Now that wearable sensors have become more commonplace, it is possible to monitor individual healthcare-related activity outside the clinic, unleashing potential for early detection of events in ...diseases such as Parkinson’s disease (PD). However, the unsupervised and “open world” nature of this type of data collection make such applications difficult to develop. In this proof-of-concept study, we used inertial sensor data from Verily Study Watches worn by individuals for up to 23 h per day over several months to distinguish between seven subjects with PD and four without. Since motor-related PD symptoms such as bradykinesia and gait abnormalities typically present when a PD subject is walking, we initially used human activity recognition (HAR) techniques to identify walk-like activity in the unconstrained, unlabeled data. We then used these “walk-like” events to train one-dimensional convolutional neural networks (1D-CNNs) to determine the presence of PD. We report classification accuracies near 90% on single 5-s walk-like events and 100% accuracy when taking the majority vote over single-event classifications that span a duration of one day. Though based on a small cohort, this study shows the feasibility of leveraging unconstrained wearable sensor data to accurately detect the presence or absence of PD.
OBJECTIVES: To examine Montreal Cognitive Assessment (MoCA) performance in patients with Parkinson's disease (PD) with “normal” global cognition according to Mini‐Mental State Examination (MMSE) ...score.
DESIGN: A cross‐sectional comparison of the MoCA and the MMSE.
SETTING: Two movement disorders centers at the University of Pennsylvania and the Philadelphia Veterans Affairs Medical Center.
PARTICIPANTS: A convenience sample of 131 patients with idiopathic PD who were screened for cognitive and psychiatric complications.
MEASUREMENTS: Subjects were administered the MoCA and MMSE, and only subjects defined as having a normal age‐ and education‐adjusted MMSE score were included in the analyses (N=100). As previously recommended in patients without PD, a MoCA score less than 26 was used to indicate the presence of at least mild cognitive impairment (MCI).
RESULTS: Mean MMSE and MoCA scores±standard deviation were 28.8±1.1 and 24.9±3.1, respectively. More than half (52.0%) of subjects with normal MMSE scores had cognitive impairment according to their MoCA score. Impairments were seen in numerous cognitive domains, including memory, visuospatial and executive abilities, attention, and language. Predictors of cognitive impairment on the MoCA using univariate analyses were male sex, older age, lower educational level, and greater disease severity; older age was the only predictor in a multivariate model.
CONCLUSION: Approximately half of patients with PD with a normal MMSE score have cognitive impairment based on the recommended MoCA cutoff score. These results suggest that MCI is common in PD and that the MoCA is a more sensitive instrument than the MMSE for its detection.
IMPORTANCE Biochemical abnormalities present in GBA (mut/wt) carriers may offer new pathogenetic insights to and potential therapeutic targets in Parkinson disease (PD). OBJECTIVE To determine ...whether patients having PD with vs without GBA mutations differ in clinical phenotype or plasma protein expression. DESIGN AND SETTING Case-control study of patients having PD with vs without GBA mutations. Clinical characteristics were compared between groups, and biochemical profiling of 40 plasma proteins was performed to identify proteins that differed in expression between groups. PARTICIPANTS The discovery cohort included 20 patients having PD with GBA mutations. Clinical characteristics of GBA -associated PD cases were compared with those of 242 patients having PD in whom GBA mutations were excluded by full gene sequencing. MAIN OUTCOME MEASURES Biochemical profiling was available for all 20 GBA -associated PD cases, as well as a subset (87 of 242) of the GBA -negative PD cases. The replication cohort included 19 patients having PD with GBA mutations and 41 patients having PD without GBA mutations. RESULTS Compared with patients having PD without GBA mutations, patients having PD with GBA mutations were younger at disease onset (P = .04) and were more likely to demonstrate cognitive dysfunction (P = .001). In a multiple regression model that included age, sex, and assay batch as covariates, GBA mutation status was significantly associated with plasma levels of interleukin 8 (P = .001), monocyte chemotactic protein 1 (P = .008), and macrophage inflammatory protein 1α (P = .005). The association between interleukin 8 and GBA mutation status was replicated (P = .03) in a separate cohort of patients having PD with vs without GBA mutations. CONCLUSIONS AND RELEVANCE Patients having PD with GBA mutations have earlier age at disease onset and are more likely to demonstrate cognitive dysfunction. Monocyte-associated inflammatory mediators may be elevated in patients having PD with GBA mutations.
While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine ...plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI).
Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide.
Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study.
In Parkinson disease (PD), Alzheimer disease (AD) copathology is common and clinically relevant. However, the longitudinal progression of AD CSF biomarkers-β-amyloid 1-42 (Aβ
), phosphorylated tau ...181 (p-tau
), and total tau (t-tau)-in PD is poorly understood and may be distinct from clinical AD. Moreover, it is unclear whether CSF p-tau
and serum neurofilament light (NfL) have added prognostic utility in PD, when combined with CSF Aβ
. First, we describe longitudinal trajectories of biofluid markers in PD. Second, we modified the AD β-amyloid/tau/neurodegeneration (ATN) framework for application in PD (ATN
) using CSF Aβ
(A), p-tau
(T), and serum NfL (N) and tested ATN
prediction of longitudinal cognitive decline in PD.
Participants were selected from the Parkinson's Progression Markers Initiative cohort, clinically diagnosed with sporadic PD or as controls, and followed up annually for 5 years. Linear mixed-effects models (LMEMs) tested the interaction of diagnosis with longitudinal trajectories of analytes (log transformed, false discovery rate FDR corrected). In patients with PD, LMEMs tested how baseline ATN
status (AD A+T+N± vs not) predicted clinical outcomes, including Montreal Cognitive Assessment (MoCA; rank transformed, FDR corrected).
Participants were 364 patients with PD and 168 controls, with comparable baseline mean (±SD) age (patients with PD = 62 ± 10 years; controls = 61 ± 11 years; Mann-Whitney Wilcoxon:
= 0.4) and sex distribution (patients with PD = 231 male individuals 63%; controls = 107 male individuals 64%; χ
:
= 1). Patients with PD had overall lower CSF p-tau
(β = -0.16, 95% CI -0.23 to -0.092,
= 2.2e-05) and t-tau than controls (β = -0.13, 95% CI -0.19 to -0.065,
= 4e-04), but not Aβ
(
= 0.061) or NfL (
= 0.32). Over time, patients with PD had greater increases in serum NfL than controls (β = 0.035, 95% CI 0.022 to 0.048,
= 9.8e-07); slopes of patients with PD did not differ from those of controls for CSF Aβ
(
= 0.18), p-tau
(
= 1), or t-tau (
= 0.96). Using ATN
, PD classified as A+T+N± (n = 32; 9%) had worse cognitive decline on global MoCA (β = -73, 95% CI -110 to -37,
= 0.00077) than all other ATN
statuses including A+ alone (A+T-N-; n = 75; 21%).
In patients with early PD, CSF p-tau
and t-tau were low compared with those in controls and did not increase over 5 years of follow-up. Our study shows that classification using modified ATN
(incorporating CSF Aβ
, CSF p-tau
, and serum NfL) can identify biologically relevant subgroups of PD to improve prediction of cognitive decline in early PD.
It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, ...and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies.BACKGROUND AND OBJECTIVESIt is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies.Participants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score <21 and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I cognition score ≥3 as secondary end points for PPMI. In addition, estimated dementia probability by PD disease duration was tabulated for each study and end point.METHODSParticipants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score <21 and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I cognition score ≥3 as secondary end points for PPMI. In addition, estimated dementia probability by PD disease duration was tabulated for each study and end point.For the PPMI cohort, 417 participants with PD (mean age 61.6 years, 65% male) were followed, with an estimated probability of dementia at year 10 disease duration of 9% (site investigator diagnosis), 15% (MoCA), or 12% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 participants with PD (mean age 69.3 years, 67% male) were followed, with 184 participants (47% of cohort) eventually diagnosed with dementia. The interval-censored curve for the Penn cohort had a median time to dementia of 15 years (95% CI 13-15); the estimated probability of dementia was 27% at 10 years of disease duration, 50% at 15 years, and 74% at 20 years.RESULTSFor the PPMI cohort, 417 participants with PD (mean age 61.6 years, 65% male) were followed, with an estimated probability of dementia at year 10 disease duration of 9% (site investigator diagnosis), 15% (MoCA), or 12% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 participants with PD (mean age 69.3 years, 67% male) were followed, with 184 participants (47% of cohort) eventually diagnosed with dementia. The interval-censored curve for the Penn cohort had a median time to dementia of 15 years (95% CI 13-15); the estimated probability of dementia was 27% at 10 years of disease duration, 50% at 15 years, and 74% at 20 years.Results from two large, prospective studies suggest that dementia in PD occurs less frequently, or later in the disease course, than previous research studies have reported.DISCUSSIONResults from two large, prospective studies suggest that dementia in PD occurs less frequently, or later in the disease course, than previous research studies have reported.
The etiology and natural history of Parkinson's disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may ...develop during the prodromal stage of PD and precede PD diagnosis by years.
We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications.
This review was based on a workshop, Parkinson's Disease Premotor Symptom Symposium, held 7-8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina.
Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood.
This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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