker for the study of the neurodegeneration-related microstructural changes in bvFTD. Further longitudinal studies should determine the diagnostic and prognostic utility of this novel neuroimaging biomarker.


Assuntos
Doença de Alzheimer/patologia , Atrofia/patologia , Demência Frontotemporal/patologia , Idoso , Encéfalo/patologia , Estudos de Coortes , Imagem de Difusão por Ressonância Magnética/métodos , Imagem de Tensor de Difusão/métodos , Feminino , Demência Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Substância Branca/patologia
8.
Cogn Behav Neurol ; 32(1): 46-53, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30896577

RESUMO

Four patients with primary progressive aphasia displayed a greater deficit in understanding words they heard than words they read, and a further deficiency in naming objects orally rather than in writing. All four had frontotemporal lobar degeneration-transactive response DNA binding protein Type A neuropathology, three determined postmortem and one surmised on the basis of granulin gene (GRN) mutation. These features of language impairment are not characteristic of any currently recognized primary progressive aphasia variant. They can be operationalized as manifestations of dysfunction centered on a putative auditory word-form area located in the superior temporal gyrus of the left hemisphere. The small size of our sample makes the conclusions related to underlying pathology and auditory word-form area dysfunction tentative. Nonetheless, a deeper assessment of such patients may clarify the nature of pathways that link modality-specific word-form information to the associations that mediate their recognition as concepts. From a practical point of view, the identification of these features in patients with primary progressive aphasia should help in the design of therapeutic interventions where written communication modalities are promoted to circumvent some of the oral communication deficits.


Assuntos
Afasia Primária Progressiva/fisiopatologia , Percepção de Forma/fisiologia , Degeneração Lobar Frontotemporal/patologia , Percepção da Fala/fisiologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Temporal/patologia
9.
Neurology ; 92(14): e1580-e1588, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30842294

RESUMO

OBJECTIVE: To investigate the status of the basal forebrain cholinergic system in primary progressive aphasia (PPA) as justification for cholinergic therapy. METHODS: A cohort of 36 brains from PPA participants with the neuropathology of Alzheimer disease (PPA-AD, n = 14) or frontotemporal lobar degeneration (PPA-tau, n = 12; PPA-TDP, n = 10) were used for semiquantitative rating of degeneration and gliosis of basal forebrain cholinergic neurons (BFCN). A subpopulation of 5 PPA-AD and 7 control brains underwent detailed analysis of BFCN pathology and cortical cholinergic axonal loss employing immunohistochemical and histochemical methods and stereologic analysis. RESULTS: Semiquantitatively, 11 (∼80%) PPA-AD participants were rated as having moderate/severe BFCN loss and gliosis, whereas none of the PPA-tau and only 1 (10%) PPA-TDP participant received such a rating. Detailed analysis in the subpopulation of PPA-AD participants revealed substantial tangle formation, loss of BFCN, and degeneration of cortical cholinergic axons. Compared to controls, loss of p75 low affinity neurotrophin receptor-positive BFCN was detected in the PPA-AD participants (p < 0.01). Acetylcholinesterase-positive cholinergic axons in all cortical areas studied displayed loss in PPA-AD (p < 0.005-0.0001). The loss was more severe in the language-dominant left hemisphere and, within the left hemisphere, in language-affiliated cortical areas. CONCLUSIONS: Our results demonstrate prominent depletion of BFCN and cortical cholinergic axons in PPA-AD when compared with normal control or other neuropathologic variants of PPA. The demonstration of cholinergic denervation with an anatomy that fits the clinical picture suggests that cholinergic treatment is justified in patients with PPA who have positive AD biomarkers.


Assuntos
Doença de Alzheimer/patologia , Afasia Primária Progressiva/patologia , Prosencéfalo Basal/patologia , Neurônios Colinérgicos/patologia , Degeneração Lobar Frontotemporal/patologia , Acetilcolinesterase/metabolismo , Idoso , Doença de Alzheimer/metabolismo , Afasia Primária Progressiva/metabolismo , Autopsia , Prosencéfalo Basal/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Neurônios Colinérgicos/metabolismo , Feminino , Degeneração Lobar Frontotemporal/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade
10.
Curr Opin Neurol ; 32(2): 272-278, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30672824

RESUMO

PURPOSE OF REVIEW: Over the last year, research into the immunological and inflammatory signatures of frontotemporal lobar degeneration (FTLD) has accelerated greatly. Herein, we highlight recently proposed roles of brain-resident microglia as well as peripheral myeloid cells in frontotemporal dementia (FTD)-spectrum disorders. RECENT FINDINGS: Recent unbiased genetic, transcriptomic, and proteomic surveys using human data confirm significantly altered immune-function genes as well as transcript and protein modules associated with inflammatory and immune function. Beyond human studies, novel animal models indicate important roles for both microglia and monocytes, and central involvement of genes such as Trem2, Apoe, and Tbk1. SUMMARY: The importance of neuroinflammatory activity in FTD pathophysiology is unambiguous, but whether this activity is primarily beneficial or detrimental remains unclear, with variable results reported for distinct disease paradigms. Going forward, it will be crucial to determine which types of microglial and peripheral myeloid responses are favorable, in response to which specific proteinopathies, and at which point in disease course.


Assuntos
Degeneração Lobar Frontotemporal/imunologia , Animais , Modelos Animais de Doenças , Degeneração Lobar Frontotemporal/patologia , Humanos , Inflamação/patologia , Camundongos
11.
Mol Neurobiol ; 56(5): 3451-3462, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30128653

RESUMO

Aging is characterized by progressive memory decline that can lead to dementia when associated with neurodegeneration. Here, we show in mice that aging-related memory decline involves defective biogenesis of microRNAs (miRNAs), in particular miR-183/96/182 cluster, resulting from increased protein phosphatase 1 (PP1) and altered receptor SMAD (R-SMAD) signaling. Correction of the defect by miR-183/96/182 overexpression in hippocampus or by environmental enrichment that normalizes PP1 activity restores memory in aged animals. Regulation of miR-183/96/182 biogenesis is shown to involve the neurodegeneration-related RNA-binding proteins TDP-43 and FUS. Similar alterations in miR-183/96/182, PP1, and R-SMADs are observed in the brains of patients with amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases with pathological aggregation of TDP-43. Overall, these results identify new mechanistic links between miR-183/96/182, PP1, TDP-43, and FUS in age-related memory deficits and their reversal.


Assuntos
Envelhecimento/patologia , Transtornos da Memória/complicações , Transtornos da Memória/genética , MicroRNAs/biossíntese , Degeneração Neural/complicações , Degeneração Neural/genética , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/patologia , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteína Fosfatase 1/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Proteínas Smad/metabolismo
12.
Neurobiol Aging ; 73: 190-199, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30368160

RESUMO

The majority (90%-95%) of amyotrophic lateral sclerosis (ALS) is sporadic, and ∼50% of patients develop symptoms of frontotemporal degeneration (FTD) associated with shorter survival. The genetic polymorphism rs12608932 in UNC13A confers increased risk of sporadic ALS and sporadic FTD and modifies survival in ALS. Here, we evaluate whether rs12608932 is also associated with frontotemporal disease in sporadic ALS. We identified reduced cortical thickness in sporadic ALS with T1-weighted magnetic resonance imaging (N = 109) relative to controls (N = 113), and observed that minor allele (C) carriers exhibited greater reduction of cortical thickness in the dorsal prefrontal, ventromedial prefrontal, anterior temporal, and middle temporal cortices and worse performance on a frontal lobe-mediated cognitive test (reverse digit span). In sporadic ALS with autopsy data (N = 102), minor allele homozygotes exhibited greater burden of phosphorylated tar DNA-binding protein-43 kda (TDP-43) pathology in the middle frontal, middle temporal, and motor cortices. Our findings demonstrate converging evidence that rs12608932 may modify frontotemporal disease in sporadic ALS and suggest that rs12608932 may function as a prognostic indicator and could be used to define patient endophenotypes in clinical trials.


Assuntos
Esclerose Amiotrófica Lateral/genética , Degeneração Lobar Frontotemporal/genética , Estudos de Associação Genética , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético/genética , Idoso , Alelos , Esclerose Amiotrófica Lateral/complicações , Esclerose Amiotrófica Lateral/diagnóstico por imagem , Esclerose Amiotrófica Lateral/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Proteínas de Ligação a DNA/genética , Feminino , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Degeneração Lobar Frontotemporal/etiologia , Degeneração Lobar Frontotemporal/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Prognóstico , Risco
13.
Nat Neurosci ; 22(1): 65-77, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30559480

RESUMO

Accumulation of abnormally phosphorylated TDP-43 (pTDP-43) is the main pathology in affected neurons of people with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Morphological diversity and neuroanatomical distribution of pTDP-43 accumulations allowed classification of FTLD cases into at least four subtypes, which are correlated with clinical presentations and genetic causes. To understand the molecular basis of this heterogeneity, we developed SarkoSpin, a new method for biochemical isolation of pathological TDP-43. By combining SarkoSpin with mass spectrometry, we revealed proteins beyond TDP-43 that become abnormally insoluble in a disease subtype-specific manner. We show that pTDP-43 extracted from brain forms stable assemblies of distinct densities and morphologies that are associated with disease subtypes. Importantly, biochemically extracted pTDP-43 assemblies showed differential neurotoxicity and seeding that were correlated with disease duration of FTLD subjects. Our data are consistent with the notion that disease heterogeneity could originate from alternate pathological TDP-43 conformations, which are reminiscent of prion strains.


Assuntos
Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Agregados Proteicos/fisiologia , Animais , Encéfalo/patologia , Progressão da Doença , Degeneração Lobar Frontotemporal/patologia , Células HEK293 , Humanos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Espectrometria de Massas , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Fosforilação
14.
J Neurol Neurosurg Psychiatry ; 90(2): 180-186, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30297518

RESUMO

OBJECTIVES: The combination of high YKL-40 (a glial inflammatory marker) and low sAPPß (a soluble ß fragment of amyloid precursor protein) in cerebrospinal fluid (CSF) has been associated with frontotemporal lobar degeneration (FTLD) in clinical series. We investigate these biomarkers in a neuropathologically confirmed cohort of patients with FTLD. METHODS: CSF samples were selected from the Penn FTD Center (University of Pennsylvania). Participants were followed to autopsy and had a neuropathological diagnosis of FTLD-Tau (n=24), transactive response DNA-binding protein with 43 kDa (FTLD-TDP) (n=25) or Alzheimer's disease (AD, n=97). We compared levels of YKL-40 and sAPPß between groups and with cognitively normal controls (n=77), and assessed their diagnostic utility using receiver operating characteristic curves. We also investigated the effect of AD copathology and the correlation between these CSF markers and tau burden at autopsy. RESULTS: Both FTLD groups had lower levels of sAPPß, higher levels of YKL-40 and lower sAPPß:YKL-40 ratio in CSF compared with controls. The group of pure FTLD-Tau (without AD copathology) showed higher levels of YKL-40 than AD and than pure FTLD-TDP. YKL-40 levels correlated with pathological tau burden. The sAPPß:YKL-40 ratio had an area under the curve (AUC) of 0.91 (95% CI 0.86 to 0.96) to distinguish subjects with FTLD from controls, but lower values to distinguish FTLD from AD (AUC 0.70; 95% CI 0.61 to 0.79) and to discriminate FTLD-Tau from FTLD-TDP (AUC 0.67; 95% CI 0.51 to 0.82). CONCLUSIONS: Our study provides pathological confirmation that the combination of low sAPPß and high YKL-40 in CSF is associated with FTLD. These biomarkers could be useful in particular clinical settings when FTLD is suspected.


Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Degeneração Lobar Frontotemporal/líquido cefalorraquidiano , Degeneração Lobar Frontotemporal/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Estudos de Coortes , Proteínas de Ligação a DNA/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Proteínas tau/líquido cefalorraquidiano
15.
Psychogeriatrics ; 19(3): 282-285, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30393946

RESUMO

Adult-onset leucoencephalopathy with axonal spheroids and pigmented glia (ALSP), also known as hereditary diffuse leucoencephalopathy with spheroids (HDLS), is a progressive neurocognitive disorder that predominantly affects the cerebral white matter, mainly the frontal subcortical areas and the corpus callosum. Patients with ALSP are clinically characterized by a gradual onset of cognitive and behavioural dysfunction and personality changes, followed by motor impairments such as gait disturbance and bradykinesia. Given the disease-related degenerative changes of the frontal white matter, it is no wonder that patients with ALSP present with behavioural symptoms and non-fluent aphasia, which are found in patients with frontotemporal lobar degeneration. However, behavioural symptoms and non-fluent aphasia in a patient with ALSP have rarely reported in detail. Here, we describe a patient with ALSP who initially presented with remarkable behavioural signs and non-fluent primary progressive aphasia, which resembled symptoms of frontotemporal lobar degeneration. The present case suggests that ALSP should be included in the differential diagnosis for frontotemporal lobar degeneration.


Assuntos
Degeneração Lobar Frontotemporal/patologia , Leucoencefalopatias/patologia , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Substância Branca/diagnóstico por imagem , Adulto , Humanos , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Masculino , Neuroglia , Tecnécio
16.
J Neurol ; 266(2): 330-338, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30506397

RESUMO

The applause sign, i.e., the inability to execute the same amount of claps as performed by the examiner, was originally reported as a sign specific for progressive supranuclear palsy (PSP). Recent research, however, has provided evidence for the occurrence of the applause sign in various conditions. The aim of this study was to determine the prevalence of the applause sign and correlate its presence with neuropsychological and MRI volumetry findings in frontotemporal lobar degeneration and related conditions. The applause sign was elicited with the three clap test (TCT), with a higher score indicating poorer performance. Data were recorded from 272 patients from the cohort of the German consortium for frontotemporal lobar degeneration (FTLDc): 111 with behavioral variant frontotemporal dementia (bvFTD), 98 with primary progressive aphasia (PPA), 30 with progressive supranuclear palsy Richardson's syndrome, 17 with corticobasal syndrome (CBS) and 16 with amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). For comparison, 29 healthy elderly control subjects (HC) were enrolled in the study. All subjects underwent detailed language and neuropsychological assessment. In a subset of 156 subjects, atlas-based volumetry was performed. The applause sign occurred in all patient groups (40% in PSP, 29.5% in CBS, 25% in ALS/FTD, 13.3% in PPA and 9.0% in bvFTD) but not in healthy controls. The prevalence was highest in PSP patients. It was significantly more common in PSP as compared to bvFTD, PPA and HC. The comparison between the other groups failed to show a significant difference regarding the occurrence of the applause sign. The applause sign was highly correlated to a number of neuropsychological findings, especially to measures of executive, visuospatial, and language function as well as measures of disease severity. TCT scores showed an inverse correlation with the volume of the ventral diencephalon and the pallidum. Furthermore the volume of the ventral diencephalon and pallidum were significantly smaller in patients displaying the applause sign. Our study confirms the occurrence of the applause sign in bvFTD, PSP and CBS and adds PPA and ALS/FTD to these conditions. Although still suggestive of PSP, clinically it must be interpreted with caution. From the correlation with various cognitive measures we suggest the applause sign to be indicative of disease severity. Furthermore we suggest that the applause sign represents dysfunction of the pallidum and the subthalamic nucleus, structures which are known to play important roles in response inhibition.


Assuntos
Degeneração Lobar Frontotemporal/patologia , Degeneração Lobar Frontotemporal/fisiopatologia , Globo Pálido/patologia , Índice de Gravidade de Doença , Núcleo Subtalâmico/patologia , Paralisia Supranuclear Progressiva/patologia , Paralisia Supranuclear Progressiva/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos
17.
J Neurol ; 265(12): 2960-2971, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30324308

RESUMO

OBJECTIVES: To determine the clinical, anatomical, genetic and pathological features of dual frontotemporal lobar degeneration (FTLD) pathology: FTLD-tau and FTLD-TDP-43 in a large clinicopathological cohort. METHODS: We selected subjects with mixed FTLD-TDP and FTLD-tau from 247 FTLD cases from the University of California, San Francisco, Neurodegenerative Disease Brain Bank collected between 2000 and 2016 and compared their clinical, anatomical, genetic, imaging and pathological signatures with those of subjects with pure FTLD. RESULTS: We found nine cases (3.6%) with prominent FTLD-TDP and FTLD-tau. Six cases were sporadic, whereas one case had a C9ORF72 expansion, another had a TARDBP A90V variant, and the other had an MAPT p.A152T variant. The subtypes of FTLD-TDP and FTLD-tau varied. Mixed FTLD cases were older and tended to show a higher burden of Alzheimer disease pathology (3/9, 33%). The neuroimaging signature of mixed cases, in general, included more widespread atrophy than that of pure groups. Specifically, cases of mixed corticobasal degeneration (CBD) with FTLD-TDP showed more prominent asymmetric left-sided atrophy than did those of pure CBD. However, the clinical phenotype of mixed cases was similar to that seen in pure FTLD. CONCLUSIONS: Although patients with mixed FTLD-TDP and FTLD-tau are rare, in-depth clinical, pathological and genetic investigations may shed light on the genetic and biochemical pathways that cause the accumulation of multiple proteinaceous inclusions and inform therapeutic targets that may be beneficial to each one of these abnormal protein misfoldings.


Assuntos
Encéfalo/patologia , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Tauopatias/genética , Tauopatias/patologia , Idoso , Idoso de 80 Anos ou mais , Atrofia , Encéfalo/diagnóstico por imagem , Proteína C9orf72/genética , Proteínas de Ligação a DNA/genética , Feminino , Degeneração Lobar Frontotemporal/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tauopatias/diagnóstico por imagem , Proteínas tau/genética
18.
Nat Commun ; 9(1): 4220, 2018 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-30310141

RESUMO

The stereotypical distribution of TAR DNA-binding 43 protein (TDP-43) aggregates in frontotemporal lobar degeneration (FTLD-TDP) suggests that pathological TDP-43 spreads throughout the brain via cell-to-cell transmission and correlates with disease progression, but no in vivo experimental data support this hypothesis. We first develop a doxycycline-inducible cell line expressing GFP-tagged cytoplasmic TDP-43 protein (iGFP-NLSm) as a cell-based system to screen and identify seeding activity of human brain-derived pathological TDP-43 isolated from sporadic FTLD-TDP and familial cases with Granulin (FTLD-TDP-GRN) or C9orf72 repeat expansion mutations (FTLD-TDP-C9+). We demonstrate that intracerebral injections of biologically active pathogenic FTLD-TDP seeds into transgenic mice expressing cytoplasmic human TDP-43 (lines CamKIIa-hTDP-43NLSm, rNLS8, and CamKIIa-208) and non-transgenic mice led to the induction of de-novo TDP-43 pathology. Moreover, TDP-43 pathology progressively spreads throughout the brain in a time-dependent manner via the neuroanatomic connectome. Our study suggests that the progression of FTLD-TDP reflects the templated cell-to-cell transneuronal spread of pathological TDP-43.


Assuntos
Encéfalo/patologia , Proteínas de Ligação a DNA/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Extratos de Tecidos/metabolismo , Animais , Citoplasma/metabolismo , Hipocampo/patologia , Humanos , Camundongos , Neurônios/metabolismo , Neurônios/patologia
19.
J Clin Neurosci ; 58: 172-180, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30348585

RESUMO

Frontotemporal dementia results from different neurodegenerative diseases heterogeneous from a clinical, neuropathological and genetic point of view. Our main objective was to analyze the sociodemographic, clinical, neuropathological and molecular characteristics of cases with frontotemporal lobar degeneration from different Neurological Tissue Banks. FTD has been considered as a disease with onset below 65. However, diagnosis at higher ages is increasingly common. In our study, there was a correlation between symptoms and disease course with certain neuropathological diagnoses, with different distribution depending on age and sex. Combined pathology with Alzheimer's and vascular pathology was observed and presence of argyrophilic grains, with a different distribution in the different subgroups and a particular clinical and progression phenotype. Low percentage of APOE4 was detected. H1/H1 haplotype of the MAPT gene was the most frequent and appeared in relationship with 4R tauopathies. These results point to biologically significant differences between the different types of FTLD.


Assuntos
Degeneração Lobar Frontotemporal/classificação , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
20.
Acta Neuropathol Commun ; 6(1): 75, 2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30092839

RESUMO

The combined fluorescent and Aß-binding properties of the dietary spice curcumin could yield diagnostic purpose in the search for a non-invasive Aß-biomarker for Alzheimer's disease (AD). However, evidence on the binding properties of curcumin, its conjugates and clinically used bio-available formulations to AD neuropathological hallmarks is scarce. We therefore assessed the binding properties of different curcumin forms to different neuropathological deposits in post-mortem brain tissue of cases with AD, other neurodegenerative diseases, and controls. Post mortem brain tissue was histochemically assessed for the binding of curcumin, its isoforms, conjugates and bio-available forms and compared to routinely used staining methods. For this study we included brains of early onset AD, late onset AD, primary age-related tauopathy (PART), cerebral amyloid angiopathy (CAA), frontotemporal lobar degeneration (FTLD) with tau or TAR DNA-binding protein 43 (TDP-43) inclusions, dementia with Lewy bodies (DLB), Parkinson's disease (PD) and control cases without brain pathology. We found that curcumin binds to fibrillar amyloid beta (Aß) in plaques and CAA. It does not specifically bind to inclusions of protein aggregates in FTLD-tau cases, TDP-43, or Lewy bodies. Curcumin isoforms, conjugates and bio-available forms show affinity for the same Aß structures. Curcumin staining overlaps with immunohistochemical detection of Aß in fibrillar plaques and CAA, and to a lesser extent cored plaques. A weak staining of neurofibrillary tangles was observed, while other structures immunopositive for phosphorylated tau remained negative. In conclusion, curcumin, its isoforms, conjugates and bio-available forms selectively bind fibrillar Aß in plaques and CAA in post mortem AD brain tissue. Curcumin, being a food additive with fluorescent properties, is therefore an interesting candidate for in-vivo diagnostics in AD, for example in retinal fluorescent imaging.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/farmacologia , Encéfalo/efeitos dos fármacos , Curcumina/farmacologia , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/metabolismo , Autopsia , Angiopatia Amiloide Cerebral/patologia , Curcumina/classificação , Proteínas de Ligação a DNA/metabolismo , Feminino , Degeneração Lobar Frontotemporal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Ligação Proteica/efeitos dos fármacos , Estudos Retrospectivos , Tauopatias/patologia , Proteínas tau/metabolismo
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