Parkinson's Disease Participants Research Articles

Different associated factors of subjective cognitive complaints in patients with early and advanced Parkinson's disease.

Subjective cognitive complaints (SCCs), defined as cognitive decline reported by subjects or their informants, are common in the early stage of Parkinson's disease (PD). Previous studies have shown a significant association between SCCs and non-motor features as well as objective cognitive decline in PD patients. However, the discrepancy in SCC prevalence and SCC-related factors between patients with early PD and those with advanced PD remains poorly understood. We recruited a total of 114 and 69 early PD patients and advanced PD patients, respectively. Univariate and multivariate logistic regression analyses were performed for early PD and advanced PD patients. The prevalence of SCCs in the early PD and advanced PD groups was 60.5 and 68.1%, respectively. In the early PD group, the presence of SCCs in early PD participants was significantly associated with a higher nonmotor symptoms questionnaire (NMSQ) score (OR = 1.05, 95% CI = 1.00-1.10, p = 0.040). SCCs in the advanced PD group were related to lower attention scores (OR = 0.24, 95% CI = 0.05-0.90, p = 0.043) and lower visuospatial/executive abilities scores (OR = 0.18, 95% CI = 0.04-0.86, p = 0.032). The prevalence and SCC-related factors are distinct in early PD and advanced PD. These findings suggest that SCCs in PD patients with different disease statuses appear to have different related factors that may depend on different disease severities.

Hippocampal Perfusion Affects Motor and Cognitive Functions in Parkinson Disease: An Early Phase 18 F-FP-CIT Positron Emission Tomography Study.

We investigated whether hippocampal perfusion changes are associated with cognitive decline, motor deficits, and the risk of dementia conversion in patients with Parkinson disease (PD). We recruited patients with newly diagnosed and nonmedicated PD and healthy participants who underwent dual phase 18 F-N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane positron emission tomography scans. Patients were classified into 3 groups according to hippocampal perfusion measured by standard uptake value ratios (SUVRs): (1) PD hippocampal hypoperfusion group (1 standard deviation [SD] below the mean hippocampal SUVR of healthy controls; PD-hippo-hypo), (2) PD hippocampal hyperperfusion group (1 SD above the mean; PD-hippo-hyper), and (3) the remaining patients (PD-hippo-normal). We compared the baseline cognitive performance, severity of motor deficits, hippocampal volume, striatal dopamine transporter (DAT) availability, and risk of dementia conversion among the groups. We included 235 patients (PD-hippo-hypo, n = 21; PD-hippo-normal, n = 157; PD-hippo-hyper, n = 57) and 48 healthy participants. Patients in the PD-hippo-hypo group were older and had smaller hippocampal volumes than those in the other PD groups. The PD-hippo-hypo group showed less severely decreased DAT availability in the putamen than the other groups despite similar severities of motor deficit. The PD-hippo-hypo group had a higher risk of dementia conversion compared to the PD-hippo-normal (hazard ratio = 2.59, p = 0.013) and PD-hippo-hyper (hazard ratio = 3.73, p = 0.006) groups, despite similar cognitive performance at initial assessment between groups. Hippocampal hypoperfusion may indicate a reduced capacity to cope with neurodegenerative processes in terms of the development of motor deficits and cognitive decline in patients with PD. ANN NEUROL 2024;95:388-399.

Levetiracetam for the treatment of mild cognitive impairment in Parkinson’s disease: a double-blind controlled proof-of-concept trial protocol

BackgroundMild memory impairment, termed amnestic mild cognitive impairment (aMCI), is associated with rapid progression towards dementia in Parkinson’s disease (PD). Studies have shown hyperactivation of hippocampal DG/CA3 subfields during an episodic memory task as a biomarker of aMCI related to Alzheimer’s disease. This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative treatment to target DG/CA3 hyperactivation and improve episodic memory deficits in aMCI in PD. Based on previous work, it is hypothesized that levetiracetam will normalize DG/CA3 overactivation in PD-aMCI participants and improve memory performance.MethodsTwenty-eight PD-aMCI participants, 28 PD participants without memory impairment (PD-nMI), and 28 healthy controls will be recruited. PD-aMCI participants will undertake a 12-week randomized, placebo-controlled, double-blind cross-over trial with a 14-day treatment of 125 mg levetiracetam or placebo twice daily, separated by a 4-week washout period. After each treatment period, participants will complete an episodic memory task designed to tax hippocampal subregion-specific function during high-resolution functional magnetic resonance imaging (fMRI). PD-nMI and healthy controls will undergo the fMRI protocol only, to compare baseline DG/CA3 subfield activity.ResultsEpisodic memory task performance and functional activation in the DG/CA3 subfield during the fMRI task will be primary outcome measures. Global cognition, PD severity, and adverse events will be measured as secondary outcomes. Recruitment, eligibility, and study completion rates will be explored as feasibility outcomes.ConclusionsThis study, the first of its kind, will establish hippocampal subregion functional impairment and proof of concept of levetiracetam as an early therapeutic option to reduce dementia risk in PD.Trial registrationClinicalTrials.gov, NCT04643327. Registered on 25 November 2020.

Medication-invariant resting aperiodic and periodic neural activity in Parkinson's disease.

Parkinson's disease (PD) has been associated with greater total power in canonical frequency bands (i.e., alpha, beta) of the resting electroencephalogram (EEG). However, PD has also been associated with a reduction in the proportion of total power across all frequency bands. This discrepancy may be explained by aperiodic activity (exponent and offset) present across all frequency bands. Here, we examined differences in the eyes-open (EO) and eyes-closed (EC) resting EEG of PD participants (N = 26) on and off medication, and age-matched healthy controls (CTL; N = 26). We extracted power from canonical frequency bands using traditional methods (total alpha and beta power) and extracted separate parameters for periodic (parameterized alpha and beta power) and aperiodic activity (exponent and offset). Cluster-based permutation tests over spatial and frequency dimensions indicated that total alpha and beta power, and aperiodic exponent and offset were greater in PD participants, independent of medication status. After removing the exponent and offset, greater alpha power in PD (vs. CTL) was only present in EO recordings and no reliable differences in beta power were observed. Differences between PD and CTL in the resting EEG are likely driven by aperiodic activity, suggestive of greater relative inhibitory neural activity and greater neuronal spiking. Our findings suggest that resting EEG activity in PD is characterized by medication-invariant differences in aperiodic activity which is independent of the increase in alpha power with EO. This highlights the importance of considering aperiodic activity contributions to the neural correlates of brain disorders.

Screening of Crucial Cytosolicproteins Interconnecting the Endoplasmic Reticulum and Mitochondria in Parkinson's Disease and the Impact of Anti-Parkinson Drugs in the Preservation of Organelle Connectivity.

Mitochondrial dysfunction is well-established in Parkinson's disease (PD); however, its dysfunctions associating with cell organelle connectivity remain unknown. We aimed to establish the crucial cytosolic protein involved in organelle connectivity between mitochondria and the endopalmic reticulum (ER) through a computational approach by constructing an organelle protein network to extract functional clusters presenting the crucial PD protein connecting organelles. Then, we assessed the influence of anti-parkinsonism drugs (n = 35) on the crucial protein through molecular docking and molecular dynamic simulation and further validated its gene expression in PD participants under, istradefylline (n = 25) and amantadine (n = 25) treatment. Based on our investigation, D-aspartate oxidase (DDO )protein was found to be the critical that connects both mitochondria and the ER. Further, molecular docking showed that istradefylline has a high affinity (-9.073 kcal/mol) against DDO protein, which may disrupt mitochondrial-ER connectivity. While amantadine (-4.53 kcal/mol) shows negligible effects against DDO that contribute to conformational changes in drug binding, Successively, DDO gene expression was downregulated in istradefylline-treated PD participants, which elucidated the likelihood of an istradefylline off-target mechanism. Overall, our findings illuminate the off-target effects of anti-parkinsonism medications on DDO protein, enabling the recommendation of off-target-free PD treatments.

Baseline prevalence and longitudinal assessment of autonomic dysfunction in early Parkinson's disease.

Autonomic dysfunction (AutD) is common and debilitating in Parkinson's disease (PD). Predictors of AutD are unclear, and data are limited on the biological relevance of AutD in PD. Here, we evaluated the baseline prevalence and 2-year longitudinal assessment of AutD in patients with de novo PD compared with healthy controls (HC). Moreover, we also assessed various variables that could predict longitudinal changes in AutD in early PD. Parkinson's Progression Markers Initiative (PPMI) was utilized to evaluate untreated PD participants at baseline and HC. Autonomic function was assessed using the 25-item Scale for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT) score at baseline and 2years. Clinical and biological variables were measured for their correlations with AuD for up to 2years. Two hundred and ninety PD subjects and 170 HC were enrolled and followed for 2years. SCOPA-AUT mean (SD) scores increased from baseline 8.49 ± 5.23 to 10.12 ± 5.77 at year 2 in PD subjects (p < 0.001) versus from 4.98 ± 3.34 to 5.03 ± 374 in HC (p = 0.496), with a significant difference between the groups (p < 0.001). Among them, 242 PD participants and 151 HC completed the SCOPA-AUT assessment, including sexual function. In the multivariate analysis, a higher baseline SCOPA-AUT score was associated with higher baseline MDS-UPDRS Part I scores (p < 0.001). Moreover, a longitudinal increase in autonomic function severity was associated with the white race (p = 0.010) at baseline. In contrast, there was no association with the CSF biomarkers. MDS-UPDRS Part I score may predict AuD in patients with early PD, which is correlated with nonmotor symptoms and race.

Prevalence and clinical aspects of obstructive sleep apnea in Parkinson disease: A meta-analysis.

Obstructive sleep apnea (OSA) frequently occurs in Parkinson Disease (PD), probably caused by upper airway dysfunctions or shared pathogenetic mechanisms. OSA may precede PD diagnosis or worsen throughout its course, but its relationship with clinical features and dopaminergic medication remains unclear. This meta-analysis aimed to provide a reliable estimate of OSA prevalence in the PD population (PD-OSA) and to clarify its clinical associated factors to help clinicians in understanding the underlying pathophysiological mechanisms. A systematic literature search was performed up to April 2023 using the PubMed, Scopus, and PsycINFO databases. Articles were included if they provided data on PD patients with and without OSA. Pooled prevalence for PD-OSA was calculated using the proportions of PD participants diagnosed with OSA. Demographic and clinical features associated with PD-OSA were explored by comparing PD patients with and without OSA. Seventeen studies were included in the meta-analysis. Pooled OSA prevalence was 45% of a total sample of 1448 PD patients and was associated with older age, male sex, higher body mass index (BMI), more severe motor disturbances and periodic limb movements, reduced risk of rapid eye movement sleep behavior disorder, intake of dopamine agonists, and worse excessive daytime sleepiness. No relationship emerged with cognitive functioning and neuropsychiatric manifestations. OSA affects nearly half of PD patients as a secondary outcome of predisposing factors such as older age and higher BMI in addition to PD-related motor impairment. Future studies should focus on determining the impact of both clinical features and dopaminergic medication on the development of PD-OSA.

66 Association of Executive Functions and Instrumental Activities of Daily Living in Parkinson’s Disease

Objective:Executive function (EF) abilities tend to decline with age, and disproportionately so for people with neurodegenerative disorders such as Parkinson’s Disease (PD), where EF deficits are commonly seen in the early stages of the disease. Due to their nature, EF are essential for performing tasks of daily life, particularly for the more complex instrumental activities of daily living (IADL), and deficits can impair the ability to execute IADL in PD participants. The aim of this study was to examine how EF impairments relate to IADL deficits in both healthy elderly controls and PD participants.Participants and Methods:Seventy-four participants with idiopathic PD and 66 elderly controls were recruited. All participants were non-demented. A comprehensive neuropsychological assessment was administered including the following measures of EF: Hayling Sentence Completion, Brixton Spatial Anticipation, Trail Making Test A and B, Stroop Color-Word Test, Symbol Span (Wechsler Memory Scale-III), Digit Span (Wechsler Adult Intelligence Scale-III), F-A-S test, and Semantic Fluency (Animals and Actions). Z scores were calculated from respective test manuals. Independence was measured using the 8-item Lawton IADL Scale where items are coded from 0 (dependent) to 1 (independent) and the total score ranges from 0 to 8. Motor impairments were assessed using Part III of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale. Regression models were run with each cognitive measure as the dependent variable, with group (control vs. PD), age, sex, education, and motor severity as predictors, to examine the effect of group on each cognitive variable. Correlations were then run between the total IADL score, demographic variables, and cognitive variables for each participant group separately to identify the relationship between IADL and EF measures.Results:PD participants were predominantly males (n=51, 68.9%), with an average age of 70.64±6.03 and 15.22±2.78 education years. Controls were predominantly female (n=34, 51.5%) and had an average age of 71.19±7.75 and 15.85±2.82 education years. Regarding IADL function, all participants were relatively independent in their IADLs (PD: 7.72±0.69, range 4-8, Controls: 7.98±0.13, range 7-8). The most difficult IADL items for PD participants were shopping (8.2% dependent) and food preparation (12.2% dependent). When correcting for age, education, sex, and motor severity, only the Stroop Interference z-score was significant for participant group (b=0.44, t=2.14, p=0.034), where controls had slightly lower scores (-0.33±0.77) than PD participants (-0.31±0.91). Correlations in controls were significant between IADL total score and Hayling trials 1 (r=0.35, p=0.005) and 2 (r=0.33, p=0.008), and semantic fluency actions trial (r=0.34, p=0.006). In PD participants, IADL total score was only correlated with semantic fluency (animals trial, r=0.26, p=0.028).Conclusions:There were only weak associations between EF abilities and IADL in both healthy controls and PD participants, suggesting that impairments in EF do not necessarily translate into worse ability to execute IADL in PD. More correlations were found in the control group, which may be confounded by the inclusion (in both groups) of participants who already had cognitive impairment. This highlights a further need to examine whether EF impairments in people with PD influence IADL functioning above and beyond normal aging and whether specific deficits have more real-life consequences not attainable through IADL questionnaires.

3 The Relationship Between Depression, Anxiety, and Autonomic Dysfunction in de novo Parkinson’s Disease Patients Over Time

Objective:Autonomic dysfunction is an important non-motor symptom of Parkinson’s disease (PD), with point prevalence estimates of approximately 50-70%. Common presentations include cardiovascular dysregulation, gastrointestinal dysfunction, impaired thermoregulation, and sexual dysfunction. In the present study, we sought to examine whether autonomic symptoms would predict trajectories of change in depression and anxiety over a 5-year period in newly diagnosed individuals with PD. Given that alterations in autonomic nervous system functioning (e.g., reduced heart rate variability, lower autonomic arousal) are frequently observed in individuals who have anxiety and depression, as well as the negative influence these symptoms can have on quality of life/functioning, we predicted that greater autonomic symptoms would be related to increased mood symptoms over time.Participants and Methods:Participants included 414 individuals from the Parkinson’s Progression Markers Initiative, a prospective study of newly diagnosed and untreated individuals with PD. The PD participants (mean age=61.6+9.7, mean education=15.6+3.0, 92.5% non-Hispanic White) were followed annually for up to five years. Self-reported autonomic symptoms were measured using the Scales for Outcomes in Parkinson’s Disease-Autonomic Dysfunction (SCOPA-AUT), which consists of a total score and 6 subdomain scores (gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, sexual). Mood measures included the Geriatric Depression Scale (GDS) and State-Trait Anxiety Inventory (STAI). Motor severity was assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III. Bootstrapped linear regressions were performed to evaluate the relationship between autonomic symptoms (subdomains) and mood using data from the last visit (year 5). For longitudinal analyses, bootstrapped multilevel modeling was used to examine a) changes in SCOPA-AUT total over time (unconditional growth model only) and b) the relationship between mood and SCOPA-AUT total score over time, controlling for age/sex and motor severity.Results:Autonomic symptoms explained 28.2% of the total variance in trait anxiety, with unique predictors of gastrointestinal (/3=.266, p&lt;.001) and thermoregulatory (ß=.202, p=.004) symptoms. For depression, autonomic symptoms explained 27.9% of the total variance, with unique predictors of gastrointestinal (ß=.225, p=.012), thermoregulatory (ß=.178, p=.013), and cardiovascular (ß=.154, p=.012) symptoms. There was a gradual linear increase in total autonomic symptoms over time (b=0.86, p&lt;.001). Greater total autonomic symptoms were associated with higher average trait anxiety (b=0.54, p&lt;.001), slightly greater increase in trait anxiety over time (b=0.04, p&lt;.05), and occasion-to-occasion fluctuations in trait anxiety (b=0.24, p&lt;.001). Similarly, increased total autonomic symptoms were associated with higher average depressive symptoms (b=0.14, p&lt;.001), minimally greater increase in depressive symptoms over time (b=0.01, p&lt;.05), and occasion-to-occasion fluctuations in depressive symptoms (b=0.08, p&lt;.001). Motor severity did not explain individual differences or trajectories of change in depression or trait anxiety.Conclusions:Autonomic symptoms, particularly gastrointestinal, cardiovascular, and thermoregulatory dysfunction, were related to increased mood symptoms in PD patients and predicted increases in depression/anxiety over time. Our findings do not distinguish between two theoretical possibilities - whether autonomic symptoms lead to depression/anxiety versus involvement of co-occurring neural systems underlying both. Regardless, our study highlights the importance of treating autonomic dysfunction in early PD, and future work should incorporate additional measures of autonomic dysfunction (e.g., physiological probes).

Integrity of the nucleus basalis of meynert and self-reported cognitive dysfunction during wearing-off periods in parkinson's disease.

Cognition in Parkinson's Disease can be impacted by the wearing-off phenomenon which results from changes in dopaminergic tone throughout the day. Given the well-established role of the cholinergic basal forebrain in cognition, we hypothesized that the Nucleus Basalis of Meynert may support cognitive processes during wearing-off periods. Specifically, we evaluated whether worsening of cognitive symptoms during wearing-off is more likely to occur with structural degeneration of the Nucleus Basalis of Meynert. Cognitive wearing-off was evaluated via the Movement Disorders Society Non-Motor Fluctuation Assessment Questionnaire in 33 Parkinson's Disease participants undergoing evaluation for deep brain stimulation. Pre-operative diffusion MRIs were used to measure brain diffusion metrics of the Nucleus Basalis of Meynert and control regions (caudate and putamen). The number of cognitive symptoms which worsened during OFF periods positively correlated with mean diffusivity (ρ = 0.561, p = 0.0007) and generalized fractional anisotropy (ρ=-0.447, p = 0.009) within the Nucleus Basalis of Meynert but not in the caudate or putamen. Meanwhile, stable cognitive symptoms, and ON-state cognitive performance as measured by the DRS-2 did not correlate with Nucleus Basalis of Meynert metrics. Correlations were corrected for age, sex, scanner type, disease duration, education and LEDD. Our study suggests that reduced structural integrity of the Nucleus Basalis of Meynert is associated with worsening of participant-reported cognitive deficits during OFF periods, but not overall cognitive functioning in the ON-state. These findings support the hypothesis that structural integrity of the cholinergic Nucleus Basalis of Meynert may provide resilience to cognitive worsening during dopamine-related wearing-off.

Dynamic evaluation of spine kinematics in individuals with Parkinson’s disease and freezing of gait

BackgroundFreezing of gait (FoG) is an episodic failure of gait exposing people with Parkinson’s disease (PD) to a high risk of falling. Despite growing evidence of the interconnection between impaired trunk control and FoG, a detailed description of spinal kinematics during walking is still lacking in this population. Research questionDo spinal alterations impact gait performance in individuals with PD and FoG? MethodsWe analyzed kinematic data of 47 PD participants suffering (PD-FOG, N = 24) or not suffering from FoG (PD-NFOG, N = 23) and 15 healthy controls (HCO) during quiet standing and unperturbed walking. We estimated the main spinal variables (i.e., spinal length, lordosis and kyphosis angles, trunk inclination), the pelvis angles, and the shoulder-pelvis angles during gait and standing. We studied differences across conditions and groups and the relationships between postural and gait parameters using linear regression methods. ResultsDuring standing and walking, both PD groups showed increased trunk inclination and decreased lordosis angle with respect to HCO, as well as a decreased range in variation of kyphosis angle, pelvic obliquity, and shoulder-pelvis angles. Only PD-FOG participants showed reduced range of lordosis angle and spinal length compared to HCO. PD-FOG individuals were also not able to straighten their spine during walking compared to standing. Stride length and velocity were decreased in both patient groups compared to HCO, while swing duration was reduced only in the PD-FOG group. In individuals with FoG, trunk inclination and lordosis angle showed moderate but significant positive correlations with all gait alterations. SignificanceSpine alterations impacted gait performance in individuals with PD suffering from FoG. Excessive trunk inclination and poor mastering of the lordosis spinal region may create an unfavourable postural precondition for forward walking. Physical therapy should target combined spinal and stepping alterations in these individuals.

Contrastive stress in persons with Parkinson's disease who speak Mandarin: Task effect in production and preserved perception

BackgroundSpeech in persons with Parkinson's disease (PD) is characterized by impaired prosody (e.g., monotone, abnormal rate, reduced loudness). Most studies on prosodic abnormalities in PD have been obtained from individuals who speak non-tone languages, where prosodic contrasts do not systematically contribute to lexical meanings. In a tone language such as Mandarin, pitch not only carries affective information but also serves to distinguish lexical meanings. It is not known how well persons with PD, who speak a tone language, convey contrastive stress (specific intonational cues signaling topic and theme) for discourse purposes in production, or how well they perceive these contrasts. MethodExperiment 1 investigated production of contrastive stress by persons with PD who speak Mandarin using two different speech tasks, Elicitation and Repetition. PD participants and healthy controls (HC) produced short sentences with focus in different positions during the two task conditions. As an indirect measurement of the quality of the participants’ production of contrastive stress, healthy listeners served as raters to identify focus positions in the sentences and provide goodness ratings to each produced contrastive stress. Experiment 2 examined perceptual ability, measuring PD participants' identification through listening of contrastive stress on utterances produced by a healthy speaker. ResultsFor the Production Study (Experiment 1), the results revealed significantly poorer performance in the PD than the HC group in Elicitation and Repetition. Consistent with previous studies, a task effect was found; study participants demonstrated better performance in Repetition than in Elicitation. Results for the examination of perceptual ability in Experiment 2 revealed that PD and HC participants were equally successful in perceiving contrastive stress in Mandarin utterances produced by a healthy speaker. DiscussionThis study extended previous literature by measuring production and perception of contrastive stress in persons with PD who speak a tone language. Contrastive stress was detected with decreased accuracy in speech produced by persons with PD compared to healthy controls. However, performance was relatively preserved in a repetition condition compared to an elicitation condition. In contrast to the production results, speakers with PD were as successful as HC in perceiving sentential focus, consistent with previous research reporting a discrepancy between production and perception in persons with PD.

H - 68 Effects of Depression, Apathy and Anxiety in Hispanic Parkinson Disease Individuals' Cognition.

Previous research in individuals with Parkinson's disease (PD) found that heightened apathy is associated with worse executive function. Most studies to-date have involved primarily White, non-Hispanic individuals. Indeed, recent research suggests that mood/motivation's relationship to cognitive decline differs between Hispanic and non-Hispanic individuals (Thakur et al., 2021). In this study, we examined relationships between depression, apathy, anxiety, and cognition in Hispanic PD participants who were seen in a specialized movement disorders center. Participants included 31 non-demented Hispanic individuals with PD (age mean = 59.94, SD = 8.49years; education mean = 14.39, SD = 2.79; 83.9% male) who completed neuropsychological and mood measures (Beck Depression Inventory-II, Apathy Scale, STAI-Trait Anxiety Scale). Prevalence estimates were calculated using established cut-offs (BDI-II:14, AS:14, STAI-Trait:40). Cognitive raw scores were z-scored and averaged into the composites: attention (WAIS-III Digit Span Forward, Backward), processing speed (Stroop Word, Trails A), executive function (Trails B, Stroop Color-Word), and memory (Hopkin's Verbal Learning Test, WMS-III Logical Memory delayed recalls). Non-parametric partial correlations (correcting for age/education) assessed mood and cognitive composite relationships. 17% had clinically significant depressive symptoms, 12% had apathy, and 35% had anxiety. More depressive symptoms were significantly associated with worse memory (r = -0.54, p = 0.007). Greater anxiety symptoms trended with worse processing speed (r = -0.41, p = 0.065) and memory (r = -0.38, p = 0.094). Apathy did not relate to cognition (p's > 0.05). This pattern of associations differs from existing studies with predominantly White, non-Hispanic samples (Butterfield et al., 2010; Ratajska, et al.,2022), highlighting the importance of further investigating ethnic differences in PD.

Non-steroidal anti-inflammatory drug use and markers of Parkinson's disease progression: A retrospective cohort study

BackgroundPrevious studies demonstrated reduced incidence of Parkinson's disease (PD) with regular non-steroidal anti-inflammatory drug (NSAID) exposure, particularly ibuprofen. No studies have investigated the impact of NSAID exposure on markers of disease progression for established PD. MethodsThis is a retrospective observational study using two cohorts. The Deprenyl and Tocopheral Anti-Oxidative Therapy of Parkinsonism (DATATOP) study enrolled 800 drug naïve people with PD with a median follow-up duration of 6.5 years. The DATATOP primary outcome measures were mortality at last study visit. The Parkinson's Progression Markers Initiative (PPMI) cohort was limited to drug naïve PD participants (423 at time of analysis). The PPMI primary outcome measure was annual rate of change in ipsilateral putamen 123I-ioflupane binding ratio at four years study duration. Regular NSAID exposure was defined as any scheduled NSAID use (as needed use was excluded). Analysis was performed separately for recent exposure and cumulative exposure time (CET). ResultsTotal CET median and interquartile range (years) for ibuprofen, non-aspirin NSAID, and aspirin were respectively 0.9 (0.3–2.9), 1.1 (0.3–2.6), and 1.5 (0.4–2.8) for DATATOP and 0.4 (0.01–2.2), 1.4 (0.3–4.4), and 5.5 (2.6–7.1) for PPMI. Exposure was usually discontinuous. Exposure to ibuprofen was low in both cohorts. There was no significant association between NSAID recent exposure or CET and primary outcome measures in either cohort. ConclusionsNSAID exposure in established PD does not appear to provide protective effect although exposure may not have occurred continuously enough in these two cohorts to provide benefit. Statistical power for ibuprofen exposure analyses was limited.

Validating virtual administration of neuropsychological testing in Parkinson disease: a pilot study

COVID-19 has highlighted the need for remote cognitive testing, but the reliability and validity of virtual cognitive testing in Parkinson disease (PD) is unknown. Therefore, we assessed PD participants enrolled in an observational, cognition-focused study with an extensive cognitive battery completed both in-person and via video conference close in time. Data for 35 PD participants with normal cognition to mild dementia were analyzed. Only one test (semantic verbal fluency) demonstrated a difference in score by administration type, with a significantly better score virtually. Only three tests demonstrated good reliability for in-person versus virtual testing, but reliability values for visit 1 versus visit 2 were similarly low overall. Trail Making Test B was successfully administered virtually to only 18 participants due to technical issues. Virtual and in-person cognitive testing generate similar scores at the group level, but with poor to moderate reliability for most tests. Mode of test administration, learning effects, and technical difficulties explained little of the low test–retest reliability, indicating possible significant short-term variability in cognitive performance in PD in general, which has implications for clinical care and research. In-person cognitive testing with a neuropsychologist remains the gold standard, and it remains to be determined if virtual cognitive testing is feasible in PD.

Neuroinflammation is linked to dementia risk in Parkinson's disease.

The development of dementia is a devastating aspect of Parkinson's disease (PD), affecting nearly half of patients within 10 years post-diagnosis. For effective therapies to prevent and slow progression to PD dementia (PDD), the key mechanisms that determine why some people with PD develop early dementia, while others remain cognitively unaffected, need to be understood. Neuroinflammation and tau protein accumulation have been demonstrated in post-mortem PD brains, and in many other neurodegenerative disorders leading to dementia. However, whether these processes mediate dementia risk early on in the PD disease course is not established. To this end, we used PET neuroimaging with 11C-PK11195 to index neuroinflammation and 18F-AV-1451 for misfolded tau in early PD patients, stratified according to dementia risk in our 'Neuroinflammation and Tau Accumulation in Parkinson's Disease Dementia' (NET-PDD) study. The NET-PDD study longitudinally assesses newly-diagnosed PD patients in two subgroups at low and high dementia risk (stratified based on pentagon copying, semantic fluency, MAPT genotype), with comparison to age- and sex-matched controls. Non-displaceable binding potential (BPND) in 43 brain regions (Hammers' parcellation) was compared between groups (pairwise t-tests), and associations between BPND of the tracers tested (linear-mixed-effect models). We hypothesized that people with higher dementia risk have greater inflammation and/or tau accumulation in advance of significant cognitive decline. We found significantly elevated neuroinflammation (11C-PK11195 BPND) in multiple subcortical and restricted cortical regions in the high dementia risk group compared with controls, while in the low-risk group this was limited to two cortical areas. The high dementia risk group also showed significantly greater neuroinflammation than the low-risk group concentrated on subcortical and basal ganglia regions. Neuroinflammation in most of these regions was associated with worse cognitive performance (Addenbrooke's Cognitive Examination-III score). Overall neuroinflammation burden also correlated with serum levels of pro-inflammatory cytokines. In contrast, increases in 18F-AV-1451 (tau) BPND in PD versus controls were restricted to subcortical regions where off-target binding is typically seen, with no relationship to cognition found. Whole-brain 18F-AV-1451 burden correlated with serum phosphorylated tau181 levels. Although there was minimal regional tau accumulation in PD, regional neuroinflammation and tau burden correlated in PD participants, with the strongest association in the high dementia risk group, suggesting possible co-localization of these pathologies. In conclusion, our findings suggest that significant regional neuroinflammation in early PD might underpin higher risk for PDD development, indicating neuroinflammation as a putative early modifiable aetiopathological disease factor to prevent or slow dementia development using immunomodulatory strategies.

Anxiety Change After Dopamine Therapy in Parkinson Disease is Independent of Motor Improvement

Several anxiety syndromes have been associated with Parkinson disease (PD), but their interactions with dopamine replacement therapy (DRT) and motor function dynamics are not completely understood. We sought to delineate how DRT impacts anxiety phenomenology in PD and whether these changes are dissociable from improved motoric function. We compared anxiety responses to DRT in two cohorts: 1) a study of 200 PD participants who completed neuropsychiatric assessments before and after taking their dopaminergic medications ("On-Off"); 2) participants in the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort who completed the State-Trait Anxiety Inventory (STAI) at the time of DRT initiation and a subsequent study visit (n=113, mean 8-month interval). Among On-Off participants transitioning acutely to the On-state, scores on the Hamilton anxiety rating scale decreased by 37% (t=14.8, df=199, p <0.0001). Among PPMI participants, STAI-state scores decreased by 10.4% following DRT initiation (t=4.5, df=112, p <0.0001). Item-level anxiety changes exhibited weak and nonsignificant correlations (Spearman ρ: -0.24 to 0.33) with objective MDS-UPDRS motor improvements in both immediate and sustained dopamine replacement contexts. Dopamine repletion effected immediate relief of anxiety in an On-Off state comparison. A similar benefit was observed in the longitudinal PPMI cohort by comparing anxiety before and after DRT initiation, suggesting DRT confers sustained anxiolytic effects in early PD. The weak correlations between improvements to anxiety and motor function on both timescales support the view that these changes are not mediated by improved motor function.

Quantitative sleep electroencephalogram and cognitive performance in Parkinson's disease with and without rapid eye movement sleep behavior disorder.

Parkinson's disease (PD) patients with REM sleep behavior disorder (RBD) are at greater risk for cognitive decline and RBD has been associated with alterations in sleep-related EEG oscillations. This study evaluates differences in sleep quantitative EEG (qEEG) and cognition in PD participants with (PD-RBD) and without RBD (PD-no-RBD). In this cross-sectional study, polysomnography (PSG)-derived qEEG and a comprehensive level II neuropsychological assessment were compared between PD-RBD (n = 21) and PD-no-RBD (n = 31). Following artifact rejection, qEEG analysis was performed in the frontal and central leads. Measures included Scalp-slow wave (SW) density, spindle density, morphological properties of SW and sleep spindles, SW-spindle phase-amplitude coupling, and spectral power analysis in NREM and REM. The neurocognitive battery had at least two tests per domain, covering five cognitive domains as recommended by the Movement Disorders Society Task Force for PD-MCI diagnosis. Differences in qEEG features and cognitive performance were compared between the two groups. Stepwise linear regression was performed to evaluate predictors of cognitive performance. Multiple comparisons were corrected using the Benjamini-Hochberg method. Spindle density and SW-spindle co-occurrence percent were lower in participants with PD-RBD compared to PD-no-RBD. The PD-RBD group also demonstrated higher theta spectral power during REM. Sleep spindles and years of education, but not RBD, were predictors of cognitive performance. PD participants with RBD have alterations in sleep-related qEEG compared to PD participants without RBD. Although PD-RBD participants had worse cognitive performance compared to PD-no-RBD, regression models suggest that lower sleep spindle density, rather than presence of RBD, predicts worse comprehensive cognitive score. Future studies should include longitudinal evaluation to determine whether sleep-related qEEG alterations are associated with more rapid cognitive decline in PD-RBD.

Utilizing speech analysis to differentiate progressive supranuclear palsy from Parkinson's disease

IntroductionDistinguishing Parkinson's disease (PD) from Progressive supranuclear palsy (PSP) at early disease stages is important for clinical trial enrollment and clinical care/prognostication. MethodsWe recruited 21 participants with PSP(n = 11) or PD(n = 10) with reliable caregivers. Standardized passage reading, counting, and sustained phonation were recorded on the BioDigit Home tablet (BioSensics LLC, Newton, MA USA), and speech features from the assessments were analyzed using the BioDigit Speech platform (BioSensics LLC, Newton, MA USA). An independent t-test was performed to compare each speech feature between PSP and PD participants. We also performed Spearman's correlations to evaluate associations between speech measures and clinical scores (e.g., PSP rating scales and MoCA). In addition, the model's performance in classifying PSP and PD was evaluated using Rainbow passage reading analysis. ResultsDuring Rainbow passage reading, PSP participants had a significantly slower articulation rate (2.45(0.49) vs 3.60(0.47) words/minute), lower speech-to-pause ratio (2.33(1.08) vs 3.67(1.18)), intelligibility dynamic time warping (DTW, 0.26(0.19) vs 0.53(0.26)), and similarity DTW (0.43(0.27) vs 0.67(0.13)) compared to PD participants. PSP participants also had longer pause times (17.24(5.47) vs 8.45(3.13) sec) and longer total signal times (52.44(6.67) vs (36.67(6.73) sec) when reading the passage. In terms of the phonation ‘a’, PSP participants showed a significant higher spectral entropy, spectral centroid, and spectral spread compared to PD participants and no differences were found for phonation ‘e’. PD participants had more accurate reverse number counts than PSP participants (14.89(3.86) vs 7.36(4.67)). PSP Rating Scale (PSPRS) dysarthria (r = 0.79, p = 0.004) and bulbar item scores (r = 0.803, p = 0.005) were positively correlated with articulation rate in reverse number counts. Correct reverse number counts were positively correlated with total Montreal Cognitive Assessment scores (r = 0.703, p = 0.016). Machine learning models using passage reading-derived measures obtained an AUC of 0.93, and the sensitivity/specificity in correctly classifying PSP and PD participants were 0.95 and 0.90, respectively. ConclusionOur study demonstrates the feasibility of differentiating PSP from PD using a digital health technology platform. Further multi-center studies are needed to expand and validate our initial findings.

At-Home Blood Pressure Measurements Provide Better Assessments of Orthostatic Hypotension in Parkinson's Disease.

Orthostatic hypotension (OH) is common in Parkinson's Disease (PD). It is intermittent, exacerbated by stressors including meals, medications, and dehydration, and frequently is unrecognized. Although intermittent, assessment is usually by a single "in clinic" BP measurement. This study examines whether 10 home measurements are more sensitive in detecting OH than a single "in clinic" measurement. Participants (44 people with PD and 16 controls) were instructed to measure lying and standing BP at home. BP was measured on five consecutive days upon waking and before bedtime. Symptoms were also assessed using the Movement Disorder Society United Parkinson's Disease Rating Scale and the Non-Motor Questionnaire. While a postural drop in systolic BP (≥20 mmHg) was recorded "in clinic" in thirteen of the forty-four PD participants, a postural drop was found in at least one of the ten home measurements in twenty-eight of the forty-four participants. Morning hypertension and variability in lying systolic BP was more common in these subjects than in those without a postural drop or the controls. A greater number of measurements of lying and standing BP are more likely to reveal orthostatic hypotension, variation in systolic BP, and hypertension than a single office measurement in people with PD.