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A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Humanos , InmunofenotipificaciónRESUMEN
Genome-wide association studies have successfully identified many genetic risk loci for dementia, but exact biological mechanisms through which genetic risk factors contribute to dementia remains unclear. Integrating CSF proteomic data with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of dementia. We tested to what extent effects of known dementia risk loci can be observed in CSF levels of 665 proteins (proximity extension-based (PEA) immunoassays) in a deeply-phenotyped mixed-memory clinic cohort (n=502, mean age (sd) = 64.1 [8.7] years, 181 female [35.4%]), including patients with Alzheimer's disease (AD, n=213), dementia with Lewy bodies (DLB, n=50) and frontotemporal dementia (FTD, n=93), and controls (n=146). Validation was assessed in independent cohorts (n=99 PEA platform, n=198, MRM-targeted mass spectroscopy and multiplex assay). We performed additional analyses stratified according to diagnostic status (AD, DLB, FTD and controls separately), to explore whether associations between CSF proteins and genetic variants were specific to disease or not. We identified four AD risk loci as protein quantitative trait loci (pQTL): CR1-CR2 (rs3818361, P=1.65e-08), ZCWPW1-PILRB (rs1476679, P=2.73e-32), CTSH-CTSH (rs3784539, P=2.88e-24) and HESX1-RETN (rs186108507, P=8.39e-08), of which the first three pQTLs showed direct replication in the independent cohorts. We identified one AD-specific association between a rare genetic variant of TREM2 and CSF IL6 levels (rs75932628, P = 3.90e-7). DLB risk locus GBA showed positive trans effects on seven inter-related CSF levels in DLB patients only. No pQTLs were identified for frontotemporal dementia, either for the total sample as for analyses performed within FTD only. pQTL variants were involved in the immune system, highlighting the importance of this system in the pathophysiology of dementia. We further identified pQTLs in stratified analyses for AD and DLB, hinting at disease-specific pQTLs in dementia. Dissecting the contribution of risk loci to neurobiological processes aids in understanding disease mechanisms underlying dementia.
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Autosomal dominant Alzheimer's disease (ADAD) offers a unique opportunity to study pathophysiological changes in a relatively young population with few comorbidities. A comprehensive investigation of proteome changes occurring in ADAD could provide valuable insights into AD-related biological mechanisms and uncover novel biomarkers and therapeutic targets. Furthermore, ADAD might serve as a model for sporadic AD, but in-depth proteome comparisons are lacking. We aimed to identify dysregulated CSF proteins in ADAD and determine the degree of overlap with sporadic AD. We measured 1472 proteins in CSF of PSEN1 or APP mutation carriers (n = 22) and age- and sex-matched controls (n = 20) from the Amsterdam Dementia Cohort using proximity extension-based immunoassays (PEA). We compared protein abundance between groups with two-sided t-tests and identified enriched biological pathways. Using the same protein panels in paired plasma samples, we investigated correlations between CSF proteins and their plasma counterparts. Finally, we compared our results with recently published PEA data from an international cohort of sporadic AD (n = 230) and non-AD dementias (n = 301). All statistical analyses were false discovery rate-corrected. We detected 66 differentially abundant CSF proteins (65 increased, 1 decreased) in ADAD compared to controls (q < 0.05). The most strongly upregulated proteins (fold change >1.8) were related to immunity (CHIT1, ITGB2, SMOC2), cytoskeletal structure (MAPT, NEFL) and tissue remodelling (TMSB10, MMP-10). Significant CSF-plasma correlations were found for the upregulated proteins SMOC2 and LILR1B. Of the 66 differentially expressed proteins, 36 had been measured previously in the sporadic dementias cohort, 34 of which (94%) were also significantly upregulated in sporadic AD, with a strong correlation between the fold changes of these proteins in both cohorts (rs = 0.730, P < 0.001). Twenty-nine of the 36 proteins (81%) were also upregulated among non-AD patients with suspected AD co-pathology. This CSF proteomics study demonstrates substantial biochemical similarities between ADAD and sporadic AD, suggesting involvement of the same biological processes. Besides known AD-related proteins, we identified several relatively novel proteins, such as TMSB10, MMP-10 and SMOC2, which have potential as novel biomarkers. With shared pathophysiological CSF changes, ADAD study findings might be translatable to sporadic AD, which could greatly expedite therapy development.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Metaloproteinasa 10 de la Matriz , Proteómica , Proteoma , Biomarcadores , Péptidos beta-AmiloidesRESUMEN
INTRODUCTION: There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants. METHODS: Adults (45-65 years) with a parental history of AD were enrolled (n = 82). CSF and blood biomarkers were collected at baseline and year 2. RESULTS: CSF total tau (t-tau), phosphorylated tau (p-tau), and amyloid beta (Aß)40 were elevated at year 2 compared to baseline. CSF soluble platelet-derived growth factor receptor ß (sPDGFRß) levels, a marker of pericyte injury, correlated positively with t-tau, p-tau, Aß40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRß and tau were significantly lower in B/AA than NHW. DISCUSSION: Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race-related differences in these relationships. HIGHLIGHTS: Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high-risk middle-aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non-Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Lesiones del Sistema Vascular , Persona de Mediana Edad , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Enfermedades Neuroinflamatorias , Proteínas tau/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
INTRODUCTION: In this study, we investigated biomarkers in a midlife, racially diverse, at-risk cohort to facilitate early identification and intervention. We examined neuroimaging measures, including resting state functional magnetic resonance imaging (fMRI), white matter hyperintensity vo (WMH), and hippocampal volumes, alongside cerebrospinal fluid (CSF) markers. METHODS: Our data set included 76 cognitively unimpaired, middle-aged, Black Americans (N = 29, F/M = 17/12) and Non-Hispanic White (N = 47, F/M = 27/20) individuals. We compared cerebrospinal fluid phosphorylated tau141 and amyloid beta (Aß)42 to fMRI default mode network (DMN) subnetwork connectivity, WMH volumes, and hippocampal volumes. RESULTS: Results revealed a significant race × Aß42 interaction in Black Americans: lower Aß42 was associated with reduced DMN connectivity and increased WMH volumes regions but not in non-Hispanic White individuals. DISCUSSION: Our findings suggest that precuneus DMN connectivity and temporal WMHs may be linked to Alzheimer's disease risk pathology during middle age, particularly in Black Americans. HIGHLIGHTS: Cerebrospinal fluid (CSF) amyloid beta (Aß)42 relates to precuneus functional connectivity in Black, but not White, Americans. Higher white matter hyperintensity volume relates to lower CSF Aß42 in Black Americans. Precuneus may be a hub for early Alzheimer's disease pathology changes detected by functional connectivity.
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The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-ß42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-ß42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Adolescente , Adulto , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Antígenos de Neoplasias , Clorhidrato de Atomoxetina/uso terapéutico , Biomarcadores , Moléculas de Adhesión Celular , Disfunción Cognitiva/patología , Estudios Cruzados , Método Doble Ciego , Reposicionamiento de Medicamentos , Humanos , Inflamación , Persona de Mediana Edad , Neuroprotección , Norepinefrina , Proteínas tauRESUMEN
INTRODUCTION: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODS: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTS: During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]). DISCUSSION: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Microglía/patología , Inflamación , Apolipoproteínas E/genéticaRESUMEN
There are few detailed investigations of neurologic complications in severe acute respiratory syndrome coronavirus 2 infection. We describe 3 patients with laboratory-confirmed coronavirus disease who had encephalopathy and encephalitis develop. Neuroimaging showed nonenhancing unilateral, bilateral, and midline changes not readily attributable to vascular causes. All 3 patients had increased cerebrospinal fluid (CSF) levels of anti-S1 IgM. One patient who died also had increased levels of anti-envelope protein IgM. CSF analysis also showed markedly increased levels of interleukin (IL)-6, IL-8, and IL-10, but severe acute respiratory syndrome coronavirus 2 was not identified in any CSF sample. These changes provide evidence of CSF periinfectious/postinfectious inflammatory changes during coronavirus disease with neurologic complications.
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Betacoronavirus , Encefalopatías/virología , Infecciones por Coronavirus/complicaciones , Citocinas/líquido cefalorraquídeo , Encefalitis Viral/virología , Neumonía Viral/complicaciones , Adulto , Encefalopatías/líquido cefalorraquídeo , COVID-19 , Infecciones por Coronavirus/líquido cefalorraquídeo , Infecciones por Coronavirus/virología , Encefalitis Viral/líquido cefalorraquídeo , Resultado Fatal , Femenino , Georgia , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/líquido cefalorraquídeo , Neumonía Viral/virología , SARS-CoV-2RESUMEN
Among patients with coronavirus disease (COVID-19), IgM levels increased early after symptom onset for those with mild and severe disease, but IgG levels increased early only in those with severe disease. A similar pattern was observed in a separate serosurveillance cohort. Mild COVID-19 should be investigated separately from severe COVID-19.
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COVID-19/inmunología , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Índice de Severidad de la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/fisiopatología , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Georgia , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Estudios Prospectivos , SARS-CoV-2RESUMEN
OBJECTIVE: Compared to older Caucasians, older African Americans have higher risks of developing Alzheimer disease (AD) and lower cerebrospinal fluid (CSF) tau biomarker levels. It is not known whether tau-related differences begin earlier in life or whether race modifies other AD-related biomarkers such as inflammatory proteins. METHODS: We performed multiplex cytokine analysis in a healthy middle-aged cohort with family history of AD (n = 68) and an older cohort (n = 125) with normal cognition (NC), mild cognitive impairment, or AD dementia. After determining baseline interleukin (IL)-9 level and AD-associated IL-9 change to differ according to race, we performed immunohistochemical analysis for proteins mechanistically linked to IL-9 in brains of African Americans and Caucasians (n = 38), and analyzed postmortem IL-9-related gene expression profiles in the publicly available Mount Sinai cohort (26 African Americans and 180 Caucasians). RESULTS: Compared to Caucasians with NC, African Americans with NC had lower CSF tau, p-Tau181 , and IL-9 levels in both living cohorts. Conversely, AD was only correlated with increased CSF IL-9 levels in African Americans but not Caucasians. Immunohistochemical analysis revealed perivascular, neuronal, and glial cells immunoreactive to IL-9, and quantitative analysis in independent US cohorts showed AD to correlate with molecular changes (upstream differentiation marker and downstream effector cell marker) of IL-9 upregulation only in African Americans but not Caucasians. INTERPRETATION: Baseline and AD-associated IL-9 differences between African Americans and Caucasians point to distinct molecular phenotypes for AD according to ancestry. Genetic and nongenetic factors need to be considered in future AD research involving unique populations. ANN NEUROL 2019;86:407-418.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Negro o Afroamericano , Encéfalo/metabolismo , Disfunción Cognitiva/líquido cefalorraquídeo , Interleucina-9/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Anciano , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Población BlancaRESUMEN
The Washington University School of Medicine Knight Alzheimer Disease Research Center's "African American Participation in Alzheimer Disease Research: Effective Strategies" Workshop convened to address a major limitation of the ongoing scientific progress regarding Alzheimer's disease and related dementias (ADRD): participants in most ADRD research programs overwhelmingly have been limited to non-Hispanic white persons, thus precluding knowledge as to how ADRD may be represented in non-white individuals. Factors that may contribute to successful recruitment and retention of African Americans into ADRD research were discussed and organized into actionable next steps as described within this report.
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Enfermedad de Alzheimer/etnología , Negro o Afroamericano/estadística & datos numéricos , Ensayos Clínicos como Asunto , Selección de Paciente , Anciano , Femenino , Humanos , Masculino , Estados UnidosRESUMEN
As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139-146.
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Esclerosis Amiotrófica Lateral/genética , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Proteínas/genética , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Proteína C9orf72 , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosforilación , Análisis de Supervivencia , Adulto JovenRESUMEN
In a large multicentre sample of cognitively normal subjects, as a function of age, gender and APOE genotype, we studied the frequency of abnormal cerebrospinal fluid levels of Alzheimer's disease biomarkers including: total tau, phosphorylated tau and amyloid-ß1-42. Fifteen cohorts from 12 different centres with either enzyme-linked immunosorbent assays or Luminex® measurements were selected for this study. Each centre sent nine new cerebrospinal fluid aliquots that were used to measure total tau, phosphorylated tau and amyloid-ß1-42 in the Gothenburg laboratory. Seven centres showed a high correlation with the new Gothenburg measurements; therefore, 10 cohorts from these centres are included in the analyses here (1233 healthy control subjects, 40-84 years old). Amyloid-ß amyloid status (negative or positive) and neurodegeneration status (negative or positive) was established based on the pathological cerebrospinal fluid Alzheimer's disease cut-off values for cerebrospinal fluid amyloid-ß1-42 and total tau, respectively. While gender did not affect these biomarker values, APOE genotype modified the age-associated changes in cerebrospinal fluid biomarkers such that APOE ε4 carriers showed stronger age-related changes in cerebrospinal fluid phosphorylated tau, total tau and amyloid-ß1-42 values and APOE ε2 carriers showed the opposite effect. At 40 years of age, 76% of the subjects were classified as amyloid negative, neurodegeneration negative and their frequency decreased to 32% at 85 years. The amyloid-positive neurodegeneration-negative group remained stable. The amyloid-negative neurodegeneration-positive group frequency increased slowly from 1% at 44 years to 16% at 85 years, but its frequency was not affected by APOE genotype. The amyloid-positive neurodegeneration-positive frequency increased from 1% at 53 years to 28% at 85 years. Abnormally low cerebrospinal fluid amyloid-ß1-42 levels were already frequent in midlife and APOE genotype strongly affects the levels of cerebrospinal fluid amyloid-ß1-42, phosphorylated tau and total tau across the lifespan without influencing the frequency of subjects with suspected non-amyloid pathology.
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Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Cognición/fisiología , Fragmentos de Péptidos/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Análisis de Varianza , Apolipoproteínas E/genética , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Neurodegenerativas/etiología , Pruebas Neuropsicológicas , Índice de Severidad de la EnfermedadRESUMEN
Natural history and mechanisms for persistent cognitive symptoms ("brain fog") following acute and often mild COVID-19 are unknown. In a large prospective cohort of people who underwent testing a median of 9 months after acute COVID-19 in the New York City/New Jersey area, we found that cognitive dysfunction is common; is not influenced by mood, fatigue, or sleepiness; and is correlated with MRI changes in very few people. In a subgroup that underwent cerebrospinal fluid analysis, there are no changes related to Alzheimer's disease or neurodegeneration. Single-cell gene expression analysis in the cerebrospinal fluid shows findings consistent with monocyte recruitment, chemokine signaling, cellular stress, and suppressed interferon response-especially in myeloid cells. Longitudinal analysis shows slow recovery accompanied by key alterations in inflammatory genes and increased protein levels of CXCL8, CCL3L1, and sTREM2. These findings suggest that the prognosis for brain fog following COVID-19 correlates with myeloid-related chemokine and interferon-responsive genes.
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COVID-19 , Disfunción Cognitiva , SARS-CoV-2 , Análisis de la Célula Individual , Humanos , COVID-19/líquido cefalorraquídeo , COVID-19/patología , COVID-19/complicaciones , Masculino , Análisis de la Célula Individual/métodos , Femenino , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/patología , Disfunción Cognitiva/virología , Disfunción Cognitiva/genética , Persona de Mediana Edad , SARS-CoV-2/aislamiento & purificación , Anciano , Receptores Inmunológicos/genética , Estudios Prospectivos , Adulto , Imagen por Resonancia Magnética , Glicoproteínas de Membrana , Interleucina-8RESUMEN
INTRODUCTION: South Asian (SA) and East Asian (EA) older adults represent the fastest-growing racial/ethnic groups of Americans at risk for dementia. While recruiting older SA adults into a brain health study, we encountered unexpected hesitancy toward structural brain magnetic resonance imaging (MRI) analysis and stigmatizing attitudes related to internal locus of control (LoC) for future dementia risks. We hypothesized that support for MRI-related research was influenced by these attitudes as well as personal MRI experience, perceived MRI safety, and concerns for personal risk for future dementia/stroke. METHODS: We developed a brief cross-sectional survey to assess older adults' MRI experiences and perceptions, desire to learn of six incidental findings of increasing impact on health, and attitudes related to dementia (including LoC) and research participation. We recruited a convenience sample of 256 respondents (74% reporting as 50+) from the New Jersey/New York City area to complete the survey (offered in English, Chinese, Korean, and Spanish) and modeled the proportional odds (PO) for favorable attitudes toward research activities. RESULTS: Seventy-seven SA and 84 EA respondents were analyzed alongside 95 White, Black, or Hispanic adults. White (PO = 2.54, p = 0.013) and EA (PO = 2.14, p = 0.019) respondents were both more likely than SA respondents to endorse healthy volunteers' participation in research, and the difference between White and SA respondents was mediated by the latter's greater internal LoC for dementia risks. EA respondents had more worries for future dementia/stroke than SA respondents (p = 0.006) but still shared SA respondents' lower wish (measured by proportion of total) to learn of incidental MRI findings. DISCUSSION: SA-and EA compared to SA-older adults had low desire to learn of incidental MRI findings but had different attitudes toward future dementia/stroke risks. A culturally appropriate protocol to disclose incidental MRI findings may improve SA and EA participation in brain health research. Highlights: Older Asian Americans have limited interest in incidental findings on research MRISouth Asians are most likely to attribute dementia to people's own behaviorsSouth Asians' attitudes mediate lower support for healthy volunteers in researchSouth and East Asians differ in dementia worries and research-related attitudes.
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Frontotemporal dementia (FTD) is an increasingly recognized cause of dementia. This review discusses the different FTD clinical syndromes and frontotemporal lobar degeneration (FTLD) pathological correlates as well as new genetic and proteomic findings that have added to our understanding of FTLD pathogenesis. Various diagnostic modalities including the use of biomarkers will also be addressed. Finally we will highlight future directions in the FTD field. More research is needed to elucidate the cellular mechanisms of neurodegeneration in FTLD and improve clinical diagnostic capabilities.
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Degeneración Lobar Frontotemporal/diagnóstico , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Lóbulo Frontal/patología , Degeneración Lobar Frontotemporal/patología , Humanos , Neuroimagen , Lóbulo Temporal/patologíaRESUMEN
Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.
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Modelos Animales de Enfermedad , Descubrimiento de Drogas , Degeneración Lobar Frontotemporal/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Animales , HumanosRESUMEN
Clinical prediction of underlying pathologic substrates in people with Alzheimer's disease (AD) dementia or related dementia syndromes (ADRD) has limited accuracy. Etiologic biomarkers - including cerebrospinal fluid (CSF) levels of AD proteins and cerebral amyloid PET imaging - have greatly modernized disease-modifying clinical trials in AD, but their integration into medical practice has been slow. Beyond core CSF AD biomarkers (including beta-amyloid 1-42, total tau, and tau phosphorylated at threonine 181), novel biomarkers have been interrogated in single- and multi-centered studies with uneven rigor. Here, we review early expectations for ideal AD/ADRD biomarkers, assess these goals' future applicability, and propose study designs and performance thresholds for meeting these ideals with a focus on CSF biomarkers. We further propose three new characteristics: equity (oversampling of diverse populations in the design and testing of biomarkers), access (reasonable availability to 80% of people at risk for disease, along with pre- and post-biomarker processes), and reliability (thorough evaluation of pre-analytical and analytical factors influencing measurements and performance). Finally, we urge biomarker scientists to balance the desire and evidence for a biomarker to reflect its namesake function, indulge data- as well as theory-driven associations, re-visit the subset of rigorously measured CSF biomarkers in large datasets (such as Alzheimer's disease neuroimaging initiative), and resist the temptation to favor ease over fail-safe in the development phase. This shift from discovery to application, and from suspended disbelief to cogent ingenuity, should allow the AD/ADRD biomarker field to live up to its billing during the next phase of neurodegenerative disease research.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Reproducibilidad de los Resultados , Péptidos beta-Amiloides , Biomarcadores , Proteínas tau , Fragmentos de PéptidosRESUMEN
Gene therapies have greatly changed the outlook in spinal muscular atrophy (SMA), and this disorder provides a rare opportunity to study longitudinal biomarker changes correlated with reduced disease burden and improved clinical outcomes. Recent work suggests clinical response to correlate with declining cerebrospinal fluid (CSF) levels of the neurodegenerative marker neurofilament light chain (NfL) in children receiving serial anti-sense oligonucleotide therapy. However, change in CSF NfL levels is no longer a practical biomarker as more children undergo single-dose gene replacement therapy. Here we leverage serial CSF samples (median of 4 per child) collected in 13 children with SMA undergoing anti-sense oligonucleotide therapy to characterize the longitudinal profiles of NfL as well as inflammatory and neuronal proteins. In contrast to neurodegeneration in adults, we found NfL levels to first decrease following initiation of treatment but then increase upon further treatment and improved motor functions. We then examined additional CSF inflammatory and neuronal markers for linear association with motor function during SMA treatment. We identified longitudinal IL-8 levels to inversely correlate with motor functions determined by clinical examination (F(1, 47) = 12.903, p = 0.001) or electromyography in the abductor pollicis brevis muscle (p = 0.064). In keeping with this, lower baseline IL-8 levels were associated with better longitudinal outcomes, even though this difference diminished over 2 years in the younger group. We thus propose CSF IL-8 as a biomarker for baseline function and short-term treatment response in SMA, and a candidate biomarker for future treatment trials in other neurodegenerative disorders.