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Visit-to-visit blood pressure variability (BPV) predicts age-related hippocampal atrophy, neurodegeneration, and memory decline in older adults. Beat-to-beat BPV may represent a more reliable and efficient tool for prospective risk assessment, but it is unknown whether beat-to-beat BPV is similarly associated with hippocampal neurodegeneration, or with plasma markers of neuroaxonal/neuroglial injury. Independently living older adults without a history of dementia, stroke, or other major neurological disorders were recruited from the community (N = 104; age = 69.5 ± 6.7 (range 55-89); 63% female). Participants underwent continuous blood pressure monitoring, brain MRI, venipuncture, and cognitive testing over two visits. Hippocampal volumes, plasma neurofilament light, and glial fibrillary acidic protein levels were assessed. Beat-to-beat BPV was quantified as systolic blood pressure average real variability during 7-min of supine continuous blood pressure monitoring. The cross-sectional relationship between beat-to-beat BPV and hippocampal volumes, cognitive domain measures, and plasma biomarkers was assessed using multiple linear regression with adjustment for demographic covariates, vascular risk factors, and average systolic blood pressure. Elevated beat-to-beat BPV was associated with decreased left hippocampal volume (P = .008), increased plasma concentration of glial fibrillary acidic protein (P = .006), and decreased memory composite score (P = .02), independent of age, sex, average systolic blood pressure, total intracranial volume, and vascular risk factor burden. In summary, beat-to-beat BPV is independently associated with decreased left hippocampal volume, increased neuroglial injury, and worse memory ability. Findings are consistent with prior studies examining visit-to-visit BPV and suggest beat-to-beat BPV may be a useful marker of hemodynamic brain injury in older adults.

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Background: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) show differential vulnerability to large-scale brain functional networks. Plasma neurofilament light (NfL), a promising biomarker of neurodegeneration, has been linked in AD patients to glucose metabolism changes in AD-related regions. However, it is unknown whether plasma NfL would be similarly associated with disease-specific functional connectivity changes in AD and bvFTD. Objective: Our study examined the associations between plasma NfL and functional connectivity of the default mode and salience networks in patients with AD and bvFTD. Methods: Plasma NfL and neuroimaging data from patients with bvFTD (n = 16) and AD or mild cognitive impairment (n = 38; AD + MCI) were analyzed. Seed-based functional connectivity maps of key regions within the default mode and salience networks were obtained and associated with plasma NfL in these patients. RESULTS: We demonstrated divergent associations between NfL and functional connectivity in AD + MCI and bvFTD patients. Specifically, AD + MCI patients showed lower default mode network functional connectivity with higher plasma NfL, while bvFTD patients showed lower salience network functional connectivity with higher plasma NfL. Further, lower NfL-related default mode network connectivity in AD + MCI patients was associated with lower Montreal Cognitive Assessment scores and higher Clinical Dementia Rating sum-of-boxes scores, although NfL-related salience network connectivity in bvFTD patients was not associated with Neuropsychiatric Inventory Questionnaire scores. CONCLUSIONS: Our findings indicate that plasma NfL is differentially associated with brain functional connectivity changes in AD and bvFTD.

Asunto(s)

Enfermedad de Alzheimer , Biomarcadores , Demencia Frontotemporal , Imagen por Resonancia Magnética , Proteínas de Neurofilamentos , Humanos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/diagnóstico por imagen , Femenino , Demencia Frontotemporal/sangre , Demencia Frontotemporal/fisiopatología , Demencia Frontotemporal/diagnóstico por imagen , Masculino , Anciano , Proteínas de Neurofilamentos/sangre , Persona de Mediana Edad , Biomarcadores/sangre , Disfunción Cognitiva/sangre , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiopatología , Red en Modo Predeterminado/fisiopatología , Red en Modo Predeterminado/diagnóstico por imagen

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BACKGROUND: Plasma neurofilament light chain (NFL) is a biomarker of inflammation and neurodegenerative diseases such as Alzheimer's disease (AD). However, the underlying neural mechanisms by which NFL affects cognitive function remain unclear. In this study, we investigated the effects of inflammation on cognitive integrity in patients with cognitive impairment through the functional interaction of plasma NFL with large-scale brain networks. METHODS: This study included 29 cognitively normal, 55 LowNFL patients, and 55 HighNFL patients. Group independent component analysis (ICA) was applied to the resting-state fMRI data, and 40 independent components (IC) were extracted for the whole brain. Next, the dynamic functional network connectivity (dFNC) of each subject was estimated using the sliding-window method and k-means clustering, and five dynamic functional states were identified. Finally, we applied mediation analysis to investigate the relationship between plasma NFL and dFNC indicators and cognitive scales. RESULTS: The present study explored the dynamics of whole-brain FNC in controls and LowNFL and HighNFL patients and highlighted the temporal properties of dFNC states in relation to psychological scales. A potential mechanism for the association between dFNC indicators and NFL levels in cognitively impaired patients. CONCLUSIONS: Our findings suggested the decreased ability of information processing and communication in the HighNFL group, which helps us to understand their abnormal cognitive functions clinically. Characteristic changes in the inflammation-coupled dynamic brain network may provide alternative biomarkers for the assessment of disease severity in cognitive impairment patients.

Asunto(s)

Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , Disfunción Cognitiva/diagnóstico por imagen , Inflamación/diagnóstico por imagen , Imagen por Resonancia Magnética

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BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is increasingly recognized as a manifestation preceding the α-synucleinopathies like Parkinson's disease (PD). Neurofilament light chain (NfL) have been reported to be higher in synucleinopathies as a sign of neurodegeneration. OBJECTIVE: To evaluate whether plasma NfL is valuable in reflecting cognitive and motor status in iRBD and PD with a premorbid history of RBD (PDRBD), and predicting disease progression in iRBD. METHODS: Thirty-one patients with iRBD, 30 with PDRBD, and 18 healthy controls were included in the cross-sectional and prospective study. Another cohort from the Parkinson's Progression Markers Initiative (PPMI) dataset was enrolled for verification analysis. All patients received evaluations of cognitive, motor, and autonomic function by a battery of clinical tests at baseline and follow-up. Blood NfL was measured by the Quanterix Simoa HD-1. RESULTS: In our cohort, 26 patients with iRBD completed the follow-up evaluations, among whom eight (30.8%) patients displayed phenoconversion. Baseline plasma NfL cutoff value of 22.93 pg/mL performed best in distinguishing the iRBD converters from non-converters (sensitivity: 75.0%, specificity: 83.3%, area under the curve: 0.84). Cognitive and motor function were significantly correlated with NfL levels in PDRBD (correlation coefficients: -0.379, 0.399; respectively). Higher baseline NfL levels in iRBD were significantly associated with higher risks for cognitive, motor, autonomic function progression, and phenoconversion at follow-up (hazard ratios: 1.069, 1.065, 1.170, 1.065; respectively). The findings were supported by the PPMI dataset. CONCLUSION: Plasma NfL is valuable in reflecting disease severity of PDRBD and predicting disease progression and phenoconversion in iRBD.

Asunto(s)

Enfermedad de Parkinson , Trastorno de la Conducta del Sueño REM , Sinucleinopatías , Humanos , Trastorno de la Conducta del Sueño REM/complicaciones , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/metabolismo , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Estudios Prospectivos , Estudios Transversales , Filamentos Intermedios/metabolismo , Progresión de la Enfermedad

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BACKGROUND: The longitudinal dynamics of neurofilament light chain (NfL) in multiple system atrophy (MSA) were incompletely illuminated. This study aimed to explore whether the plasma NfL (pNfL) could serve as a potential biomarker of clinical diagnosis and disease progression for MSA. METHODS: We quantified pNfL concentrations in both a large cross-sectional cohort with 214 MSA individuals, 65 PD individuals, and 211 healthy controls (HC), and a longitudinal cohort of 84 MSA patients. Propensity score matching (PSM) was used to balance the age between the three groups. The pNfL levels between groups were compared using Kruskal-Wallis test. Linear mixed models were performed to explore the disease progression-associated factors in longitudinal MSA cohort. Random forest model as a complement to linear models was employed to quantify the importance of predictors. RESULTS: Before and after matching the age by PSM, the pNfL levels could reliably differentiate MSA from HC and PD groups, but only had mild potential to distinguish PD from HC. By combining linear and nonlinear models, we demonstrated that pNfL levels at baseline, rather than the change rate of pNfL, displayed potential prognostic value for progression of MSA. The combination of baseline pNfL levels and other modifiers, such as subtypes, Hoehn-Yahr stage at baseline, was first shown to improve the diagnosis accuracy. CONCLUSIONS: Our study contributed to a better understanding of longitudinal dynamics of pNfL in MSA, and validated the values of pNfL as a non-invasive sensitive biomarker for the diagnosis and progression. The combination of pNfL and other factors is recommended for better monitoring and prediction of MSA progression.

Asunto(s)

Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Humanos , Pronóstico , Estudios Longitudinales , Atrofia de Múltiples Sistemas/diagnóstico , Estudios Transversales , Filamentos Intermedios , Enfermedad de Parkinson/diagnóstico , Biomarcadores , Proteínas de Neurofilamentos , Progresión de la Enfermedad

RESUMEN

OBJECTIVE: Background: Plasma neurofilament light chain (NFL) is a recognized biomarker for Alzheimer's disease (AD) and inflammation. Intrinsically organized default mode network core subsystem and frontoparietal network (FPN) and their interactions support complex cognitive function. The present study investigated the inflammatory effect on cognitive integrity via plasma NFL coupling internetwork interactions in AD. OBJECTIVE: Objective: This study investigates the hypothesis that inflammation-related plasma NFL could affect the interactions of the core subsystem and FPN, which leads to the aggravation of the clinical symptoms of AD-spectrum patients. OBJECTIVE: Methods: A total of 112 AD-spectrum participants underwent complete resting-state fMRI, neuropsychological tests, and plasma NFL at baseline (n = 112) and after approximately 17 months of follow-up (n = 112). The specific intersystem changes in the core subsystem and FPN were calculated and compared across groups. Then, the classifications of different AD-spectrum groups were analyzed using the association of plasma NFL and the changed intersystem interacting regions. Finally, mediation analysis was applied to investigate the significance of plasma NFL coupling networks on cognitive impairments in these subjects. OBJECTIVE: Results: Discrimination of disease-related interactions of the core subsystem and FPN was found in AD-spectrum patients, which was the neural circuit fundamental to plasma NFL disrupting cognitive integrity. Furthermore, the clinical significance of plasma NFL coupling networks on AD identification and monitoring cognitive impairments were revealed in these subjects. CONCLUSION: The characteristic change in inflammation-related plasma NFL coupled with brain internetwork interactions could be used as a potential observation indicator in the progression of AD patients.

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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/diagnóstico , Biomarcadores , Encéfalo/diagnóstico por imagen , Cognición , Disfunción Cognitiva/diagnóstico por imagen , Humanos , Inflamación/diagnóstico por imagen , Filamentos Intermedios , Proteínas de Neurofilamentos

RESUMEN

INTRODUCTION: Neurofilament light chain (NfL) is becoming increasingly notable in neurological diseases including AD, and it has been suggested as a new peripherical biomarker of neurodegeneration. We aimed to compare plasma NfL levels among Subjective Cognitive Decline (SCD), Mild Cognitive Impairment (MCI), and AD patients and to evaluate relationships between NfL and CSF biomarkers and neuropsychological scores. MATERIALS AND METHODS: We enrolled 110 patients (34 SCD, 53 MCI, and 23 AD), who underwent clinical and neuropsychological evaluation, APOE genotyping, and plasma NfL analysis. Ninety-one patients underwent at least one amyloid burden biomarker (CSF and/or amyloid PET); 86 patients also underwent CSF phosphorylated-tau (p-tau) and total-tau (t-tau) measurement. Patients were classified as A + if they presented at least one positive amyloid biomarker or A- if not. RESULTS: NfL levels were significantly increased in AD and MCI compared to SCD patients. These differences depend on A status, e.g., SCD A + had lower NfLs than MCI A + but comparable with MCI A-. Similarly, MCI A + had higher NfL levels than MCI A-, but comparable with AD. NfL levels correlated with p-tau in SCD, with all CSF biomarkers in MCI patients. No correlations were found in AD subgroup. In SCD, NfL levels were negatively correlated with memory test scores. CONCLUSIONS: Plasma NfL levels might be a promising biomarker for neurodegeneration to discriminate cognitive decline due to AD from other conditions causing cognitive impairment in prodromal stages. Considering correlations with CSF p-tau and memory tests in SCD, NfL might be a useful peripheral biomarker also in preclinical phases of AD.

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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides , Biomarcadores , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Humanos , Filamentos Intermedios , Proteínas de Neurofilamentos , Pruebas Neuropsicológicas , Proteínas tau

RESUMEN

Objective:To investigate the relationship between rapid eye movement sleep behavior disorder(RBD)and neurofilament light chain(NfL)levels in patients with Parkinson's disease(PD).Methods:General clinical data of 121 PD patients and 38 healthy controls(HC)who visited the Department of Geriatric Neurology of the First Affiliated Hospital of Kunming Medical University from June 2019 to January 2021 were collected in a prospective study.According to the Rapid Eye Movement Sleep Behavior Disorder Questionnaire(RBDSQ), PD patients were divided into a PD with RBD group(PD-RBD, RBDSQ≥6)and a PD without RBD group(PD-NRBD, RBDSQ<6). General clinical data and plasma NfL levels of patients in the groups were compared.In addition, symptoms during exercise, during non-exercise, and sleep quality in the groups were also compared.Results:Plasma NfL levels were higher in the PD group than in the HC group(19.39 ng/L, 12.58-31.78; 14.85 ng/L, 9.78-22.15; Z=-2.492, P<0.05); plasma NfL levels were significantly higher in the PD-RBD group than in the PD-NRBD group and in the HC group(25.29 ng/L, 19.09-34.75; 17.14 ng/L, 11.70-26.67; 14.85 ng/L, 9.78-22.15; Z=-3.434, P<0.01); there was no significant difference in plasma NfL levels between the HC group and the PD-NRBD group( P>0.05). Receiver operating characteristic(ROC)curve analysis showed that, when the plasma NfL cutoff was set at 17.86 ng/L, PD-RBD and PD-NRBD could be distinguished( AUC=0.70, 95% CI=0.60-0.80, sensitivity 82%, specificity 54%). Binary logistic regression identified NfL level as an independent predictor of PD-RBD( β=0.068, OR=1.103, P=0.003). Conclusions:PD-RBD patients have increased plasma NfL levels, which can potentially serve as a biomarker for PD with RBD.

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This study investigated the potential association between levels of plasma neurofilament light chain (NfL) and cognitive function in patients suffering from Parkinson's disease (PD) in P.R. China.We collected a total of 168 participants (130 PD patients and 38 healthy controls),and evaluated the relationship of plasma NfL levels with cognitive dysfunction in PD patients. Our results shown that plasma NfL levels increased with an increase in cognitive impairment across the three groups of PD patients: PD with normal cognition (PD-NC), 17.9 ± 8.9 pg/ml; PD with mild cognitive impairment (PD-MCI),21.9 ± 10.3 pg/ml; and PD dementia (PDD), 35.7 ± 21.7 pg/ml. Higher MMSE scores were associated with lower plasma NfL levels (r = -0.49, 95% CI -0.61 to -0.34, p < 0.0001). Our results associating plasma NfL levels with cognitive dysfunction in PD are consistent with previous studies carried out in several countries/district, based on our meta-analysis.

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Disfunción Cognitiva/sangre , Disfunción Cognitiva/psicología , Proteínas de Neurofilamentos/sangre , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/psicología , Anciano , Biomarcadores/sangre , Cognición/fisiología , Disfunción Cognitiva/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedad de Parkinson/diagnóstico

RESUMEN

BACKGROUND: Plasma NfL (pNfL) levels are elevated in many neurological disorders. However, the utility of pNfL in a clinical setting has not been established. OBJECTIVE: In a cohort of diverse older participants, we examined: 1) the association of pNfL to age, sex, Hispanic ethnicity, diagnosis, and structural and amyloid imaging biomarkers; and 2) its association to baseline and longitudinal cognitive and functional performance. METHODS: 309 subjects were classified at baseline as cognitively normal (CN) or with cognitive impairment. Most subjects had structural MRI and amyloid PET scans. The most frequent etiological diagnosis was Alzheimer's disease (AD), but other neurological and neuropsychiatric disorders were also represented. We assessed the relationship of pNfL to cognitive and functional status, primary etiology, imaging biomarkers, and to cognitive and functional decline. RESULTS: pNfL increased with age, degree of hippocampal atrophy, and amyloid load, and was higher in females among CN subjects, but was not associated with Hispanic ethnicity. Compared to CN subjects, pNfL was elevated among those with AD or FTLD, but not those with neuropsychiatric or other disorders. Hippocampal atrophy, amyloid positivity and higher pNfL levels each added unique variance in predicting greater functional impairment on the CDR-SB at baseline. Higher baseline pNfL levels also predicted greater cognitive and functional decline after accounting for hippocampal atrophy and memory scores at baseline. CONCLUSION: pNfL may have a complementary and supportive role to brain imaging and cognitive testing in a memory disorder evaluation, although its diagnostic sensitivity and specificity as a stand-alone measure is modest. In the absence of expensive neuroimaging tests, pNfL could be used for differentiating neurodegenerative disease from neuropsychiatric disorders.

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Enfermedad de Alzheimer/sangre , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/sangre , Estado Funcional , Proteínas de Neurofilamentos/sangre , Negro o Afroamericano , Factores de Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Atrofia , Encéfalo/metabolismo , Encéfalo/patología , Cognición , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/fisiopatología , Estudios de Cohortes , Demencia Vascular/sangre , Demencia Vascular/diagnóstico por imagen , Demencia Vascular/fisiopatología , Femenino , Degeneración Lobar Frontotemporal/sangre , Degeneración Lobar Frontotemporal/diagnóstico por imagen , Degeneración Lobar Frontotemporal/fisiopatología , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Hispánicos o Latinos , Humanos , Enfermedad por Cuerpos de Lewy/sangre , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Enfermedad por Cuerpos de Lewy/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Factores Sexuales , Población Blanca

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White matter hyperintensities (WMH) is mainly caused by cerebrovascular injury and may also increase the possibilities of progression to Alzheimer's disease. The present study aims to determine whether plasma neurofilament light (NFL) protein levels could predict the progression of WMH volume in elderly persons without dementia. The present study enrolled 1029 non-dementia participants from the Alzheimer's Disease Neuroimaging Initiative in which all had measurements of plasma NFL and WMH at baseline and 589 had longitudinal measurements during follow-up. Spearman correlation analyses and regression models were used to assess cross-sectional and longitudinal associations between plasma NFL and WMH. Plasma NFL concentration had a moderately strong correlation with WMH at baseline (r = 0.17, p < 0.001). Longitudinal analyses showed that higher baseline plasma NFL concentration was associated with accelerated progression of WMH (ß=0.015, p = 0.007). Furthermore, higher change rates of plasma NFL could predict faster progression of WMH in the future (ß=0.581, p = 0.002). The results of the study suggest that plasma NFL level might be used as a noninvasive biomarker to track variation trend in WMH in elderly persons without dementia.

Asunto(s)

Encéfalo/patología , Proteínas de Neurofilamentos/sangre , Sustancia Blanca/patología , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino