Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
1.
J Neurol Neurosurg Psychiatry ; 94(7): 541-549, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36977552

RESUMO

BACKGROUND: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). METHODS: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (ß=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007). CONCLUSIONS: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.


Assuntos
Demência Frontotemporal , Degeneração Lobar Frontotemporal , Humanos , Proteína C9orf72/genética , Progressão da Doença , Demência Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Inflamação , Interleucina-6 , Mutação , Proteínas tau/genética , Fator de Necrose Tumoral alfa
2.
Elife ; 112022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-35616532

RESUMO

Background: Neuronal- and circuit-level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (Aß) in preclinical models of Alzheimer's disease (AD). These relationships remain poorly understood in patients with AD. Methods: Using empirical spectra from magnetoencephalography and computational modeling (neural mass model), we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and Aß, measured by positron emission tomography, in patients with AD. Results: Patients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher Aß depositions. Conclusions: Our results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and Aß in patients with AD. Funding: This study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM and GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimer's Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL (KGR), 2019-A-013-SUP (KGR); grants from the Alzheimer's Association: AARG-21-849773 (KGR); PCTRB-13-288476 (KAV), and made possible by Part the CloudTM (ETAC-09-133596); a grant from Tau Consortium (GDR and WJJ), and a gift from the S. D. Bechtel Jr. Foundation.


Assuntos
Doença de Alzheimer , Amiloidose , Amiloide , Peptídeos beta-Amiloides , Biomarcadores , Humanos , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau
3.
J Am Geriatr Soc ; 66(1): 150-156, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29355911

RESUMO

BACKGROUND/OBJECTIVES: Brief cognitive screens lack the sensitivity to detect mild cognitive impairment (MCI) or support differential diagnoses. The objective of this study was to validate the 10-minute, tablet-based University of California, San Francisco (UCSF) Brain Health Assessment (BHA) to overcome these limitations. DESIGN: Cross-sectional. SETTING: UCSF Memory and Aging Center. PARTICIPANTS: Older adults (N = 347) (neurologically healthy controls (n = 185), and individuals diagnosed with MCI (n = 99), dementia (n = 42), and as normal with concerns (n = 21)). MEASUREMENTS: The BHA includes subtests of memory, executive function and speed, visuospatial skills, and language and an optional informant survey. Participants completed the Montreal Cognitive Assessment (MoCA) and criterion-standard neuropsychological tests. Standardized structural 3T brain magnetic resonance imaging was performed in 145 participants. RESULTS: At a fixed 85% specificity rate, the BHA had 100% sensitivity to dementia and 84% to MCI; the MoCA had 75% sensitivity to dementia and 25% to MCI. The BHA had 83% sensitivity to MCI likely due to AD and 88% to MCI unlikely due to AD, and the MoCA had 58% sensitivity to MCI likely AD and 24% to MCI unlikely AD. The BHA subtests demonstrated moderate to high correlations with the criterion-standard tests from their respective cognitive domains. Memory test performance correlated with medial temporal lobe volumes; executive and speed with frontal, parietal, and basal ganglia volumes; and visuospatial with right parietal volumes. CONCLUSION: The BHA had excellent combined sensitivity and specificity to detect dementia and MCI, including MCI due to diverse etiologies. The subtests provide efficient, valid measures of neurocognition that are critical in making a differential diagnosis.


Assuntos
Encéfalo , Programas de Rastreamento , Transtornos Neurocognitivos/diagnóstico , Testes Neuropsicológicos/estatística & dados numéricos , Idoso , Estudos Transversais , Humanos , Imageamento por Ressonância Magnética , São Francisco , Sensibilidade e Especificidade , Inquéritos e Questionários
4.
J Alzheimers Dis ; 55(1): 249-258, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27716661

RESUMO

Patients with pathogenic truncating mutations in the prion gene (PRNP) usually present with prolonged disease courses with severe neurofibrillary tangle and cerebral amyloidosis pathology, but more atypical phenotypes also occur, including those with dysautonomia and peripheral neuropathy. We describe the neurological, cognitive, neuroimaging, and electrophysiological features of a 31-year-old man presenting with an orbitofrontal syndrome, gastrointestinal symptoms, and peripheral neuropathy associated with PRNP Q160X nonsense mutation, with symptom onset at age 27. The mutation was also detected in his asymptomatic father and a symptomatic paternal cousin; several members of prior generations died from early onset dementia. This is the first report of a family affected with the nonsense PRNP mutation Q160X displaying clear autosomal dominant disease in multiple family members and reduced penetrance. This case strengthens the evidence suggesting an association between PRNP truncating mutations and prion systemic amyloidosis. PRNP gene testing should be considered in any patient with atypical dementia, especially with early onset and neuropathy, even in the absence of a family history.


Assuntos
Códon sem Sentido , Doenças Priônicas/genética , Doenças Priônicas/fisiopatologia , Proteínas Priônicas/genética , Adulto , Encéfalo/diagnóstico por imagem , Progressão da Doença , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Linhagem , Nervos Periféricos/fisiopatologia , Fenótipo , Doenças Priônicas/diagnóstico por imagem
5.
Neurology ; 82(6): 512-20, 2014 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-24415571

RESUMO

OBJECTIVE: To investigate whether patients with behavioral variant frontotemporal dementia (bvFTD) have dysregulation in satiety-related hormonal signaling using a laboratory-based case-control study. METHODS: Fifty-four participants (19 patients with bvFTD, 17 patients with Alzheimer disease dementia, and 18 healthy normal controls [NCs]) were recruited from a tertiary-care dementia clinic. During a standardized breakfast, blood was drawn before, during, and after the breakfast protocol to quantify levels of peripheral satiety-related hormones (ghrelin, cortisol, insulin, leptin, and peptide YY) and glucose. To further explore the role of patients' feeding abnormalities on hormone levels, patients were classified into overeating and nonovereating subgroups based on feeding behavior during separate laboratory-based standardized lunch feeding sessions. RESULTS: Irrespective of their feeding behavior in the laboratory, patients with bvFTD, but not patients with Alzheimer disease dementia, have significantly lower levels of ghrelin and cortisol and higher levels of insulin compared with NCs. Furthermore, while laboratory feeding behavior did not predict alterations in levels of ghrelin, cortisol, and insulin, only patients with bvFTD who significantly overate in the laboratory demonstrated significantly higher levels of leptin compared with NCs, suggesting that leptin may be sensitive to particularly severe feeding abnormalities in bvFTD. CONCLUSIONS: Despite a tendency to overeat, patients with bvFTD have a hormonal profile that should decrease food intake. Aberrant hormone levels may represent a compensatory response to the behavioral or neuroanatomical abnormalities of bvFTD.


Assuntos
Biomarcadores/sangue , Comportamento Alimentar , Demência Frontotemporal/sangue , Hiperfagia/sangue , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/fisiopatologia , Glicemia , Estudos de Casos e Controles , Feminino , Demência Frontotemporal/complicações , Demência Frontotemporal/fisiopatologia , Grelina/sangue , Humanos , Hidrocortisona/sangue , Hiperfagia/etiologia , Hiperfagia/fisiopatologia , Insulina/sangue , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Peptídeo YY/sangue
6.
J Neurol Neurosurg Psychiatry ; 84(9): 956-62, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23543794

RESUMO

BACKGROUND: The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored. OBJECTIVE: To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared with neurologically healthy normal controls (NC) and Alzheimer's disease (AD) as dementia controls. DESIGN: Case control. SETTING: Academic medical centres. PARTICIPANTS: 129 svPPA, 39 PGRN, 186 NC and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN and NC cohorts underwent serum analysis for tumour necrosis factor α (TNF-α) levels. OUTCOME MEASURES: χ(2) Comparison of autoimmune prevalence and follow-up logistic regression. RESULTS: There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared with NC. CONCLUSIONS: svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared with NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 aggregation.


Assuntos
Doenças Autoimunes/patologia , Degeneração Lobar Frontotemporal/patologia , Proteinopatias TDP-43/patologia , Idoso , Doença de Alzheimer/patologia , Afasia Primária Progressiva/patologia , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/psicologia , Estudos de Coortes , Escolaridade , Feminino , Degeneração Lobar Frontotemporal/epidemiologia , Degeneração Lobar Frontotemporal/psicologia , Humanos , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Testes Neuropsicológicos , Prevalência , Progranulinas , Escalas de Graduação Psiquiátrica , Proteinopatias TDP-43/epidemiologia , Fator de Necrose Tumoral alfa/metabolismo
7.
Neurocase ; 18(4): 305-17, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22060063

RESUMO

In 2009, inclusions containing the fused in sarcoma (FUS) protein were identified as a third major molecular class of pathology underlying the behavioral variant frontotemporal dementia (bvFTD) syndrome. Due to the low prevalence of FUS pathology, few clinical descriptions have been published and none provides information about specific social-emotional deficits despite evidence for severe behavioral manifestations in this disorder. We evaluated a patient with bvFTD due to FUS pathology using a comprehensive battery of cognitive and social- emotional tests. A structural MRI scan and genetic tests for tau, progranulin, and FUS mutations were also performed. The patient showed preserved general cognitive functioning and superior working memory, but severe deficits in emotion attribution, sensitivity to punishment, and diminished capacity for interpersonal warmth and empathy. The gray matter atrophy pattern corresponded to this focal deficit profile, with preservation of dorsolateral fronto-parietal regions associated with executive functioning but severe damage to right worse than left frontoinsula, temporal pole, subgenual anterior cingulate, medial orbitofrontal cortex, amygdala, and caudate. This patient demonstrates the striking focality associated with FUS neuropathology in patients with bvFTD.


Assuntos
Demência Frontotemporal/psicologia , Proteína FUS de Ligação a RNA/metabolismo , Adulto , Autopsia , Comportamento , Encéfalo/patologia , Tomada de Decisões , Depressão/etiologia , Função Executiva , Evolução Fatal , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Humanos , Comportamento Impulsivo/psicologia , Idioma , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Testes Neuropsicológicos , Proteína FUS de Ligação a RNA/genética , Percepção Espacial , Teoria da Mente
8.
J Int Neuropsychol Soc ; 9(6): 913-24, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-14632250

RESUMO

Coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB) can produce a higher incidence of neuropsychological complications than other types of highly invasive noncardiac vascular surgery. Cognitive complications most likely arise from either embolization or hypoxia. An alternative surgical procedure has been developed that allows CABG to be performed without stopping the heart ("off-pump" CABG, or OPCABG). This study examined the neuropsychological performance of patients undergoing OPCABG, hypothesizing that patients undergoing OPCABG would show fewer cognitive deficits than patients whose hearts were stopped. A 1-hr neuropsychological battery was administered preoperatively to 43 patients before prospective randomization to either CPB CABG or OPCABG, and again to 34 of those patients 2 to 3 months postoperatively by an examiner blind to surgical condition. Neuropsychological status did not change 2.5 months postsurgically in either OPCABG or CABG groups. However, both groups showed dramatic presurgical cognitive deficits in multiple domains, particularly verbal memory and psychomotor speed. This corroborates previous research suggesting that patients requiring CABG surgery may evidence significant presurgical cognitive deficits as a result of existing vascular disease.


Assuntos
Ponte Cardiopulmonar , Transtornos Cognitivos/complicações , Ponte de Artéria Coronária , Doença das Coronárias/complicações , Idoso , Atenção , Transtornos Cognitivos/cirurgia , Doença das Coronárias/cirurgia , Feminino , Seguimentos , Coração Auxiliar/estatística & dados numéricos , Humanos , Masculino , Memória de Curto Prazo , Pessoa de Meia-Idade , Atividade Motora , Testes Neuropsicológicos , Complicações Pós-Operatórias , Período Pós-Operatório , Resolução de Problemas , Estudos Prospectivos , Desempenho Psicomotor , Resultado do Tratamento , Comportamento Verbal
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA