Distinguishing Prodromal Dementia With Lewy Bodies From Prodromal Alzheimer Disease: A Longitudinal Study.

Background and Objectives: It can be clinically challenging to differentiate dementia with Lewy bodies (DLB) and Alzheimer disease (AD). As potential therapies emerge with the goal of slowing or halting misfolded protein aggregation, it is imperative to be able to identify individuals before the disease becomes disabling. Differentiating between DLB and AD in the preclinical or prodromal phase of DLB and AD becomes more important. Studies are needed to validate the proposed criteria for prodromal DLB. Methods: Longitudinal data were obtained from the Uniform Data Set of the National Alzheimer's Coordinating Center. Included participants had a baseline diagnosis of normal or mild cognitive impairment and a consecutive 2-year follow-up diagnosis of DLB or AD. We examined whether core DLB clinical features, supportive neuropsychiatric features, and neuropsychological data in the 2 years preceding the dementia diagnosis distinguished DLB from AD. Results: We identified 143 participants with DLB and 429 age-matched/sex-matched participants with AD. The presence of 2 or more core DLB features in the year before dementia diagnosis yielded the greatest AUC (0.793; 95% CI 0.748-0.839) in distinguishing prodromal DLB from prodromal AD. Sleep disturbances, hallucinations, and a cognitive profile of worse processing speed, attention, and visuoconstruction performance were evident at least 2 years before the dementia diagnosis in DLB compared with AD. Discussion: Data from this multisite, longitudinal, well-characterized research North American cohort support the validity of the recently published criteria for prodromal DLB. In the prodromal stage, patients who subsequently develop DLB are more likely to have core DLB clinical features and worse attention, processing speed, and visuospatial performance than those who go on to develop AD. Differentiation of DLB and AD before dementia emerges provides an opportunity for early, disease-specific intervention and overall management.

Psychiatric predictors of quality of life in Parkinson's disease: A three-year longitudinal study.

INTRODUCTION: Parkinson's disease (PD) is associated with worsened quality of life (QOL) over time. Few longitudinal studies exist investigating the relationship of psychiatric comorbidities with QOL in people with PD (PwP). We sought to determine specific psychiatric symptoms associated with decreasing QOL in PwP over time. METHODS: We recruited PwP without dementia from a movement disorders clinic at an academic medical center. Participants were evaluated annually with motor and neuropsychological assessments at each visit. QOL was measured using the Parkinson's Disease Questionnaire-39 (PDQ-39). We assessed psychiatric symptoms, including depression (Beck Depression Inventory II, BDI-II), anxiety (Beck Anxiety Index, BAI), and apathy (Apathy Scale). Psychosis and impulse control disorders (ICDs) were recorded as present or absent. Using random coefficient regression, we analyzed psychiatric features associated with worsened QOL in PwP over three years. RESULTS: From the 105 participants enrolled at baseline, 67 completed three years of follow up. Mean PDQ-39 scores increased from 16.0 at baseline to 19.8 at year three. In multivariate analysis, higher BDI-II scores, BAI scores, and apathy scores were uniquely associated with worsened QOL over time (p < 0.001 for all measures), while presence of ICDs (p = 0.18) or psychosis (p = 0.10) were not. Changes in the BAI score and the BDI-II score exerted similar effects on the overall PDQ-39 score. CONCLUSION: Depression, anxiety, and apathy are all associated with worsening quality of life over time in PwP, while presence of ICDs and psychosis are not. Treatment of these symptoms may lead to improved QOL in PwP.

Determining the role of statins in Parkinson's disease risk reduction and disease modification: A comprehensive meta-analysis of 4 million participants' data.

BACKGROUND: Many observational studies have examined the association between statins and the incidence of Parkinson's disease (PD) in high-risk populations. On the other hand, clinical trials as well as other observational studies investigated the safety and efficacy of statins in slowing disease progression in PD patients. However, the evidence has been inconclusive in both questions. To that end, we conducted this systematic review and meta-analysis to synthesize evidence on the role of statins in decreasing the risk of PD among high-risk populations and as a possible disease-modifying agent for patients with PD. METHODS: A comprehensive literature search of electronic databases including PubMed, Scopus, Cochrane, and Web of Science has been performed. Relevant studies were chosen and data were extracted and analyzed using RevMan software version 5.4.1. RESULTS: Twenty-five studies (14 cohort, 9 case-control, and 2 randomized controlled trials) have been included in the present systematic review. Of them, 21 studies reported the association between statins and PD risk. Statins were found to significantly reduce the risk of developing PD (pooled RR 0.86, 95% CI [0.77-0.95], p < 0.005). Four studies investigated statins as a disease-modifying agent. The pooled mean difference (MD) in the UPDRS-III from baseline to endpoint did not differ significantly between the statin and control groups (MD -1.34 points, 95% CI [-3.81 to 1.14], p = 0.29). CONCLUSION: Although epidemiological observational studies showed that statin use was associated with a reduced risk of PD, current evidence is insufficient to support the role of statins in slowing the progression of PD. These findings are limited by the fact that most of the included studies are observational studies which carry a high risk of confounding bias which highlights the need for future well-designed RCTs.

Long-Term Dementia Risk in Parkinson Disease.

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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. DISCUSSION: 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.

Factors Associated With Increased Health Care Utilization for Patients With Dementia With Lewy Bodies: A Narrative Review.

Numerous studies have demonstrated that dementia is associated with increased utilization of health care services, which in turn results in increased costs of care. Dementia with Lewy bodies (DLB) is associated with greater costs of care relative to other forms of dementia due to higher rates of hospitalization and nursing home placement directly related to neuropsychiatric symptoms, parkinsonism, increased susceptibility to delirium, and elevated rates of caregiver burden. There is a critical need for researchers to identify potentially modifiable factors contributing to increased costs of care and poor clinical outcomes for patients with DLB, which may include comorbidities, polypharmacy/contraindicated medications, and access to specialty care. Previous research has utilized Medicare claims data, limiting the ability to study patients with early-onset (ie, prior to age 65) DLB. Integrated health systems offer the ability to combine electronic medical record data with Medicare, Medicaid, and commercial claims data and may therefore be ideal for utilization research in this population. The goals of this narrative review are to 1) synthesize and describe the current literature on health care utilization studies for patients with DLB, 2) highlight the current gaps in the literature, and 3) provide recommendations for stakeholders, including researchers, health systems, and policymakers. It is important to improve current understanding of potentially modifiable factors associated with increased costs of care among patients with DLB to inform public health policies and clinical decision-making, as this will ultimately improve the quality of patient care.

Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer's Disease: A Pragmatic Review for Clinicians.

This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners.

Optimizing Screening for Intrastriatal Interventions in Huntington's Disease Using Predictive Models.

BACKGROUND: Intrastriatal delivery of potential therapeutics in Huntington's disease (HD) requires sufficient caudate and putamen volumes. Currently, volumetric magnetic resonance imaging is rarely done in clinical practice, and these data are not available in large research cohorts such as Enroll-HD. OBJECTIVE: The objective of this study was to investigate whether predictive models can accurately classify HD patients who exceed caudate and putamen volume thresholds required for intrastriatal therapeutic interventions. METHODS: We obtained and merged data for 1374 individuals across three HD cohorts: IMAGE-HD, PREDICT-HD, and TRACK-HD/TRACK-ON. We imputed missing data for clinical variables with >72% non-missing values and used the model-building algorithm BORUTA to identify the 10 most important variables. A random forest algorithm was applied to build a predictive model for putamen volume >2500 mm3 and caudate volume >2000 mm3 bilaterally. Using the same 10 predictors, we constructed a logistic regression model with predictors significant at P < 0.05. RESULTS: The random forest model with 1000 trees and minimal terminal node size of 5 resulted in 83% area under the curve (AUC). The logistic regression model retaining age, CAG repeat size, and symbol digit modalities test-correct had 85.1% AUC. A probability cutoff of 0.8 resulted in 5.4% false positive and 66.7% false negative rates. CONCLUSIONS: Using easily obtainable clinical data and machine learning-identified initial predictor variables, random forest, and logistic regression models can successfully identify people with sufficient striatal volumes for inclusion cutoffs. Adopting these models in prescreening could accelerate clinical trial enrollment in HD and other neurodegenerative disorders when volume cutoffs are necessary enrollment criteria. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The gephyrin scaffold modulates cortical layer 2/3 pyramidal neuron responsiveness to single whisker stimulation.

Gephyrin is the main scaffolding protein at inhibitory postsynaptic sites, and its clusters are the signaling hubs where several molecular pathways converge. Post-translational modifications (PTMs) of gephyrin alter GABAA receptor clustering at the synapse, but it is unclear how this affects neuronal activity at the circuit level. We assessed the contribution of gephyrin PTMs to microcircuit activity in the mouse barrel cortex by slice electrophysiology and in vivo two-photon calcium imaging of layer 2/3 (L2/3) pyramidal cells during single-whisker stimulation. Our results suggest that, depending on the type of gephyrin PTM, the neuronal activities of L2/3 pyramidal neurons can be differentially modulated, leading to changes in the size of the neuronal population responding to the single-whisker stimulation. Furthermore, we show that gephyrin PTMs have their preference for selecting synaptic GABAA receptor subunits. Our results identify an important role of gephyrin and GABAergic postsynaptic sites for cortical microcircuit function during sensory stimulation.

Efficacy of the iron-chelating agent, deferiprone, in patients with Parkinson's disease: A systematic review and meta-analysis.

INTRODUCTION: Several studies have reported iron accumulation in the basal ganglia to be associated with the development of Parkinson's Disease (PD). Recently, a few trials have examined the efficacy of using the iron-chelating agent Deferiprone (DFP) for patients with PD. We conducted this meta-analysis to summarize and synthesize evidence from published randomized controlled trials about the efficacy of DFP for PD patients. METHODS: A comprehensive literature search of four electronic databases was performed, spanning until February 2023. Relevant RCTs were selected, and their data were extracted and analyzed using the RevMan software. The primary outcome was the change in the Unified Parkinson's Disease Rating Scale (UPDRS-III). RESULTS: Three RCTs with 431 patients were included in this analysis. DFP did not significantly improve UPDRS-III score compared to placebo (Standardized mean difference -0.06, 95% CI [-0.69, 0.58], low certainty evidence). However, it significantly reduced iron accumulation in the substantia nigra, putamen, and caudate as measured by T2*-weighted MRI (with high certainty evidence). CONCLUSION: Current evidence does not support the use of DFP in PD patients. Future disease-modification trials with better population selection, adjustment for concomitant medications, and long-term follow up are recommended.

Low-Income Older Adults' Vulnerability to Anticholinergic Medication-Associated Frailty.

BACKGROUND: A growing body of research supports the negative impact of anticholinergic drug burden on physical frailty. However, prior research has been limited to homogeneous white European populations, and few studies have evaluated how anticholinergic burden tools compare in their measurement function and reliability with minority community-dwelling adult populations. This study investigated the association between anticholinergic drug exposure and frailty by conducting a sensitivity analysis using multiple anticholinergic burden tools in a diverse cohort. METHODS: A comprehensive psychometric approach was used to assess the performance of five clinical Anticholinergic Burden Tools: Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic Drug Scale (ADS), average daily dose, total standardized daily doses (TSDD), and Cumulative Anticholinergic Burden scale (CAB). Spearman correlation matrix and intraclass correlation coefficients (ICC) were used to determine the association among the variables. Ordinal logistic regression is used to evaluate the anticholinergic burden measured by each scale to determine the prediction of frailty. Model performance is determined by the area under the curve (AUC). RESULTS: The cohort included 80 individuals (mean age 69 years; 55.7% female, 71% African American). All anticholinergic burden tools were highly correlated (p < 0.001), ICC3 0.66 (p < 0.001, 95% confidence interval (CI) 0.53-0.73). Among individuals prescribed anticholinergics, 33% were robust, 44% were prefrail, and 23% were frail. All five tools predicted prefrail and frail status (p < 0.05) with low model misclassification rates for frail individuals (AUC range 0.78-0.85). CONCLUSION: Anticholinergic burden tools evaluated in this cohort of low-income African American older adults were highly correlated and predicted prefrail and frail status. Findings indicate that clinicians can select the appropriate instrument for the clinic setting and research question while maintaining confidence that all five tools will produce reliable results. Future anticholinergic research is needed to unravel the association between interventions such as deprescribing on incident frailty in longitudinal data.

Cholinergic Nucleus 4 Degeneration and Cognitive Impairment in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Cholinergic nucleus 4 (Ch4) degeneration is associated with cognitive impairment in Parkinson's disease and dementia with Lewy bodies, but it is unknown if Ch4 degeneration is also present in isolated rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: The aim was to determine if there is evidence of Ch4 degeneration in patients with iRBD and if it is associated with cognitive impairment. METHODS: We analyzed the clinical and neuropsychological data of 35 iRBD patients and 35 age- and sex-matched healthy controls. Regional gray matter density (GMD) was calculated for Ch4 using probabilistic maps applied to brain magnetic resonance imaging (MRI). RESULTS: Ch4 GMD was significantly lower in the iRBD group compared to controls (0.417 vs. 0.441, P = 0.02). Ch4 GMD was also found to be a significant predictor of letter number sequencing (ß-coefficient = 58.31, P = 0.026, 95% confidence interval [7.47, 109.15]), a measure of working memory. CONCLUSIONS: iRBD is associated with Ch4 degeneration, and Ch4 degeneration in iRBD is associated with impairment in working memory. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cholinergic nucleus 4 grey matter density is associated with apathy in Parkinson's disease.

Objective: The generation and maintenance of goal-directed behavior is subserved by multiple brain regions that receive cholinergic inputs from the cholinergic nucleus 4 (Ch4). It is unknown if Ch4 degeneration contributes to apathy in Parkinson's disease (PD). Method: We analyzed data from 106 pre-surgical patients with PD who had brain MRIs and completed the Frontal Systems Behavior Scales (FrSBe). Eighty-eight patients also completed the Beck Depression Inventory-2nd Edition. Cholinergic basal forebrain grey matter densities (GMD) were measured by applying probabilistic maps to T1 MPRAGE sequences processed using voxel-based morphometry methods. We used linear and hierarchical regression modelling to examine the association between Ch4 GMD and the FrSBe Apathy subscale scores. We used similar methods to assess the specificity of this association and potential associations between Ch4 target regions and apathy. Results: Ch4 GMD (p = .021) and Ch123 GMD (p = .032) were significantly associated with Apathy subscale scores on univariate analysis. Ch4 GMD, but not Ch123 GMD, remained significantly associated with apathy when adjusting for age, sex, levodopa equivalent doses, and disease duration. Centromedial amygdala GMD, which receives cholinergic inputs from Ch4, was also associated with apathy. Ch4 GMD was not associated with depression or disinhibition, nor was it associated with executive dysfunction when adjusting for clinical and demographic variables. Conclusions: Ch4 GMD is specifically associated with apathy in PD. Ch4 degeneration results in cholinergic denervation of multiple cortical and limbic regions, which may contribute to the cognitive and emotional-affective processing deficits that underlie the behavioral symptoms of apathy.

One Minute of EEG Data Provides Sufficient and Reliable Data for Identifying Lewy Body Dementia.

OBJECTIVE: To determine the minimum duration of electroencephalography (EEG) data necessary to differentiate EEG features of Lewy body dementia (LBD), that is, dementia with Lewy bodies and Parkinson disease dementia, from non-LBD patients, that is, Alzheimer disease and Parkinson disease. METHODS: We performed quantitative EEG analysis for 16 LBD and 14 non-LBD patients. After artifact removal, a fast Fourier transform was performed on 90, 60, and thirty 2-second epochs to derive dominant frequency; dominant frequency variability; and dominant frequency prevalence. RESULTS: In LBD patients, there were no significant differences in EEG features derived from 90, 60, and thirty 2-second epochs (all P >0.05). There were no significant differences in EEG features derived from 3 different groups of thirty 2-second epochs (all P >0.05). When analyzing EEG features derived from ninety 2-second epochs, we found that LBD had significantly reduced dominant frequency, reduced dominant frequency variability, and reduced dominant frequency prevalence alpha compared with the non-LBD group (all P <0.05). These same differences were observed between the LBD and non-LBD groups when analyzing thirty 2-second epochs. CONCLUSIONS: There were no differences in EEG features derived from 1 minute versus 3 minutes of EEG data, and both durations of EEG data equally differentiated LBD from non-LBD.

Anticholinergic Medication Burden in Parkinson's Disease Outpatients.

BACKGROUND: Individuals with Parkinson's disease (PD) may be especially vulnerable to future cognitive decline from anticholinergic medications. OBJECTIVE: To characterize anticholinergic medication burden, determine the co-occurrence of anticholinergic and cholinesterase inhibitors, and to assess the correlations among anticholinergic burden scales in PD outpatients. METHODS: We studied 670 PD outpatients enrolled in a clinic registry between 2012 and 2020. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Drug Burden Index-Anticholinergic component (DBI-Ach). Correlations between scales were assessed with weighted kappa coefficients. RESULTS: Between 31.5 to 46.3% of PD patients were taking medications with anticholinergic properties. Among the scales applied, the ACB produced the highest prevalence of medications with anticholinergic properties (46.3%). Considering only medications with definite anticholinergic activity (scores of 2 or 3 on ACB, ADS, or ARS), the most common anticholinergic drug classes were antiparkinsonian (8.2%), antipsychotic (6.4%), and urological (3.3%) medications. Cholinesterase inhibitors and medications with anticholinergic properties were co-prescribed to 5.4% of the total cohort. The most highly correlated scales were ACB and ADS (κ= 0.71), ACB and ARS (κ= 0.67), and ADS and ARS (κ= 0.55). CONCLUSION: A high proportion of PD patients (20%) were either taking antiparkinsonian, urological, or antipsychotic anticholinergic medications or were co-prescribed anticholinergic medications and cholinesterase inhibitors. By virtue of its detection of a high prevalence of anticholinergic medication usage and its high correlation with other scales, our data support use of the ACB scale to assess anticholinergic burden in PD patients.

Prodromal Dementia With Lewy Bodies: Evolution of Symptoms and Predictors of Dementia Onset.

BACKGROUND: Research criteria for prodromal dementia with Lewy bodies (DLB) were published in 2020, but little is known regarding prodromal DLB in clinical settings. METHODS: We identified non-demented participants without neurodegenerative disease from the National Alzheimer's Coordinating Center Uniform Data Set who converted to DLB at a subsequent visit. Prevalence of neuropsychiatric and motor symptoms were examined up to 5 years prior to DLB diagnosis. RESULTS: The sample included 116 participants clinically diagnosed with DLB and 348 age and sex-matched (1:3) Healthy Controls. Motor slowing was present in approximately 70% of participants 3 years prior to DLB diagnosis. In the prodromal phase, 50% of DLB participants demonstrated gait disorder, 70% had rigidity, 20% endorsed visual hallucinations, and over 50% of participants endorsed REM sleep behavior disorder. Apathy, depression, and anxiety were common prodromal neuropsychiatric symptoms. The presence of 1+ core clinical features of DLB in combination with apathy, depression, or anxiety resulted in the greatest AUC (0.815; 95% CI: 0.767, 0.865) for distinguishing HC from prodromal DLB 1 year prior to diagnosis. The presence of 2+ core clinical features was also accurate in differentiating between groups (AUC = 0.806; 95% CI: 0.756, 0.855). CONCLUSION: A wide range of motor, neuropsychiatric and other core clinical symptoms are common in prodromal DLB. A combination of core clinical features, neuropsychiatric symptoms and cognitive impairment can accurately differentiate DLB from normal aging prior to dementia onset.

Antimuscarinic Anticholinergic Medications in Parkinson Disease: To Prescribe or Deprescribe?

The relative importance of antimuscarinic anticholinergic medications for Parkinson's disease (PD) declined after the introduction of levodopa, such that anticholinergic medications are now much more likely to be prescribed for clinical indications other than parkinsonism. Recent studies have found an association between anticholinergic medication exposure and future risk of dementia in older individuals and those with PD. These findings provide a further reason to avoid the use of anticholinergic medications to treat motor symptoms of PD. More importantly, they raise the question of whether one of the goals of PD treatment should be to deprescribe all medications with anticholinergic properties, regardless of their indication, to reduce dementia risk. In this review, we discuss the use of anticholinergic medications in PD, the evidence supporting the association between anticholinergic medications and future dementia risk, and the potential implications of these findings for clinical care in PD.

Olfaction, cholinergic basal forebrain degeneration, and cognition in early Parkinson disease.

INTRODUCTION: Impaired olfaction and reduced cholinergic nucleus 4 (Ch4) volume both predict greater cognitive decline in Parkinson's disease (PD). We examined the relationship between olfaction, longitudinal change in cholinergic basal forebrain nuclei and their target regions, and cognition in early PD. METHODS: We analyzed a cohort of 97 PD participants from the Parkinson's Progression Markers Initiative with brain MRIs at baseline, 1 year, 2 years, and 4 years. Using probabilistic maps, regional grey matter density (GMD) was calculated for Ch4, cholinergic nuclei 1, 2, and 3 (Ch123), and their target regions. RESULTS: Baseline University of Pennsylvania Smell Identification Test score correlated with change in GMD of all regions of interest (all p < 0.05). Rate of change of Ch4 GMD was correlated with rate of change of Ch123 (p = 0.034), cortex (p = 0.001), and amygdala GMD (p < 0.001), but not hippocampus GMD (p = 0.38). Rate of change of Ch123 GMD was correlated with rate of change of cortex (p = 0.001) and hippocampus (p < 0.001), but not amygdala GMD (p = 0.133). In a linear regression model including change in GMD of all regions of interest and age as predictors, change in cortex GMD (߈slope= 38.2; 95 % CI: [0.47, 75.9]) and change in hippocampus GMD (߈slope= 24.8; 95 % CI: [0.80, 48.8]) were significant predictors of Montreal Cognitive Assessment score change over time. CONCLUSION: Impaired olfaction is associated with degeneration of the cholinergic basal forebrain and bilateral cortex, amygdala, and hippocampus in PD. The relationship between impaired olfaction and cognitive decline may be mediated by greater atrophy of the cortex and hippocampus.

The Effect of Education on Symptom Onset and Severity of Huntington's Disease.

BACKGROUND: Huntington disease (HD) is an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. Little is known about the effects of environmental factors on HD symptom onset and severity. OBJECTIVE: To evaluate the relationship between education level and age of diagnosis, symptom onset, and symptom severity in HD. METHODS: This study evaluated 4537 adult-onset, motor-manifest HD participants from the Enroll-HD global registry. Education level was assessed using International Standard Classification of Education categories, stratified into three education groups corresponding to pre-secondary, secondary, and post-secondary educational attainment. Motor and behavioral symptoms of HD, cognition, and functional capacity were measured using baseline Unified Huntington's Disease Rating Scale (UHDRS), Mini-Mental State Exam (MMSE), Symbol Digit Modalities Test (SDMT), verbal fluency, and Stroop assessments. RESULTS: After adjusting for CAG repeats, higher level of education predicted lower age of onset of motor symptoms, depression, irritability, and cognitive impairment (all P-values < 0.001). After adjusting for age of enrollment and CAG repeats, the highest education level predicted the lowest UHDRS motor scores, higher UHDRS total functional capacity and functional assessment scores, and higher SDMT, MMSE, verbal fluency, and Stroop assessment scores (all P-values < 0.001). CONCLUSIONS: HD participants with higher education levels have earlier age of diagnosis and age of symptom onset, but lower motor exam scores and higher functional assessment scores. Earlier recognition of symptoms in more highly educated participants may explain earlier symptom onset and diagnosis. Better performance on motor and functional assessments may be explained by higher cognitive reserve in those with greater education.

Factor structure of the BDI-II in Parkinson's disease.

OBJECTIVE: There is substantial heterogeneity in depressive symptomology for individuals with Parkinson's disease (PD). It is unknown whether the Beck Depression Inventory-Second Edition (BDI-II) is capable of identifying such phenotypic variations of depression. METHOD: We investigated the factor structure of the BDI-II and its associations with demographic characteristics and other nonmotor symptoms in PD. We reviewed the cases of 236 patients with a confirmed PD diagnosis. Evaluations included the BDI-II, Montreal Cognitive Assessment (MoCA), Apathy Scale (AS), and Geriatric Anxiety Inventory (GAI). We used exploratory structural equation modeling (ESEM) with target rotations as this method integrates aspects of exploratory and confirmatory factor analysis. We conducted hierarchical regressions to assess for associations between the BDI-II factors and gender, age, education, disease duration, cognition, anxiety, and apathy. RESULTS: ESEM supported the retention of a Somatic factor and an Affective factor that accounted for 53% of the model variance. Model goodness-of-fit measures were within normal limits. Higher AS scores were positively associated with the Somatic and Affective factors. Higher GAI scores were positively associated only with the Affective factor. There were no other significant relationships with factor scores. CONCLUSIONS: This study supports the retention of a two-factor model of the BDI-II in PD. These unique clusters of depressive symptoms in PD can be used to guide clinical decisions about the need for further psychiatric evaluation and the appropriateness of different therapeutic interventions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).