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Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for treating motor symptoms, these interventions can lead to further worsening of speech. The interplay between dopaminergic medication, STN circuitry, and their downstream effects on speech in PD is not yet fully understood. Here, we investigate the effect of dopaminergic medication on STN circuitry and probe its association with speech and cognitive functions in PD patients. We found that changes in intrinsic functional connectivity of the STN were associated with alterations in speech functions in PD. Interestingly, this relationship was characterized by altered functional connectivity of the dorsolateral and ventromedial subdivisions of the STN with the language network. Crucially, medication-induced changes in functional connectivity between the STN's dorsolateral subdivision and key regions in the language network, including the left inferior frontal cortex and the left superior temporal gyrus, correlated with alterations on a standardized neuropsychological test requiring oral responses. This relation was not observed in the written version of the same test. Furthermore, changes in functional connectivity between STN and language regions predicted the medication's downstream effects on speech-related cognitive performance. These findings reveal a previously unidentified brain mechanism through which dopaminergic medication influences speech function in PD. Our study sheds light into the subcortical-cortical circuit mechanisms underlying impaired speech control in PD. The insights gained here could inform treatment strategies aimed at mitigating speech deficits in PD and enhancing the quality of life for affected individuals.
Assuntos
Idioma , Doença de Parkinson , Fala , Núcleo Subtalâmico , Humanos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Núcleo Subtalâmico/fisiopatologia , Núcleo Subtalâmico/efeitos dos fármacos , Masculino , Fala/fisiologia , Fala/efeitos dos fármacos , Feminino , Pessoa de Meia-Idade , Idoso , Imageamento por Ressonância Magnética , Dopamina/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiopatologia , Cognição/efeitos dos fármacos , Dopaminérgicos/farmacologia , Dopaminérgicos/uso terapêuticoRESUMO
OBJECTIVE: To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD). METHODS: We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aß42, and CSF Aß42/Aß40 or amyloid-ß PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes. RESULTS: Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment. INTERPRETATION: Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024;96:526-538.
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Doença de Alzheimer , Biomarcadores , Doença por Corpos de Lewy , Proteínas tau , Humanos , Feminino , Masculino , Idoso , Proteínas tau/sangue , Proteínas tau/líquido cefalorraquidiano , Doença por Corpos de Lewy/sangue , Doença por Corpos de Lewy/patologia , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Fosforilação , Doença de Alzheimer/sangue , Doença de Alzheimer/patologia , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Pessoa de Meia-Idade , Disfunção Cognitiva/sangue , Amiloidose/sangue , PrognósticoRESUMO
OBJECTIVE: This study was undertaken to study pareidolias, or perceived meaningful objects in a meaningless stimulus, in patients across the Lewy body (LB) disease spectrum, where most do not report hallucinations or delusions. METHODS: We studied illusory responses on the Noise Pareidolia Task in 300 participants (38 cognitively impaired LB, 65 cognitively unimpaired LB, 51 Alzheimer disease spectrum [AD-s], 146 controls). Pairwise between-group comparisons examined how diagnosis impacts the number of illusory responses. Ordinal regression analysis compared the number of illusory responses across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions. RESULTS: Cognitively impaired LB participants were 12.3, 4.9, and 4.6 times more likely than control, cognitively unimpaired LB, and AD-s participants, respectively, to endorse illusory responses. After adjusting for age, sex, and education, the probability of endorsing 1 or more illusory responses was 61% in the cognitively impaired LB group, compared to 26% in AD-s, 25% in cognitively unimpaired LB, and 12% in control participants. All results were similar after repeated analysis only in participants without hallucinations or delusions. In LB without hallucinations or delusions, 52% with mild cognitive impairment and 66.7% with dementia endorsed at least 1 illusory response. INTERPRETATION: We found illusory responses are common in cognitively impaired LB patients, including those without any reported psychosis. Our data suggest that, prior to the onset of hallucinations and delusions, the Noise Pareidolia Task can easily be used to screen for unobtrusive pareidolias in all LB patients. ANN NEUROL 2023;93:702-714.
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Doença de Alzheimer , Disfunção Cognitiva , Ilusões , Doença por Corpos de Lewy , Humanos , Doença por Corpos de Lewy/psicologia , Doença de Alzheimer/psicologia , AlucinaçõesRESUMO
Parkinson's disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research-L-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography-mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as L-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research.
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Doença de Parkinson , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Dopa Descarboxilase/genética , Proteômica , Biomarcadores/líquido cefalorraquidiano , Plasma/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre , Descarboxilases de Aminoácido-L-AromáticoRESUMO
INTRODUCTION: Early cognitive decline may manifest in subtle differences in speech. METHODS: We examined 238 cognitively unimpaired adults from the Framingham Heart Study (32-75 years) who completed amyloid and tau PET imaging. Speech patterns during delayed recall of a story memory task were quantified via five speech markers, and their associations with global amyloid status and regional tau signal were examined. RESULTS: Total utterance time, number of between-utterance pauses, speech rate, and percentage of unique words significantly correlated with delayed recall score although the shared variance was low (2%-15%). Delayed recall score was not significantly different between ß-amyoid-positive (Aß+) and -negative (Aß-) groups and was not associated with regional tau signal. However, longer and more between-utterance pauses, and slower speech rate were associated with increased tau signal across medial temporal and early neocortical regions. DISCUSSION: Subtle speech changes during memory recall may reflect cognitive impairment associated with early Alzheimer's disease pathology. HIGHLIGHTS: Speech during delayed memory recall relates to tau PET signal across adulthood. Delayed memory recall score was not associated with tau PET signal. Speech shows greater sensitivity to detecting subtle cognitive changes associated with early tau accumulation. Our cohort spans adulthood, while most PET imaging studies focus on older adults.
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Doença de Alzheimer , Disfunção Cognitiva , Adulto , Idoso , Humanos , Doença de Alzheimer/patologia , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/patologia , Memória , Tomografia por Emissão de Pósitrons/métodos , Fala , Proteínas tau/metabolismoRESUMO
INTRODUCTION: Amyloid positron emission tomography (PET) acquisition timing impacts quantification. METHODS: In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases. RESULTS: CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan. DISCUSSION: The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols. HIGHLIGHTS: Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.
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INTRODUCTION: In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. METHODS: We constructed a protein co-expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically-relevant outcomes. RESULTS: We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p-tau181 (M4: ß = 2.44, p < 0.001, M7: ß = 2.57, p < 0.001) and executive function performance (M4: ß = -2.00, p = 0.005, M7: ß = -2.39, p < 0.001). DISCUSSION: In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post-translational modifications for early cognitive and pathological changes.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Doença de Alzheimer/patologia , Proteínas tau/genética , Proteínas tau/líquido cefalorraquidiano , Proteômica , Biomarcadores/líquido cefalorraquidiano , Processamento de Proteína Pós-Traducional , Cognição , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidianoRESUMO
BACKGROUND: APOE genotype is associated with Alzheimer disease. Thus, the concentration of apolipoprotein E (apoE) isoforms in cerebrospinal fluid (CSF) could be altered in dementia. However, conflicting results have been obtained in different studies. Carefully validated and standardized assays could improve the interpretation of research findings, allow their replication in other laboratories, and generalize their application. METHODS: To evaluate this hypothesis, we aimed to develop, validate, and standardize a new measurement procedure using LC-MS/MS. Purified recombinant apoE protein standards (E2, E3, E4) were thoroughly characterized and used to assign the concentration of a matrix-matched calibration material that contained each apoE isoform, which ensured the metrological traceability of results. RESULTS: The assay of each isoform in human CSF was precise (≤11%CV) and of moderate throughput (approximately 80 samples per day). It demonstrated good linearity and parallelism for lumbar CSF, ventricular CSF, and bovine CSF. The use of an SI-traceable matrix-matched calibrator enabled precise and accurate measurements. There was no association observed between total apoE concentration and the number of Æ4 alleles in a cohort of 322 participants. However, the concentration of each isoform was significantly different in heterozygotes, with E4 > E3 > E2. Isoform concentrations were associated with cognitive and motor symptoms but contributed negligibly to a predictive model of cognitive impairment that included established CSF biomarkers. CONCLUSIONS: Our method simultaneously measures each apoE isoform in human CSF with excellent precision and accuracy. A secondary matrix-matched material has been developed and is available to other laboratories to improve interlaboratory agreement.
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Doença de Alzheimer , Apolipoproteína E4 , Humanos , Animais , Bovinos , Cromatografia Líquida , Apolipoproteína E4/genética , Apolipoproteína E4/líquido cefalorraquidiano , Espectrometria de Massas em Tandem , Apolipoproteínas E/genética , Doença de Alzheimer/líquido cefalorraquidiano , Isoformas de Proteínas , Peptídeos beta-Amiloides/líquido cefalorraquidianoRESUMO
BACKGROUND: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor. OBJECTIVE: The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease. METHOD: Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [18 F]fluorodeoxyglucose ([18 F]FDG) PET and [11 C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level. RESULTS: We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density. CONCLUSION: Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [18 F]FDG PET and [11 C]UCB-J PET in Lewy body patients. The magnitude of reduced [18 F]FDG uptake was greater than the corresponding decline in [11 C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença por Corpos de Lewy , Humanos , Doença por Corpos de Lewy/diagnóstico por imagem , Doença por Corpos de Lewy/metabolismo , Fluordesoxiglucose F18 , Glucose/metabolismo , Corpos de Lewy/metabolismo , Tomografia por Emissão de Pósitrons , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismoRESUMO
BACKGROUND: Cerebrovascular dysfunction in Parkinson's disease (PD) is heterogeneous and may contribute to disease pathophysiology or progression. There is a need to understand the mechanisms by which cerebrovascular dysfunction is altered in participants with PD. OBJECTIVES: The objective of this study is to test the hypothesis that participants with PD exhibit a significant reduction in the ability of the cerebral vessels to dilate in response to vasoactive challenges relative to healthy controls (HC). METHODS: The current study uses a vasodilatory challenge while participants undergo functional magnetic resonance imaging to quantify the amplitude and delay of cerebrovascular reactivity in participants with PD relative to age and sex-matched HC. An analysis of covariance was used to evaluate differences in cerebrovascular reactivity amplitude and latency between PD participants and HC. RESULTS: A significant main effect of group was observed for whole-brain cerebrovascular reactivity amplitude (F(1, 28) = 4.38, p = 0.046, Hedge's g = 0.73) and latency (F(1, 28) = 16.35, p < 0.001, Hedge's g = 1.42). Participants with PD exhibited reduced whole-brain amplitude and increased latencies in cerebrovascular reactivity relative to HC. The evaluation of regional effects indicates that the largest effects were observed in the cuneus, precuneus, and parietal regions. CONCLUSIONS: PD participants exhibited reduced and delayed cerebrovascular reactivity. This dysfunction may play an important role in chronic hypoxia, neuroinflammation, and protein aggregation, mechanisms that could lead to disease progression. Cerebrovascular reactivity may serve as an important biomarker and target for future interventions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Humanos , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Lobo Occipital , Lobo ParietalRESUMO
BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Estudos Transversais , Imageamento por Ressonância Magnética , Cerebelo , EncéfaloRESUMO
Patients with neurodegenerative movement disorders can develop cognitive impairment during the disease. Cognitive symptoms have been associated with decreased quality of life, higher caregiver burden, and earlier institutionalization, and are therefore critical for physicians to understand and address. The evaluation of cognitive performance of patients with neurodegenerative movement disorders is important for providing adequate diagnosis, management, prognosis, and support patients and their caregivers. In this review, we discuss the features of the cognitive impairment profile of commonly encountered movement disorders: Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, and Huntington's disease. In addition, we provide neurologists with practical guidance and evaluation tools for the assessment and management of these challenging patients.
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Disfunção Cognitiva , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Paralisia Supranuclear Progressiva , Humanos , Qualidade de Vida , Doença de Parkinson/complicações , Paralisia Supranuclear Progressiva/complicações , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/complicações , Atrofia de Múltiplos Sistemas/complicaçõesRESUMO
Dopaminergic medication is widely used to alleviate motor symptoms of Parkinson's disease, but these medications also impact cognition with significant variability across patients. It is hypothesized that dopaminergic medication impacts cognition and working memory in Parkinson's disease by modulating frontoparietal-basal ganglia cognitive control circuits, but little is known about the underlying causal signalling mechanisms and their relation to individual differences in response to dopaminergic medication. Here we use a novel state-space computational model with ultra-fast (490â ms resolution) functional MRI to investigate dynamic causal signalling in frontoparietal-basal ganglia circuits associated with working memory in 44 Parkinson's disease patients ON and OFF dopaminergic medication, as well as matched 36 healthy controls. Our analysis revealed aberrant causal signalling in frontoparietal-basal ganglia circuits in Parkinson's disease patients OFF medication. Importantly, aberrant signalling was normalized by dopaminergic medication and a novel quantitative distance measure predicted individual differences in cognitive change associated with medication in Parkinson's disease patients. These findings were specific to causal signalling measures, as no such effects were detected with conventional non-causal connectivity measures. Our analysis also identified a specific frontoparietal causal signalling pathway from right middle frontal gyrus to right posterior parietal cortex that is impaired in Parkinson's disease. Unlike in healthy controls, the strength of causal interactions in this pathway did not increase with working memory load and the strength of load-dependent causal weights was not related to individual differences in working memory task performance in Parkinson's disease patients OFF medication. However, dopaminergic medication in Parkinson's disease patients reinstated the relation with working memory performance. Our findings provide new insights into aberrant causal brain circuit dynamics during working memory and identify mechanisms by which dopaminergic medication normalizes cognitive control circuits.
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Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Dopaminérgicos/uso terapêutico , Gânglios da Base , Cognição/fisiologia , Imageamento por Ressonância MagnéticaRESUMO
INTRODUCTION: Post-mortem analysis provides definitive diagnoses of neurodegenerative diseases; however, only a few can be diagnosed during life. METHODS: This study employed statistical tools and machine learning to predict 17 neuropathologic lesions from a cohort of 6518 individuals using 381 clinical features (Table S1). The multisite data allowed validation of the model's robustness by splitting train/test sets by clinical sites. A similar study was performed for predicting Alzheimer's disease (AD) neuropathologic change without specific comorbidities. RESULTS: Prediction results show high performance for certain lesions that match or exceed that of research annotation. Neurodegenerative comorbidities in addition to AD neuropathologic change resulted in compounded, but disproportionate, effects across cognitive domains as the comorbidity number increased. DISCUSSION: Certain clinical features could be strongly associated with multiple neurodegenerative diseases, others were lesion-specific, and some were divergent between lesions. Our approach could benefit clinical research, and genetic and biomarker research by enriching cohorts for desired lesions.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Comorbidade , Neuropatologia , BiomarcadoresRESUMO
Tau PET has allowed for critical insights into in vivo patterns of tau accumulation and change in individuals early in the Alzheimer's disease (AD) continuum. A key methodological step in tau PET analyses is the selection of a reference region, but there is not yet consensus on the optimal region especially for longitudinal tau PET analyses. This study examines how reference region selection influences results related to disease stage at baseline and over time. Longitudinal flortaucipir ([18F]-AV1451) PET scans were examined using several common reference regions (e.g., eroded subcortical white matter, inferior cerebellar gray matter) in 62 clinically unimpaired amyloid negative (CU A-) individuals, 73 CU amyloid positive (CU A+) individuals, and 64 amyloid positive individuals with mild cognitive impairment (MCI A+) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cross-sectionally, both reference regions resulted in robust group differences between CU A-, CU A+, and MCI A+ groups, along with significant associations with CSF phosphorylated tau (pTau-181). However, these results were more focally specific and akin to Braak Staging when using eroded white matter, whereas effects with inferior cerebellum were globally distributed across most cortical regions. Longitudinally, utilization of eroded white matter revealed significant accumulation greater than zero across more regions whereas change over time was diminished using inferior cerebellum. Interestingly, the inferior temporal target region seemed most robust to reference region selection with expected cross-sectional and longitudinal signal across both reference regions. With few exceptions, baseline tau did not significantly predict longitudinal change in tau in the same region regardless of reference region. In summary, reference region selection deserves further evaluation as this methodological step may lead to disparate findings. Inferior cerebellar gray matter may be more sensitive to cross-sectional flortaucipir differences, whereas eroded subcortical white matter may be more sensitive for longitudinal analyses examining regional patterns of change.
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Doença de Alzheimer/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Carbolinas , Estudos Transversais , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neuroimagem , Substância Branca/diagnóstico por imagemRESUMO
PURPOSE: Up to 25% of patients diagnosed as idiopathic Parkinson's disease (IPD) have an atypical parkinsonian syndrome (APS). We had previously validated an automated image-based algorithm to discriminate between IPD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). While the algorithm was accurate with respect to the final clinical diagnosis after long-term expert follow-up, its relationship to the initial referral diagnosis and to the neuropathological gold standard is not known. METHODS: Patients with an uncertain diagnosis of parkinsonism were referred for 18F-fluorodeoxyglucose (FDG) PET to classify patients as IPD or as APS based on the automated algorithm. Patients were followed by a movement disorder specialist and subsequently underwent neuropathological examination. The image-based classification was compared to the neuropathological diagnosis in 15 patients with parkinsonism. RESULTS: At the time of referral to PET, the clinical impression was only 66.7% accurate. The algorithm correctly identified 80% of the cases as IPD or APS (p = 0.02) and 87.5% of the APS cases as MSA or PSP (p = 0.03). The final clinical diagnosis was 93.3% accurate (p < 0.001), but needed several years of expert follow-up. CONCLUSION: The image-based classifications agreed well with autopsy and can help to improve diagnostic accuracy during the period of clinical uncertainty.
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Atrofia de Múltiplos Sistemas , Transtornos Parkinsonianos , Encéfalo/diagnóstico por imagem , Tomada de Decisão Clínica , Diagnóstico Diferencial , Fluordesoxiglucose F18 , Humanos , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico por imagem , IncertezaRESUMO
BACKGROUND: Cerebrospinal fluid (CSF) levels of monoamine metabolites may represent biomarkers of Parkinson's disease (PD). OBJECTIVE: The aim of this study was quantification of multiple metabolites in CSF from PD versus healthy control subjects (HCs), including longitudinal analysis. METHODS: Absolute levels of multiple monoamine metabolites in CSF were quantified by liquid chromatography coupled with tandem mass spectrometry from 161 individuals with early PD and 115 HCs from the Parkinson's Progression Marker Initiative and de novo PD (DeNoPA) studies. RESULTS: Baseline levels of homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were lower in individuals with PD compared with HCs. HVA levels correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale total scores (P < 0.01). Both HVA/dopamine and DOPAC/dopamine levels correlated with caudate nucleus and raw DOPAC with putamen dopamine transporter single-photon emission computed tomography uptake ratios (P < 0.01). No metabolite changed over 2 years in drug-naive individuals, but some changed on starting levodopa treatment. CONCLUSIONS: HVA and DOPAC CSF levels mirrored nigrostriatal pathway damage, confirming the central role of dopaminergic degeneration in early PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Ácido 3,4-Di-Hidroxifenilacético , Ácido Homovanílico , Humanos , Levodopa , Neurotransmissores , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/tratamento farmacológicoRESUMO
BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated. OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging. METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score. RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (dmax = -0.20, dmin = -0.09). The bilateral putamen (dleft = -0.14, dright = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures. CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Assuntos
Doença de Parkinson , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Imageamento por Ressonância Magnética , Neuroimagem , Doença de Parkinson/complicações , Tálamo/patologiaRESUMO
Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and affects 1% of the population above 60 years old. Although Parkinson's disease commonly manifests with motor symptoms, a majority of patients with Parkinson's disease subsequently develop cognitive impairment, which often progresses to dementia, a major cause of morbidity and disability. Parkinson's disease is characterized by α-synuclein accumulation that frequently associates with amyloid-ß and tau fibrils, the hallmarks of Alzheimer's disease neuropathological changes; this co-occurrence suggests that onset of cognitive decline in Parkinson's disease may be associated with appearance of pathological amyloid-ß and/or tau. Recent studies have highlighted the appearance of the soluble form of the triggering receptor expressed on myeloid cells 2 (sTREM2) receptor in CSF during development of Alzheimer's disease. Given the known association of microglial activation with advancing Parkinson's disease, we investigated whether CSF and/or plasma sTREM2 differed between CSF biomarker-defined Parkinson's disease participant subgroups. In this cross-sectional study, we examined 165 participants consisting of 17 cognitively normal elderly subjects, 45 patients with Parkinson's disease with no cognitive impairment, 86 with mild cognitive impairment, and 17 with dementia. Stratification of subjects by CSF amyloid-ß and tau levels revealed that CSF sTREM2 concentrations were elevated in Parkinson's disease subgroups with a positive tau CSF biomarker signature, but not in Parkinson's disease subgroups with a positive CSF amyloid-ß biomarker signature. These findings indicate that CSF sTREM2 could serve as a surrogate immune biomarker of neuronal injury in Parkinson's disease.
Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/líquido cefalorraquidiano , Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , Receptores Imunológicos/sangue , Proteínas tau/líquido cefalorraquidiano , Idoso , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/complicações , Estudos Transversais , Demência/sangue , Demência/líquido cefalorraquidiano , Demência/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/classificação , Doença de Parkinson/complicaçõesRESUMO
OBJECTIVE: Low concentrations of cerebrospinal fluid (CSF) amyloid-beta (Aß-42) are associated with increased risk of cognitive decline in Parkinson's disease (PD). We sought to determine whether APOE genotype modifies the rate of cognitive decline in PD patients with low CSF Aß-42 compared to patients with normal levels. METHODS: The Parkinson's Progression Markers Initiative is a longitudinal, ongoing study of de novo PD participants, which includes APOE genotyping, CSF Aß-42 determinations, and neuropsychological assessments. We used linear mixed effects models in three PD groups (PD participants with low CSF Aß at baseline, PD participants with normal CSF Aß, and both groups combined). Having at least one copy of the APOE É4 allele, time, and the interaction of APOE É4 and time were predictor variables for cognitive change, adjusting for age, gender and education. RESULTS: 423 de novo PD participants were followed up to 5â¯years with annual cognitive assessments. 103 participants had low baseline CSF Aß-42 (39 APOE ε4+, 64 APOE ε4-). Compared to participants with normal CSF Aß-42, those with low CSF Aß-42 declined faster on most cognitive tests. Within the low CSF Aß-42 group, APOE ε4+ participants had faster rates of decline on the Montreal Cognitive Assessment (primary outcome; 0.57 points annual decline, pâ¯=â¯.005; 5-year standardized change of 1.2) and the Symbol Digit Modalities Test (1.4 points annual decline, pâ¯=â¯.002; 5-year standardized change of 0.72). DISCUSSION: PD patients with low CSF Aß-42 and APOE ε4+ showed a higher rate of cognitive decline early in the disease. Tests of global cognition (Montreal Cognitive Assessment) and processing speed (Symbol Digit Modalities Test) were the most sensitive to early cognitive decline. Results suggest that CSF Aß-42 and APOE ε4 might interact to promote early cognitive changes in PD patients.