Predictive value of abbreviated olfactory tests in prodromal Parkinson disease.

There is disagreement in the literature whether olfaction may show specific impairments in Parkinson Disease (PD) and if olfactory tests comprised of selected odors could be more specific for diagnosis. We sought to validate previously proposed subsets of the University of Pennsylvania Smell Identification Test (UPSIT) odors for predicting conversion to PD in an independent, prodromal cohort. Conversion to PD was assessed in 229 participants in the Parkinson At Risk Study who completed baseline olfactory testing with the UPSIT and up to 12 years of clinical and imaging evaluations. No commercially available or proposed subset performed better than the full 40-item UPSIT. The proposed "PD-specific" subsets also did not perform better than expected by chance. We did not find evidence for selective olfactory impairment in Parkinson disease. Shorter odor identification tests, including commercially available 10-12 item tests, may have utility for ease of use and cost, but not for superior predictive value.

Deploying Digital Health Technologies for Remote Physical Activity Monitoring of Rural Populations With Chronic Neurologic Disease.

Objective: The objective of this pilot study was to examine the feasibility of a remote physical activity monitoring program, quantify baseline activity levels, and examine predictors of activity among rurally residing adults with Parkinson disease (PD) or stroke. Design: Thirty-day observational study. Participants completed standardized assessments, connected a wearable device, and synced daily step counts via a remote monitoring platform. Setting: Community-based remote monitoring. Participants: Rurally residing adults with PD or stroke enrolled in the Veterans Health Administration. Intervention: N/A. Main Outcome Measures: Feasibility was evaluated using recruitment data (response rates), study completion (completed assessments and connected the wearable device), and device adherence (days recording ≥100 steps). Daily step counts were examined descriptively. Predictors of daily steps were explored across the full sample, then by diagnosis, using linear mixed-effects regression analyses. Results: Forty participants (n=20 PD; n=20 stroke) were included in the analysis with a mean (SD) age of 72.9 (7.6) years. Participants resided 252.6 (105.6) miles from the coordinating site. Recruitment response rates were 11% (PD) and 6% (stroke). Study completion rates were 71% (PD) and 80% (stroke). Device adherence rates were 97.0% (PD) and 95.2% (stroke). Participants with PD achieved a median [interquartile range] of 2618 [3896] steps per day and participants with stroke achieved 4832 [7383] steps. Age was the only significant predictor of daily steps for the full sample (-265 steps, 95% confidence interval [-407, -123]) and by diagnosis (PD, -175 steps, [-335, -15]; stroke, -357 steps [-603, -112]). Conclusions: A remote physical activity monitoring program for rurally residing individuals with PD or stroke was feasible. This study establishes a model for a scalable physical activity program for rural, older populations with neurologic conditions from a central coordinating site.

Serial olfactory testing for the diagnosis of prodromal Parkinson's disease in the PARS study.

BACKGROUND: The Parkinson Associated Risk Syndrome (PARS) study was designed to evaluate whether screening with olfactory testing and dopamine transporter (DAT) imaging could identify participants at risk for developing Parkinson's disease (PD). OBJECTIVE: Hyposmia on a single test has been associated with increased risk of PD, but, taken alone, lacks specificity. We evaluated whether repeating olfactory testing improves the diagnostic characteristics of this screening approach. METHODS: Participants completed up to 10 years of clinical and imaging evaluations in the PARS cohort. Olfaction was assessed with the University of Pennsylvania Smell Identification Test at baseline and on average 1.4 years later. Multiple logistic regression and Cox proportional hazards regression were used to estimate the hazard of development of clinical PD or abnormal DAT imaging. RESULTS: Of 186 participants who were initially hyposmic, 28% reverted to normosmia on repeat testing (reverters). No initially normosmic subjects and only 2% of reverters developed DAT imaging progression or clinical PD, compared to 29% of subjects with persistent hyposmia who developed abnormal DAT and 20% who developed clinical PD. The relative risk of clinical conversion to PD was 8.3 (95% CI:0.92-75.2, p = 0.06) and of abnormal DAT scan was 12.5 (2.4-156.2, p = 0.005) for persistent hyposmia, compared to reversion. CONCLUSIONS: Persistent hyposmia on serial olfactory testing significantly increases the risk of developing clinical PD and abnormal DAT imaging, compared to hyposmia on a single test. Repeat olfactory testing may be an efficient and cost-effective strategy to improve identification of at-risk patients for early diagnosis and disease modification studies.

Selected autonomic signs and symptoms as risk markers for phenoconversion and functional dependence in prodromal Parkinson's disease.

PURPOSE: To determine whether dysautonomia can stratify individuals with other prodromal markers of Parkinson's disease (PD) for risk of phenoconversion and functional decline, which may help identify subpopulations appropriate for experimental studies. METHODS: Data were obtained from Parkinson's Progression Markers Initiative. Cohorts without PD but with at-risk features were included (hyposmia and/or rapid-eye-movement-sleep behavior disorder, LRRK2 gene mutation, GBA gene mutation). Dysautonomia measures included Scales-for-Outcomes-in-Parkinson's-Disease Autonomic (SCOPA-AUT), seven SCOPA-AUT subscales, and cardiovascular dysfunction (supine hypertension, low pulse pressure, neurogenic orthostatic hypotension). Outcome measures were phenoconversion and Schwab-and-England Activities-of-Daily-Living (SE-ADL) ≤ 70, which indicates functional dependence. Cox proportional-hazards regression was used to evaluate survival to phenoconversion/SE-ADL ≤ 70 for each dysautonomia measure. If a significant association was identified, a likelihood-ratio test was employed to evaluate whether a significant interaction existed between the measure and cohort. If so, regression analysis was repeated stratified by cohort. RESULTS: Median follow-up was 30 months. On multivariable analysis, gastrointestinal and female sexual dysfunction subscales were associated with increased risk of phenoconversion, while the cardiovascular subscale and neurogenic orthostatic hypotension were associated with increased risk of SE-ADL ≤ 70; respective hazard ratios (95% confidence intervals) were 1.13 (1.01-1.27), 3.26 (1.39-7.61), 1.87 (1.16-2.99), 5.45 (1.40-21.25). Only the association between the cardiovascular subscale and SE-ADL ≤ 70 was modified by cohort. CONCLUSIONS: Symptoms of gastrointestinal and female sexual dysfunction predict phenoconversion in individuals with other risk markers for PD, while signs and symptoms of cardiovascular dysfunction may be associated with functional decline.

Risk of Drug-induced Movement Disorders with Newer Antipsychotic Agents.

Background: The last decade has seen development of numerous novel antipsychotic drugs with unique mechanisms including long-acting formulations for clinical use. A comparative assessment of these new drugs with each other and previous antipsychotics have not been performed with regards to risk for drug-induced movement disorders (DIMD). Methods: Medline was searched from January 2010 to February 2022 for primary research articles and review articles in English using the search terms "extrapyramidal" and "tardive" with individual drug names of novel antipsychotics. Results: We identified articles describing the risk of DIMD with 6 novel antipsychotics, 4 novel formulations, and 3 experimental antipsychotics. Both short- and long-term data generally showed comparable to lower risk of DIMD with novel antipsychotics and recent long-acting formulations compared to previously marketed antipsychotics. Discussion: Several novel antipsychotics, particularly lumateperone and pimavanserin, show promise in being able to treat psychosis while reducing the risk of DIMD. Long-acting paliperidone may reduce risk of DIMD while other long-acting injectable formulations of SGA have similar risk of DIMD compared to oral formulations. New drug targets for treating psychosis without dopamine blockade also show promise.

Non-tremor motor dysfunction in Lewy body dementias is associated with AD biomarkers.

Motor features of Parkinson's disease (PD) are heterogeneous and well-studied; non-tremor features of postural instability and gait dysfunction (PIGD) have been linked to worse outcomes and Alzheimer's disease (AD) co-pathology. However, these features are understudied in Lewy body dementias (LBD). Here we perform retrospective analysis of a unique cohort of LBD (n = 30) with Unified Parkinson's Disease Rating Scale (UPDRS) data collected at baseline in proximity to cerebrospinal fluid collection to test the hypothesis that LBD patients with a positive AD biomarker profile (LBD + AD = 13) would have higher PIGD burden compared with LBD patients without AD biomarker positivity (LBD-AD = 17). We find novel evidence for selective impairment of PIGD burden in LBD + AD vs LBD-AD (OR = 1.95, 95%CI = 1.02-3.70, p = 0.04) and a direct association of increasing CSF tau/Aß1-42 ratio with increasing PIGD disability in the total cohort (ß = 0.23, SE = 0.08, p = 0.01). This unique biomarker stratification approach suggests AD co-pathology may contribute to PIGD motor signs in LBD.

Gait abnormalities and non-motor symptoms predict abnormal dopaminergic imaging in presumed drug-induced Parkinsonism.

Drug-induced parkinsonism (DIP) can be clinically indistinguishable from degenerative parkinsonism, and bedside assessments are needed to differentiate between these conditions. We examined 34 U.S. Veterans with DIP using 123I-FP-CIT (DAT-SPECT) to identify underlying nigrostriatal degeneration. Participants were 94% male with mean age of 64.5 ± 7.1 years. DAT-SPECT was abnormal in 12/34 (35%). Comparing normal and abnormal imaging groups, there were no differences in age, sex, race/ethnicity, psychiatric diagnosis, motor severity, or RBD Screening Questionnaire scores. Those with underlying neurodegeneration reported significantly more non-motor symptoms (NMS), worse olfactory function on the University of Pennsylvania Smell Identification Test, and greater turning duration/steps on the instrumented Timed Up and Go. Area under the curve (AUC) combining poor olfaction and total NMS burden was 0.84 (CI 0.71-0.97), while AUC for turn steps was 0.91 (CI 0.81-1.00). Gait impairment, hyposmia, and NMS may be useful alone and in combination to identify DIP patients with underlying dopaminergic degeneration.

Olfaction as an early marker of Parkinson's disease and Alzheimer's disease.

Olfactory impairment is a common and early sign of Parkinson's disease (PD) and Alzheimer's disease (AD), the two most prevalent neurodegenerative conditions in the elderly. This phenomenon corresponds to pathologic processes emerging in the olfactory system prior to the onset of typical clinical manifestations. Clinically available tests can establish hyposmia through odor identification assessment, discrimination, and odor detection threshold. There are significant efforts to develop preventative or disease-modifying therapies that slow down or halt the progression of PD and AD. Due to the convenience and low cost of its assessment, olfactory impairment could be used in these studies as a screening instrument. In the clinical setting, loss of smell may also help to differentiate PD and AD from alternative causes of Parkinsonism and cognitive impairment, respectively. Here, we discuss the pathophysiology of olfactory dysfunction in PD and AD and how it can be assessed in the clinical setting to aid in the early and differential diagnosis of these disorders.

Modifiable Comorbidities Associated with Cognitive Decline in Parkinson's Disease.

BACKGROUND: Cognitive impairment (CI) is one of the most feared and debilitating complications of PD. No therapy has been shown to slow or prevent CI in PD. OBJECTIVE: To determine associations between modifiable comorbidities, including cardiovascular disease risk factors, mood disorders, and sleep characteristics, and rate of cognitive decline in Parkinson's disease (PD). METHODS: Data from the Parkinson's Progression Markers Initiative (PPMI) cohort was queried for baseline cardiovascular disease risk factors, mood disorders, and sleep characteristics. Linear mixed- effects models (LME) were used to examine the association between baseline factors and change in cognition, evaluated by the Montreal Cognitive Assessment (MoCA) over time. Baseline comorbidities found to affect MoCA decline were assessed for an association with focal cognitive domains using LME. RESULTS: Higher Body Mass Index (BMI) (ß = -0.009, P = 0.039), State Trait Anxiety Inventory (STAI) (ß = -0.005, P < 0.001), Geriatric Depression Scale (GDS) (ß = -0.034, P < 0.001), Epworth Sleepiness Scale (ESS) (ß = -0.017, P = 0.003), and REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) (ß = -0.037, P < 0.001) were associated with faster rates of MoCA decline. Using established cut-offs for clinically significant symptoms, being overweight, or the presence of depression, excessive day time sleepiness (EDS), and possible REM sleep behavior disorder (pRBD), were all associated with faster rate of cognitive decline. CONCLUSION: Several modifiable baseline comorbidities are associated with faster rate of CI over time in patients with PD. These associations identify potential opportunities for early intervention that could influence CI in PD.

Cognitive Profile and Markers of Alzheimer Disease-Type Pathology in Patients With Lewy Body Dementias.

OBJECTIVE: To determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)-type copathology are more impaired on confrontation naming than those without likely AD-type copathology. METHODS: We selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF ß-amyloid1-42 (Aß42), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured. We used an autopsy-validated CSF cut point (t-tau:Aß42 ratio > 0.3, n = 43), or autopsy data when available (n = 14), to categorize patients as having LBD with (LBD + AD, n = 26) and without (LBD - AD, n = 31) likely AD-type copathology. Analysis of covariance tested between-group comparisons across biologically defined groups (LBD + AD, LBD - AD) and clinical phenotypes (DLB, PDD) on confrontation naming (30-item Boston Naming Test [BNT]), executive abilities (letter fluency [LF], reverse digit span [RDS]), and global cognition (Mini-Mental State Examination [MMSE]), with adjustment for age at dementia onset, time from dementia onset to test date, and time from CSF to test date. Spearman correlation related cognitive performance to CSF analytes. RESULTS: Patients with LBD + AD performed worse on BNT than patients with LBD - AD (F = 4.80, p = 0.03); both groups performed similarly on LF, RDS, and MMSE (all p > 0.1). Clinically defined PDD and DLB groups did not differ in performance on any of these measures (all p > 0.05). A correlation across all patients showed that BNT score was negatively associated with CSF t-tau (ρ = -0.28, p < 0.05) and p-tau (ρ = -0.26, p = 0.05) but not Aß42 (p > 0.1). CONCLUSION: Markers of AD-type copathology are implicated in impaired language performance in LBD. Biologically based classification of LBD may be advantageous over clinically defined syndromes to elucidate clinical heterogeneity.

Tau pathology associates with in vivo cortical thinning in Lewy body disorders.

OBJECTIVES: To investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD). METHODS: We studied 72 LBD patients (Parkinson disease (PD) = 2, PD-MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Aß1-42  > 0.3) (LBD+AD, N = 19), and those without AD co-pathology (LBD-AD, N = 53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD-AD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Aß, and alpha-synuclein using digital histopathology in five representative neocortical regions. RESULTS: The LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P < 0.05 FWE-corrected) relative to LBD-AD. In LBD+AD, cortical thinning was most pronounced in temporal neocortex, whereas the AD reference group showed atrophy that equally encompassed temporal, parietal and frontal neocortex. In autopsied LBD, we found an inverse correlation with cortical thickness and post-mortem tau pathology, while cortical thickness was not significantly associated with Aß or alpha-synuclein pathology. INTERPRETATION: LBD+AD is characterized by temporal neocortical thinning on MRI, and cortical thinning directly correlated with post-mortem histopathologic burden of tau, suggesting that tau pathology influences the pattern of neurodegeneration in LBD.

Revisiting amantadine as a treatment for drug-induced movement disorders.

BACKGROUND: Amantadine, an aliphatic primary amine with complex actions on neurotransmitter systems in the basal ganglia, is approved for treating Parkinson's disease and drug-induced movement disorders (DIMDs). These disorders have a significant impact on clinical outcomes and quality of life in patients receiving antipsychotic treatment. METHODS: We searched PubMed up to June 1, 2019 to identify relevant studies. The following search terms were used: "amantadine" AND "dystonia," "parkinsonism, " "akathisia," "tardive dyskinesia," "catatonia," "neuroleptic malignant syndrome." Reference lists were reviewed for additional material. RESULTS: Evidence from multiple, small, controlled trials supports the efficacy of amantadine as a treatment for drug-induced parkinsonism. Studies show amantadine has a more favorable tolerability profile than anticholinergic medications in these patients. Clinical evidence from observational studies and case reports suggests that further trials might be warranted to support use of amantadine in select patients for preventing dystonic reactions and as a second-line agent for treating catatonia, neuroleptic malignant syndrome, and tardive dyskinesia. Evidence is lacking on the use of amantadine specifically for akathisia relative to other treatments. CONCLUSIONS: Amantadine is an evidence-based pharmacologic strategy for treating drug-induced parkinsonism and might be an alternative treatment for other DIMDs in select patients. Additional randomized controlled trials are needed.

Subjective Cognitive Complaint in Parkinson's Disease Patients With Normal Cognition: Canary in the Coal Mine?

OBJECTIVE: The objective of this study was to determine the frequency and impact of subjective cognitive complaint (SCC) in Parkinson's disease (PD) patients with normal cognition. METHODS: Patients with PD with expert consensus-determined normal cognition at baseline were asked a single question regarding the presence of SCC. Baseline (N = 153) and longitudinal (up to 4 follow-up visits during a 5-year period; N = 121) between-group differences in patients with PD with (+SCC) and without (-SCC) cognitive complaint were examined, including cognitive test performance and self-rated and informant-rated functional abilities. RESULTS: A total of 81 (53%) participants reported a cognitive complaint. There were no between-group differences in global cognition at baseline. Longitudinally, the +SCC group declined more than the -SCC group on global cognition (Mattis Dementia Rating Scale-2 total score, F1,431 = 5.71, P = 0.02), processing speed (Symbol Digit Modalities Test, F1,425 = 7.52, P = 0.006), and executive function (Trail Making Test Part B, F1,419 = 4.48, P = 0.04), although the results were not significant after correction for multiple testing. In addition, the +SCC group was more likely to progress to a diagnosis of cognitive impairment over time (hazard ratio = 2.61, P = 0.02). The +SCC group also demonstrated significantly lower self-reported and knowledgeable informant-reported cognition-related functional abilities at baseline, and declined more on an assessment of global functional abilities longitudinally. CONCLUSIONS: Patients with PD with normal cognition, but with SCC, report poorer cognition-specific functional abilities, and are more likely to be diagnosed with cognitive impairment and experience global functional ability decline long term. These findings suggest that SCC and worse cognition-related functional abilities may be sensitive indicators of initial cognitive decline in PD. © 2020 International Parkinson and Movement Disorder Society.

Comparing self-reported and objective monitoring of physical activity in Parkinson disease.

INTRODUCTION: Monitoring physical activity is important in Parkinson disease (PD), but patient recall may be unreliable. We examined relationships between self-reported activity, objective monitoring, and clinical characteristics. METHODS: Participants completed the self-reported Physical Activity Scale in the Elderly (PASE) to determine subjective minutes of moderate-vigorous physical activity (MVPA); a subset wore an Actigraph monitor capturing step count and objective MVPA using a PD-specific algorithm. Relationships between subjective and objective measurements were determined using partial correlations controlling for age and disease stage. RESULTS: Sixty-six subjects completed subjective reporting; median age (interquartile range [IQR]) was 70 (69-74) years and median disease duration (IQR) was 4 (1.5-7.5) years. Age-adjusted median PASE was 135.3. Median daily step count was 3615 (IQR 1772-4870), which was moderately well-correlated with PASE (ρ = 0.56, p = 0.003). Median MVPA was 8.1 min/day (IQR 2.2-23.2), which was not correlated with PASE (ρ = -0.003, p = 0.98). CONCLUSIONS: Physical activity in this cohort of Veterans with PD is low and consists mostly of low-intensity steps rather than MVPA. The symptomatic and disease-modifying potential of lower intensity activity is uncertain. These data emphasize the need for interventions to increase MVPA in PD and the importance of objective monitoring using wearable technology.

Cognitive Functional Abilities in Parkinson's Disease: Agreement Between Patients and Informants.

BACKGROUND: The Penn Parkinson's Daily Activities Questionnaire-15 (PDAQ-15) assesses cognition-related instrumental activities of daily living (IADL) in Parkinson's disease (PD). OBJECTIVES: To assess the degree and predictors of disagreement between patients (PT) and knowledgeable informants (KI) on the PDAQ-15. METHODS: We recruited 254 PT and KI pairs (PT-KI), determined predictors of agreement, and compared scores to a performance-based functional measure (Direct Assessment of Functional Status [DAFS]; N = 61). RESULTS: PT and KI total score (intraclass correlation = 0.57) and individual item (Cohen's kappa = 0.46-0.62) agreement were moderate. Patient depression, global cognition, and caregiver burden (all P < 0.05), predicted PT-KI discrepancy. PT-KI discrepancy was highest in patients with a dementia diagnosis, followed by mild cognitive impairment and then normal cognition (all P < 0.01), with PT rating themselves relatively more functionally intact as cognition worsened. DAFS performance was more highly correlated with KI (r = 0.82; P < 0.001) than PT (r = 0.62; P < 0.001) PDAQ-15 score. CONCLUSIONS: Our results support using KI as proxies when assessing cognitive IADLs in PD PTs, particularly in cases of more advanced cognitive decline.

Early and Accurate Identification of Parkinson Disease Among US Veterans.

Early and accurate identification and management of veterans at risk for Parkinson disease is an important priority area for the US Department of Veterans Affairs because of the substantial impact on quality of life and disability-adjusted life years.

Understanding physical activity in Veterans with Parkinson disease: A mixed-methods approach.

INTRODUCTION: Physical activity is critical in Parkinson disease (PD) management, but barriers and motivators of activity in Veterans with PD may be unique. We examined activity habits, including barriers and motivators, in this population. METHODS: Participants completed the Physical Activity Scale in the Elderly (PASE). Compliance with American Heart Association (AHA) recommendations was assessed. Veterans also completed the Exercise Perceptions Questionnaire (EPQ), assessing knowledge, barriers, and motivators of activity. Free-text barriers/motivators were analyzed by the overlapping clusters method. RESULTS: Seventy-five Veterans were recruited; mean age (standard deviation [SD]) was 70.5 (8.2) years and mean disease duration (SD) was 5.4 (5.2) years. Raw median PASE was 120.4 (interquartile range [IQR] 68.8-165.7); age-adjusted median PASE was 135.3. Only 9 Veterans (14.3%) were AHA-compliant. There were trends toward negative association between PASE and UPDRS-3 (r = -0.24, p = 0.06) and between PASE and PDQ-8 (r = -0.23, p = 0.08). Sixty-three subjects (84%) completed the EPQ; 27 (42.9%) preferred scheduled exercise, and only 33 (53.2%) reported that they preferred to exercise with others. Common themes of 46 free-text responses included desire to improve PD symptoms (n = 15, 32.6%) and social engagement (n = 12, 26.1%). CONCLUSIONS: Self-reported activity in Veterans with PD is low, with less than 15% of subjects meeting recommended activity targets. Qualitative analysis of barriers and motivators revealed that although many Veterans enjoy the social aspects of group exercise, they may not feel comfortable in general exercise classes aimed at younger participants without chronic illnesses. These data will be useful in designing Veteran- and/or PD-specific interventions to increase activity levels.

The importance of preclinical diagnostics in Parkinson disease.

Given the increasing recognition that neurodegeneration begins decades before the appearance of motor symptoms of Parkinson disease (PD), recent attention has turned to methods of preclinical or prodromal diagnosis. Accurate preclinical diagnosis of individuals at high risk of developing manifest motor PD can improve clinical counseling as well as provide an enriched cohort for studies of possible disease-modifying therapies. In this review article, the authors synthesize the myriad clinical, radiographic, and biochemical signatures of preclinical PD, with an emphasis on biomarkers that may provide accurate population screening for the disease. As individual biomarkers have relatively lowsensitivity and specificity, any population-based approach to preclinical diagnosis will likely combine multiple biomarkers to improve both negative and positive predictive value.