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1.
Neurology ; 103(2): e209506, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-38896810

RESUMO

OBJECTIVES: To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion. METHODS: This single-center longitudinal cohort study has followed known carriers of PRNP pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined PRNP genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF. RESULTS: Among 41 carriers and 21 controls enrolled, 28 (68%) and 15 (71%) were female, and mean ages were 47.5 and 46.1. At baseline, all individuals were asymptomatic. We observed RT-QuIC seeding activity in the CSF of 3 asymptomatic E200K carriers who subsequently converted to symptomatic and died of prion disease. 1 P102L carrier remained RT-QuIC negative through symptom conversion. No other individuals developed symptoms. The prodromal window from detection of RT-QuIC positivity to disease onset was 1 year long in an E200K individual homozygous (V/V) at PRNP codon 129 and 2.5 and 3.1 years in 2 codon 129 heterozygotes (M/V). Changes in neurodegenerative and neuroinflammatory markers were variably observed prior to onset, with increases observed for plasma NfL in 4/4 converters, and plasma GFAP, CSF NfL, CSF T-tau, and CSF beta-synuclein each in 2/4 converters, although values relative to age and fold changes relative to individual baseline were not remarkable for any of these markers. CSF PrP was longitudinally stable with mean coefficient of variation 9.0% across all individuals over up to 6 years, including data from converting individuals at RT-QuIC-positive timepoints. DISCUSSION: CSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27.


Assuntos
Biomarcadores , Doenças Priônicas , Proteínas Priônicas , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Proteínas Priônicas/genética , Proteínas Priônicas/líquido cefalorraquidiano , Proteínas Priônicas/sangue , Doenças Priônicas/genética , Doenças Priônicas/líquido cefalorraquidiano , Doenças Priônicas/sangue , Doenças Priônicas/diagnóstico , Estudos Longitudinais , Adulto , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Heterozigoto , Proteína Glial Fibrilar Ácida/sangue , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/genética , Progressão da Doença , alfa-Sinucleína/líquido cefalorraquidiano , alfa-Sinucleína/genética , alfa-Sinucleína/sangue
2.
Alzheimers Res Ther ; 16(1): 103, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38725083

RESUMO

BACKGROUND: The role of α-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood. METHODS: A total of 331 non-demented individuals were included in the study from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their α-synuclein levels: one with lower levels (α-synuclein-L) and another with higher levels (α-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of α-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between α-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition. RESULTS: Higher CSF α-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the α-synuclein-H group. Further correlation and regression analysis indicated that the CSF α-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF α-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF α-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1. CONCLUSIONS: These findings elucidate a significant connection between elevated levels of CSF α-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF α-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia.


Assuntos
Disfunção Cognitiva , alfa-Sinucleína , Proteínas tau , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , alfa-Sinucleína/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Testes Neuropsicológicos , Proteínas tau/líquido cefalorraquidiano
3.
Alzheimers Dement ; 20(6): 4351-4365, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38666355

RESUMO

INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. HIGHLIGHTS: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.


Assuntos
Doença de Alzheimer , Corpos de Lewy , alfa-Sinucleína , Humanos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , alfa-Sinucleína/genética , Feminino , Masculino , Pessoa de Meia-Idade , Corpos de Lewy/patologia , Idoso , Mutação , Encéfalo/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Progressão da Doença
4.
Ann Clin Transl Neurol ; 11(5): 1197-1210, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38436140

RESUMO

OBJECTIVE: More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD. METHODS: Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra. RESULTS: Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ2(2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2(2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2(3) = 13.87, p = 0.003). INTERPRETATION: Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.


Assuntos
Doença de Alzheimer , Biomarcadores , Doença por Corpos de Lewy , alfa-Sinucleína , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/líquido cefalorraquidiano , Idoso , Biomarcadores/líquido cefalorraquidiano , Masculino , Feminino , alfa-Sinucleína/líquido cefalorraquidiano , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Pessoa de Meia-Idade , Amiloidose/diagnóstico , Amiloidose/líquido cefalorraquidiano , Sensibilidade e Especificidade
5.
Alzheimers Dement ; 20(5): 3334-3341, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38539061

RESUMO

INTRODUCTION: Lewy body disease (LBD) is a common primary or co-pathology in neurodegenerative syndromes. An alpha-synuclein seed amplification assay (αSyn-SAA) is clinically available, but clinical performance, especially lower sensitivity in amygdala-predominant cases, is not well understood. METHODS: Antemortem CSF from neuropathology-confirmed LBD cases was tested with αSyn-SAA (N = 56). Diagnostic performance and clinicopathological correlations were examined. RESULTS: Similar to prior reports, sensitivity was 100% for diffuse and transitional LBD (9/9), and overall specificity was 96.3% (26/27). Sensitivity was lower in amygdala-predominant (6/14, 42.8%) and brainstem-predominant LBD (1/6, 16.7%), but early spread outside these regions (without meeting criteria for higher stage) was more common in αSyn-SAA-positive cases (6/7, 85.7%) than negative (2/13, 15.4%). DISCUSSION: In this behavioral neurology cohort, αSyn-SAA had excellent diagnostic performance for cortical LBD. In amygdala- and brainstem-predominant cases, sensitivity was lower, but positivity was associated with anatomical spread, suggesting αSyn-SAA detects early LBD progression in these cohorts. HIGHLIGHTS: A cerebrospinal fluid alpha-synuclein assay detects cortical LBD with high sensitivity/specificity. Positivity in prodromal stages of LBD was associated with early cortical spread. The assay provides precision diagnosis of LBD that could support clinical trials. The assay can also identify LBD co-pathology, which may impact treatment responses.


Assuntos
Autopsia , Doença por Corpos de Lewy , Sensibilidade e Especificidade , alfa-Sinucleína , Humanos , alfa-Sinucleína/líquido cefalorraquidiano , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/patologia , Feminino , Masculino , Idoso , Estudos de Coortes , Tonsila do Cerebelo/patologia , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Pessoa de Meia-Idade
6.
J Neurol ; 271(6): 3610-3615, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38492015

RESUMO

Menopause increases the risk for Parkinson's disease (PD), although the underlying biological mechanisms have not been established in patients. Here, we aimed to understand the basis of menopause-related vulnerability to PD. Main motor and non-motor scores, blood levels of estradiol, testosterone, follicle-stimulating hormone, and luteinizing hormone, CSF levels of total α-synuclein, amyloid-ß-42, amyloid-ß-40, total tau, and phosphorylated-181-tau were examined in 45 women with postmenopausal-onset PD and 40 age-matched controls. PD patients had higher testosterone and lower estradiol levels than controls, and the residual estradiol production was associated with milder motor disturbances and lower dopaminergic requirements. In PD but not in controls, follicle-stimulating hormone levels correlated with worse cognitive scores and CSF markers of amyloidopathy and neuronal loss. In conclusion, menopause-related hormonal changes might differentially contribute to clinical-pathological trajectories of PD, accounting for the peculiar vulnerability to the disease.


Assuntos
Doença de Parkinson , Pós-Menopausa , Proteínas tau , Humanos , Feminino , Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , Pós-Menopausa/sangue , Pessoa de Meia-Idade , Idoso , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/sangue , Estradiol/sangue , alfa-Sinucleína/sangue , alfa-Sinucleína/líquido cefalorraquidiano , Hormônio Foliculoestimulante/sangue , Hormônio Foliculoestimulante/líquido cefalorraquidiano , Testosterona/sangue , Testosterona/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/sangue , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Hormônio Luteinizante/sangue , Hormônio Luteinizante/líquido cefalorraquidiano
7.
Alzheimers Dement ; 20(4): 2444-2452, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38323747

RESUMO

INTRODUCTION: Lewy body disease, a frequently observed co-pathology in Alzheimer's disease (AD), can be identified antemortem in cerebrospinal fluid (CSF) by α-synuclein seed amplification assay (αS-SAA). The prevalence and clinical impact of CSF αS-SAA positivity in AD are still unknown. METHODS: αS-SAA was performed on CSF samples from 240 AD patients (preclinical, prodromal, and dementia stages), 85 controls, 84 patients with Parkinson's disease (PD), and 21 patients with PD with dementia or dementia with Lewy bodies. In AD patients, associations between αS-SAA positivity and cognitive changes were also evaluated. RESULTS: In agreement with available neuropathological studies, αS-SAA positivity was observed in 30% of AD patients (vs 9% in controls), and was associated with cognitive decline, visuospatial impairment, and behavioral disturbances. DISCUSSION: αS-SAA positivity in AD patients reflects the prevalence observed in neuropathological series and is associated with a worse clinical outcome. These data confirm the validity of CSF αS-SAA positivity as biomarker of synucleinopathy.


Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Parkinson , Sinucleinopatias , Humanos , alfa-Sinucleína/líquido cefalorraquidiano , Doença de Alzheimer/líquido cefalorraquidiano , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano
8.
J Alzheimers Dis ; 97(3): 1091-1096, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38250774

RESUMO

We analyzed Lewy body (LB) pathology in 18 autosomal dominant Alzheimer's disease (ADAD) brains via immunohistochemistry. Real-time quaking induced conversion was used to detect misfolded α-synuclein (α-syn) in 18 living ADAD cerebrospinal fluid (CSF) samples. Concomitant LB pathology was present in 44% ADAD brains. Only 6% CSF samples were positive for misfolded α-syn. In an additional AD sample, all patients with confirmed LB presented misfolded α-syn in postmortem CSF regardless of the LB staging. In conclusion, misfolded α-syn in CSF was scarce in symptomatic living ADAD individuals, in contrast to postmortem brain tissue. These results suggest late appearance of LB pathology in ADAD.


Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Humanos , alfa-Sinucleína/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Corpos de Lewy/patologia , Doença por Corpos de Lewy/patologia , Proteínas tau/líquido cefalorraquidiano
9.
Parkinsonism Relat Disord ; 121: 105968, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38168618

RESUMO

Over the last two decades there have been meaningful developments on biomarkers of neurodegenerative diseases, extensively (but not solely) focusing on their proteinopathic nature. Accordingly, in Alzheimer's disease determination of levels of total and phosphorylated tau (τ and p-τ, usually p-τ181) along with amyloid-beta1-42 (Aß1-42) by immunodetection in cerebrospinal fluid (CSF) and currently even in peripheral blood, have been widely accepted and introduced to routine diagnosis. In the case of Parkinson's disease, α-synuclein as a potential biomarker (both for diagnosis and progression tracking) has proved more elusive under the immunodetection approach. In recent years, the emergence of the so-called seed amplification assays is proving to be a game-changer, with mounting evidence under different technical approaches and using a variety of biofluids or tissues, yielding promising diagnostic accuracies. Currently the least invasive but at once more reliable source of biosamples and techniques are being sought. Here we overview these advances.


Assuntos
Doença de Alzheimer , Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano
10.
Mov Disord ; 38(11): 2125-2131, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37792643

RESUMO

BACKGROUND: Misfolded α-synuclein in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) can be detected using the real-time quaking-induced conversion (RT-QuIC) technique in cerebrospinal fluid (CSF). OBJECTIVES: The objectives are (1) to examine misfolded CSF α-synuclein incidence, and (2) to compare clinical presentation, sports history, brain volumes, and RT-QuIC α-synuclein positivity in former athletes. METHODS: Thirty former athletes with magnetic resonance imaging, neuropsychological testing, and CSF analyzed for phosphorylated tau 181 (p-tau), total tau (t-tau), amyloid-ß 42 (Aß42), and neurofilament light chain (NfL). CSF α-synuclein was detected using RT-QuIC. RESULTS: Six (20%) former athletes were α-synuclein positive. α-Synuclein positive athletes were similar to α-synuclein negative athletes on demographics, sports history, clinical features, CSF p-tau, t-tau, Aß42, and NfL; however, had lower grey matter volumes in the right inferior orbitofrontal, right anterior insula and right olfactory cortices. CONCLUSIONS: α-Synuclein RT-QuIC analysis of CSF may be useful as a prodromal biofluid marker of PD and DLB. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doença por Corpos de Lewy , Doença de Parkinson , Humanos , alfa-Sinucleína/líquido cefalorraquidiano , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença de Parkinson/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Atletas
12.
Parkinsonism Relat Disord ; 115: 105820, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37648587

RESUMO

INTRODUCTION: Physical activity benefits patients with Parkinson's disease (PD) and is assumed to possess disease-modifying potential. PD-related biomarkers, such as dopamine transporter (DAT) imaging and cerebrospinal fluid (CSF) α-synuclein (α-syn) and amyloid ß (Aß), correlate with disease severity and, to some extent, reflect disease progression and pathology. However, the association between regular physical activity and PD biomarker changes remains unknown. This study aimed to investigate the association between physical activity and longitudinal trajectories of PD biomarkers. METHODS: This retrospective study included 444 patients with a median follow-up time of 5 years from the Parkinson's Progression Markers Initiative cohort. Data collection included physical activity as scaled by the Physical Activity Scale for the Elderly questionnaire, dopamine transporter imaging, CSF assessment, and serum biomarkers. We analyzed the data using a linear mixed regression model. RESULTS: Regular physical activity was associated with a slower decline of DAT uptake in the caudate (ß = 0.063, p = 0.011) and the putamen (ß = 0.062, p = 0.023). No association was detected between regular physical activity and CSF, as well as serum biomarkers. CONCLUSION: Regular physical activity is associated with favorable PD biomarker progression, indicating a potential disease-modifying effect.


Assuntos
Doença de Parkinson , Humanos , Idoso , Doença de Parkinson/complicações , Estudos Retrospectivos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Gravidade do Paciente
13.
J Neurol ; 270(12): 5813-5818, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37592136

RESUMO

Parkinson's disease (PD) may be misdiagnosed due to the clinical overlap between PD and atypical parkinsonism. The utility of α-Synuclein (αSyn) Seed Amplification Assay (SAA) as a diagnostic indicator for PD has been reported in numerous studies, but never when administered as a validated clinical laboratory test. This study compares results from αSyn-SAA validation testing performed using well-characterized cohorts from two biorepositories to better understand the accuracy of PD clinical diagnosis. Blinded cerebrospinal fluid (CSF) specimens from a repository that included cohorts of subjects clinically diagnosed as PD or healthy controls, both with confirmatory dopamine transporter single-photon emission computed tomography (DAT SPECT) imaging, and blinded CSF specimens from a repository that included cohorts of subjects clinically diagnosed as PD or healthy controls based on clinical diagnosis alone, were tested as part of the validation studies for the diagnostic αSyn-SAA test (SYNTap® Biomarker Test). Measured αSyn-SAA test accuracy was 83.9% using clinical diagnosis as comparator, and 93.6% using clinical diagnosis with confirmatory DAT- SPECT imaging as comparator. The statistically significant discordance between accuracy determinations using specimens classified using different diagnostic inclusion criteria indicates that there is some symbiosis between dopamine-weighted imaging and αSyn-SAA results, both of which are associated with higher accuracy compared with the clinical diagnosis alone.


Assuntos
Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Dopamina
14.
Eur J Neurol ; 30(12): 3949-3967, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37573472

RESUMO

BACKGROUND AND PURPOSE: Alpha-synuclein seed amplification assays (α-syn SAAs) are promising diagnostic methods for Parkinson's disease (PD) and other synucleinopathies. However, there is limited consensus regarding the diagnostic and differential diagnostic performance of α-syn SAAs on biofluids and peripheral tissues. METHODS: A comprehensive research was performed in PubMed, Web of Science, Embase and Cochrane Library. Meta-analysis was performed using a random-effects model. A network meta-analysis based on an ANOVA model was conducted to compare the relative accuracy of α-syn SAAs with different specimens. RESULTS: The pooled sensitivity and specificity of α-syn SAAs in distinguishing PD from healthy controls or non-neurodegenerative neurological controls were 0.91 (95% confidence interval [CI] 0.89-0.92) and 0.95 (95% CI 0.94-0.96) for cerebrospinal fluid (CSF); 0.91 (95% CI 0.86-0.94) and 0.92 (95% CI 0.87-0.95) for skin; 0.80 (95% CI 0.66-0.89) and 0.87 (95% CI 0.69-0.96) for submandibular gland; 0.44 (95% CI 0.30-0.59) and 0.92 (95% CI 0.79-0.98) for gastrointestinal tract; 0.79 (95% CI 0.70-0.86) and 0.88 (95% CI 0.77-0.95) for saliva; and 0.51 (95% CI 0.39-0.62) and 0.91 (95% CI 0.84-0.96) for olfactory mucosa (OM). The pooled sensitivity and specificity were 0.91 (95% CI 0.89-0.93) and 0.50 (95% CI 0.44-0.55) for CSF, 0.92 (95% CI 0.83-0.97) and 0.22 (95% CI 0.06-0.48) for skin, and 0.55 (95% CI 0.42-0.68) and 0.50 (95% CI 0.35-0.65) for OM in distinguishing PD from multiple system atrophy. The pooled sensitivity and specificity were 0.92 (95% CI 0.89-0.94) and 0.84 (95% CI 0.73-0.91) for CSF, 0.92 (95% CI 0.83-0.97) and 0.88 (95% CI 0.64-0.99) for skin and 0.63 (95% CI 0.52-0.73) and 0.86 (95% CI 0.64-0.97) for OM in distinguishing PD from progressive supranuclear palsy. The pooled sensitivity and specificity were 0.94 (95% CI 0.90-0.97) and 0.95 (95% CI 0.77-1.00) for CSF and 0.94 (95% CI 0.84-0.99) and 0.86 (95% CI 0.42-1.00) for skin in distinguishing PD from corticobasal degeneration. CONCLUSIONS: α-Synuclein SAAs of CSF, skin, saliva, submandibular gland, gastrointestinal tract and OM are promising diagnostic assays for PD, with CSF and skin α-syn SAAs demonstrating higher diagnostic performance.


Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Metanálise em Rede , Biomarcadores/líquido cefalorraquidiano
15.
Int J Mol Sci ; 24(15)2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37569491

RESUMO

Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Our objectives were to, firstly, review inflammation investigation methods in LBD (dementia with Lewy bodies and Parkinson's disease dementia) and, secondly, identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease and other neurodegenerative diseases. A systematic scoping review was performed by searching major electronic databases (MEDLINE, Embase, Web of Science, and PSYCHInfo) to identify relevant human studies. Of the 2509 results screened, 80 studies were included. Thirty-six studies analyzed postmortem brain tissue, and 44 investigated living subjects with cerebrospinal fluid, blood, and/or brain imaging assessments. Largely cross-sectional data were available, although two longitudinal clinical studies investigated prodromal Lewy body disease. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, and lymphocytes) and inflammatory molecules (cytokines, etc.). Results of the included studies identified innate and adaptive immune system contributions to inflammation associated with Lewy body pathology and clinical disease features. Different signals in early and late-stage disease, with possible late immune senescence and dystrophic glial cell populations, were identified. The strength of these associations is limited by the varying methodologies, small study sizes, and cross-sectional nature of the data. Longitudinal studies investigating associations with clinical and other biomarker outcomes are needed to improve understanding of inflammatory activity over the course of LBD. This could identify markers of disease activity and support therapeutic development.


Assuntos
Demência , Doença por Corpos de Lewy , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença por Corpos de Lewy/patologia , Estudos Transversais , Doença de Parkinson/líquido cefalorraquidiano , Inflamação , alfa-Sinucleína/líquido cefalorraquidiano
16.
J Neurol ; 270(11): 5613-5621, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37552278

RESUMO

Parkinson's disease (PD) diagnosis is still vulnerable to bias, and a definitive diagnosis often relies on post-mortem neuropathological diagnosis. In this regard, alpha-synuclein (αsyn)-specific in vivo biomarkers remain a critical unmet need, based on its relevance in the neuropathology. Specifically, content changes in αsyn species such as total (tot-αsyn), oligomeric (o-αsyn), and phosphorylated (p-αsyn) within the cerebrospinal fluid (CSF) and peripheral fluids (i.e., blood and saliva) have been proposed as PD biomarkers possibly reflecting the neuropathological outcome. Here, we measured the p-αsyn levels in the saliva from 15 PD patients along with tot-αsyn, o-αsyn and their ratios, and compared the results with those from 23 healthy subjects (HS), matched per age and sex. We also calculated the optimal cutoff values for different αsyn species to provide information about their capability to discriminate PD from HS. We found that p-αsyn was the most abundant alpha-synuclein species in the saliva. While p-αsyn concentration did not differ between PD and HS when adjusted for total salivary proteins, the ratio p-αsyn/tot-αsyn was largely lower in PD patients than in HS. Moreover, the concentration of o-αsyn was increased in the saliva of PD patients, and tot-αsyn did not differ between PD and HS. The ROC curves indicated that no single αsyn form or ratio could provide an accurate diagnosis of PD. On the other hand, the ratio of different items, namely p-αsyn/tot-αsyn and o-αsyn, yielded more satisfactory diagnostic accuracy, suggesting that the combined measure of different species in the saliva may show more promises as a diagnostic means for PD.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/metabolismo , alfa-Sinucleína/líquido cefalorraquidiano , Curva ROC , Biomarcadores
17.
J Neurol Sci ; 452: 120760, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37544209

RESUMO

BACKGROUND: Neuroinflammation is one of the pathophysiologies of Parkinson's disease (PD). Lewy bodies, the pathological hallmark of PD, emerge as a consequence of α-synuclein aggregation, and neuroinflammation is induced concurrently with this aggregation. Imaging and cerebrospinal fluid (CSF) biomarkers that reflect PD pathophysiology have been developed or are under investigation. The IgG index of CSF is a marker of inflammation, and may also reflect the pathophysiology of PD. AIM: We examined if the IgG index reflects the pathophysiology of PD in drug-naïve PD patients. METHOD: The subjects were 20 consecutive PD patients who underwent 123I-MIBG scintigraphy for assessment of the heart to mediastinum (H/M) ratio and wash out rate, 123I-Ioflupane SPECT for examination of the specific binding ratio in the striatum, and lumbar puncture before treatment. The CSF IgG index and levels of pathogenic proteins (total α-synuclein, oligomeric α-synuclein, total tau, phosphorylated tau and amyloid Aß1-42) were determined. The IgG index was compared with the other parameters using Spearman correlation analysis. RESULTS: The IgG index showed a significant correlation with the H/M ratio in early (r = -0.563, p = 0.010) and delayed (r = -0.466, p = 0.038) images in 123I-MIBG scintigraphy and with the CSF total tau level (r = -0.513, p = 0.021). CONCLUSION: Neuroinflammation is involved in PD pathophysiology in some patients, and a higher IgG index indicates the presence of neuroinflammation accompanied by emergence of Lewy bodies.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , alfa-Sinucleína/líquido cefalorraquidiano , Corpos de Lewy , 3-Iodobenzilguanidina , Doenças Neuroinflamatórias , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Imunoglobulina G , Fragmentos de Peptídeos/líquido cefalorraquidiano
18.
J Parkinsons Dis ; 13(5): 841-844, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37393438

RESUMO

Seed amplification assays (SAA) are the first credible molecular assay for Parkinson's disease (PD). However, the value of SAA to support the clinicians' initial diagnosis of PD is not clear. In our study, we analyzed cerebrospinal fluid samples from 121 PD patients recruited through population screening methods and taken within a median delay of 38 days from diagnosis and 51 normal controls without neurodegenerative disease. SAA yielded a sensitivity of 82.6% (95% CI, 74.7% - 88.9%) and specificity of 88.2% (95% CI, 76.1% - 95.6%). These results highlight the potential of SAA to support the initial diagnosis of PD in clinical practice and research.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano
19.
Aging Clin Exp Res ; 35(8): 1741-1752, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37264166

RESUMO

AIM: To explore associations of cerebrospinal fluid biomarkers of neurodegeneration and amyloidosis with caregiver burden, cognition and functionality in dementia with Lewy bodies (DLB) paired with late-onset Alzheimer's disease (AD) and healthy older people. METHODS: Consecutive outpatients with DLB were matched with outpatients with AD according to sex, cognitive scores and dementia stage, and with cognitively healthy controls according to age and sex to investigate associations of cerebrospinal fluid amyloid-ß (Aß42,Aß40,Aß38), tau, phospho-tau Thr181, ubiquitin, α-synuclein and neurofilament light with caregiver burden, functionality, reverse digit span, a clock drawing test, Mini-Mental State Examination (MMSE) and Severe MMSE, adjusted for sex, age, education, dementia duration and APOE-ε4 alleles. RESULTS: Overall, 27 patients with DLB (78.98 ± 9.0 years-old; eleven APOE-ε4 +) were paired with 27 patients with AD (81.50 ± 5.8 years-old; twelve APOE-ε4 +) and 27 controls (78.98 ± 8.7 years-old; four APOE-ε4 +); two-thirds were women. In AD, Aß42/Aß38 and Aß42 were lower, while tau/Aß42 and phospho-tau Thr181/Aß42 were higher; α-synuclein/Aß42 was lower in DLB and higher in AD. The following corrected associations remained significant: in DLB, instrumental functionality was inversely associated with tau/phospho-tau Thr181 and tau/Aß42, and reverse digit span associated with α-synuclein; in AD, instrumental functionality was inversely associated with neurofilament light, clock drawing test scores inversely associated with phospho-tau Thr181/Aß42 and α-synuclein/Aß42, and Severe MMSE inversely associated with tau/Aß42 and tau/phospho-tau Thr181. CONCLUSIONS: Cerebrospinal fluid phospho-tau Thr181 in DLB was similar to AD, but not Aß42. In associations with test scores, biomarker ratios were superior to isolated biomarkers, while worse functionality was associated with axonal degeneration only in AD.


Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Doença de Alzheimer/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/psicologia , Proteínas tau , Fragmentos de Peptídeos , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Apolipoproteínas E/genética
20.
Alzheimers Dement ; 19(8): 3754-3759, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37102457

RESUMO

INTRODUCTION: Accumulating evidence suggests that α-synuclein (αSyn) can modulate Alzheimer's disease (AD) pathology. The aim of this study was to evaluate the prevalence and clinical features associated with cerebrospinal fluid (CSF) αSyn detected by seed amplification assay (SAA) in AD. METHODS: Eighty AD patients with CSF AT(N) biomarker positivity (mean age 70.3 ± 7.3 years) and 28 non-AD age-matched controls were included. All subjects underwent standardized clinical assessment; CSF αSyn aggregates were detected by SAA. RESULTS: CSF was αSyn-SAA positive (αSyn+) in 36/80 AD patients (45%) and in 2/28 controls (7.1%). AD αSyn+ and αSyn- patients were comparable for age, disease severity, comorbidity profile, and CSF core biomarkers. AD αSyn+ presented a higher prevalence of atypical phenotypes and symptoms. CONCLUSIONS: Our findings demonstrate that concomitant CSF αSyn pathology is present in a significant proportion of AD patients starting in the early stages and can affect clinical presentation. Longitudinal studies are warranted to evaluate the significance for the disease course.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , Estudos Longitudinais , Biomarcadores/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano
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