Data-driven sequence of cognitive decline in people with Parkinson's disease.

BACKGROUND: Understanding the sequential progression of cognitive impairments in Parkinson's disease (PD) is crucial for elucidating neuropathological underpinnings, refining the assessment of PD-related cognitive decline stages and enhancing early identification for targeted interventions. The first aim of this study was to use an innovative event-based modeling (EBM) analytic approach to estimate the sequence of cognitive declines in PD. The second aim was to validate the EBM by examining associations with EBM-derived individual-specific estimates of cognitive decline severity and performance on independent cognitive screening measures. METHODS: This cross-sectional observational study included 99 people with PD who completed a neuropsychological battery. Individuals were classified as meeting the criteria for mild cognitive impairment (PD-MCI) or subtle cognitive decline by consensus. An EBM was constructed to compare cognitively healthy individuals with those with PD-MCI or subtle cognitive disturbances. Multivariable linear regression estimated associations between the EBM-derived stage of cognitive decline and performance on two independent cognitive screening tests. RESULTS: The EBM estimated that tests assessing executive function and visuospatial ability become abnormal early in the sequence of PD-related cognitive decline. Each higher estimated stage of cognitive decline was associated with approximately 0.24 worse performance on the Dementia Rating Scale (p<0.001) and 0.26 worse performance on the Montreal Cognitive Assessment (p<0.001) adjusting for demographic and clinical variables. CONCLUSION: Findings from this study will have important clinical implications for practitioners, on specific cognitive tests to prioritise, when conducting neuropsychological evaluations with people with PD. Results also highlight the importance of frontal-subcortical system disruption impacting executive and visuospatial abilities.

Daytime impulsiveness, attention, and learning in the restless legs syndrome.

INTRODUCTION: Restless legs syndrome (RLS) is a sensorimotor condition characterized by disturbing sensations and the desire to move, often localized in the legs. Cognitive changes and impulsivity can be present in RLS, although the potential effect of commonly co-occurring attention-deficit/hyperactivity disorders (ADHD) or dopamine agonist (DA) use on these are unclear. METHOD: Twenty-three RLS patients and 22 healthy controls were included. Rey Auditory Verbal Learning Test (RAVLT), Continuous Performance Test (CPT), Beck Depression Inventory (BDI), Epworth Sleepiness Scale (ESS), State and Trait Anxiety Inventory (STAI), and Adult Attention Deficit Self-Evaluation Scale (ASRS) were administered. Performance was compared between RLS patients and controls accounting for the presence of attention-deficit/hyperactivity disorder (ADHD) and DA use. RESULTS: Age, education, BDI, ESS, STAI, and ASRS scores were similar for control and RLS groups. Control and RLS groups performed similarly on auditory verbal learning and general attention tests. In the CPT, commission error was significantly higher and response time was significantly shorter in the RLS group compared to controls (p = .014 and p = .010, respectively). These significant differences persisted after adjusting for ADHD and DA usage. CONCLUSION: In this study, RLS patients were more impulsive than the healthy individuals independent of ADHD and DA use. However, learning and attention performances of the patients are not affected.

Lewy body dementia: Overcoming barriers and identifying solutions.

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.

Research Priorities of Individuals and Caregivers With Lewy Body Dementia: A Web-based Survey.

INTRODUCTION: Lewy body dementia (LBD) is common, yet under-recognized and under-researched. To plan studies with the highest impact, engagement of the community personally affected by these conditions is essential. METHODS: A web-based survey of people living with LBD and current and former caregivers of people with LBD queried research priorities through forced ranking and exploration of burden of LBD symptoms. Specific caregiving needs in LBD and perceptions of research participation were also investigated. RESULTS: Between April 7, 2021 and July 1, 2021, 984 responses were recorded. Top research priorities included disease-modifying therapies and improved disease detection and staging. People with LBD were interested in pathophysiology and more bothered by motor symptoms; caregivers were interested in risk factors and symptomatic therapies and more bothered by neuropsychiatric symptoms. Few available LBD treatments and resources were rated as helpful, and many valuable services were never received. Previous participation in LBD research was infrequent, but interest was high. DISCUSSION: People with LBD and caregivers highlighted the need for research across all aspects of LBD, from pathophysiology and disease modification to prognosis, education, symptomatic treatments, and caregiver support. Funders should increase support for all aspects of LBD research to target the many needs identified by individuals and families living with LBD.

Research diagnostic criteria for mild cognitive impairment with Lewy bodies: A systematic review and meta-analysis.

INTRODUCTION: Operationalized research criteria for mild cognitive impairment with Lewy bodies (MCI-LB) were published in 2020. The aim of this systematic review and meta-analysis was to review the evidence for the diagnostic clinical features and biomarkers in MCI-LB set out in the criteria. METHODS: MEDLINE, PubMed, and Embase were searched on 9/28/22 for relevant articles. Articles were included if they presented original data reporting the rates of diagnostic features in MCI-LB. RESULTS: Fifty-seven articles were included. The meta-analysis supported the inclusion of the current clinical features in the diagnostic criteria. Evidence for striatal dopaminergic imaging and meta-iodobenzylguanidine cardiac scintigraphy, though limited, supports their inclusion. Quantitative electroencephalogram (EEG) and fluorodeoxyglucose positron emission tomography (PET) show promise as diagnostic biomarkers. DISCUSSION: The available evidence largely supports the current diagnostic criteria for MCI-LB. Further evidence will help refine the diagnostic criteria and understand how best to apply them in clinical practice and research. HIGHLIGHTS: A meta-analysis of the diagnostic features of MCI-LB was carried out. The four core clinical features were more common in MCI-LB than MCI-AD/stable MCI. Neuropsychiatric and autonomic features were also more common in MCI-LB. More evidence is needed for the proposed biomarkers. FDG-PET and quantitative EEG show promise as diagnostic biomarkers in MCI-LB.

Sex Differences for Clinical Correlates of Alzheimer's Pathology in People with Lewy Body Pathology.

BACKGROUND: Lewy body (LB) dementias have limited clinical diagnostic accuracy because of frequent copathologies contributing to clinical heterogeneity. Although sex differences in clinical prevalence and frequency of pure LB pathology were shown, differences for clinicopathological correlations are less known. OBJECTIVE: The aim of this study was to determine sex differences for clinical associations of Alzheimer's disease (AD) copathology in those with LB pathology. METHODS: Data were from National Alzheimer's Coordinating Center for 223 women and 468 men with limbic or neocortical LB, separated into two groups as those with high likelihood and low/intermediate likelihood for LB clinical phenotype based on pathology. Clinical associations of sex and interaction of sex and pathology for the clinical phenotype were analyzed. RESULTS: More severe AD copathology was associated with worse cognitive decline and lower likelihood of LB disease clinical phenotype. Women with more severe AD copathology and tau had worse cognitive decline and higher likelihood of AD clinical phenotype than men. Men with more severe AD copathology had lower likelihood of LB clinical phenotype than women. Interaction of sex and pathology was more pronounced in those aged between 70 and 80 years. CONCLUSIONS: AD copathology reduces the likelihood of LB clinical phenotype for both women and men; however, men may be at higher risk for LB disease underdiagnosis and women at higher risk for dementia. The use of both LB and AD biomarkers, even when LB or AD pathology is not clinically expected, is necessary for the accurate clinical diagnosis of both LB diseases and AD. © 2022 International Parkinson and Movement Disorder Society.

Sex differences for phenotype in pathologically defined dementia with Lewy bodies.

INTRODUCTION: Sex differences in dementia with Lewy bodies (DLB) have been reported in clinically defined cohorts; however, clinical diagnostic accuracy in DLB is suboptimal and phenotypic differences have not been assessed in pathologically confirmed participants. METHODS: Core DLB features were compared across 55 women and 156 men with pathologically defined DLB in the National Alzheimer's Coordinating Center. These analyses were repeated for 55 women and 55 men matched for age, education and tau burden. RESULTS: In the total sample, women died older, had fewer years of education, had higher tau burden but were less likely to be diagnosed with dementia and clinical DLB. In the matched sample, visual hallucinations continued to be less common in women, and fewer women met clinical DLB criteria. DISCUSSION: Sex impacts clinical manifestations of underlying pathologies in DLB. Despite similar underlying Lewy body pathology, women are less likely to manifest core DLB features and may be clinically underdiagnosed.

Abnormal distraction and load-specific connectivity during working memory in cognitively normal Parkinson's disease.

Visuospatial working memory impairments are common in Parkinson's disease (PD), yet the underlying neural mechanisms are poorly understood. The present study investigated abnormalities in context-dependent functional connectivity of working memory hubs in PD. Cognitively normal PD and control participants underwent fMRI while performing a visuospatial working memory task. To identify sources of dysfunction, distraction, and load-modulated connectivity were disentangled for encoding and retrieval phases of the task. Despite normal working memory performance in PD, two features of abnormal connectivity were observed, one due to a loss in normal context-related connectivity and another related to upregulated connectivity of hubs for which the controls did not exhibit context-dependent connectivity. During encoding, striatal-prefrontal coupling was lost in PD, both during distraction and high memory loads. However, long-range connectivity of prefrontal, medial temporal and occipital hubs was upregulated in a context-specific manner. Memory retrieval was characterized by different aberrant connectivity patterns, wherein precuneus connectivity was upregulated during distraction, whereas prefrontal couplings were lost as memory load approached capacity limits. Features of abnormal functional connectivity in PD had pathological and compensatory influences as they correlated with poorer working memory or better visuospatial skills. The results offer new insights into working memory-related signatures of aberrant cortico-cortical and corticostriatal functional connections, which may portend future declines in different facets of working memory.

Progressive Supranuclear Palsy and Statin Use.

INTRODUCTION: Statins were proposed to be neuroprotective; however, the effects are unknown in progressive supranuclear palsy (PSP), a pure tauopathy. METHODS: Data of 284 PSP cases and 284 age-matched, sex-matched, and race-matched controls were obtained from the environmental and genetic PSP (ENGENE-PSP) study. Cases were evaluated with the PSP Rating Scale, Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, and Neuropsychiatric Inventory. Statin associations with PSP risk, onset age, and disease features were analyzed. RESULTS: Univariate models showed lower PSP risk for type 1 statin users (simvastatin, lovastatin, pravastatin). After adjusting for confounding variables, statin use and lower PSP risk association remained only at a trend level. For PSP cases, type 1 statins were associated with 1-year older onset age; type 2 statins (atorvastatin, rosuvastatin) were associated with the lower PSP Rating Scale and Unified Parkinson's Disease Rating Scale. CONCLUSION: Statins may have inverse associations with PSP risk and motor impairment. Randomized prospective studies are required to confirm this effect. © 2020 International Parkinson and Movement Disorder Society.

Sex Differences in Cognitive Changes in De Novo Parkinson's Disease.

OBJECTIVE: To evaluate the sex differences in cognitive course over 4 years in Parkinson's disease (PD) patients with and without mild cognitive impairment (MCI) compared to controls. METHODS: Four-year longitudinal cognitive scores of 257 cognitively intact PD, 167 PD-MCI, and 140 controls from the Parkinson's Progression Markers Initiative were included. Longitudinal scores of men and women, and PD with and without MCI were compared. RESULTS: Women had better verbal memory, men had better visuospatial function. There was no interaction between sex, diagnostic group, and/or time (4-year follow-up period). CONCLUSIONS: Sex differences in cognitive course in de novo PD are similar to healthy aging. Cognitive decline rates in PD with and without MCI are similar for the first 4 years of PD.

A Picture Database for Verbs and Nouns with Different Action Content in Turkish.

In this study we present a picture database of 160 nouns and 160 verbs. All verbs and nouns are divided into two groups as action and non-action words. Age of acquisition, familiarity, imageability, name agreement and complexity norms are reported alongside frequency, word length and morpheme count for each word. Data were collected from 600 native Turkish adults in total. The results show that although several measures have weak correlations with each other, only age of acquisition had moderate downhill relationships with familiarity and frequency with familiarity and frequency having a rather strong positive correlation with each other. The norms and the picture database are available as supplemental materials for use in psycholinguistic studies in Turkish.

Risk of impairment in cognitive instrumental activities of daily living for sexual and gender minority adults with reported Parkinson's disease.

Objective: To investigate the risk of impairment in cognitive instrumental activities of daily living (IADL) for people with Parkinson's (PwP) identifying as sexual and/or gender minorities (SGM). Method: Data were obtained from Fox Insight, an online, longitudinal study with self/informant-report questionnaires from PwP and people without Parkinson's. Groups consisted of PwP without cognitive IADL impairment at baseline, identifying as (1) SGM with female sex assigned at birth (SGM-F, n = 75); (2) cisgender, heterosexual with female sex assigned at birth (CH-F, n = 2046); (3) SGM with male sex assigned at birth (SGM-M, n = 84); (4) cisgender, heterosexual with male sex assigned at birth (CH-M, n = 2056). Impairment in cognitive IADL was based on Penn Parkinson's Daily Activities Questionnaire-15 (PDAQ-15). Group differences for PDAQ-15 and impairment likelihood during follow-up were assessed with unadjusted models and adjusting for variables that differed between the groups. Results: SGM-F were the youngest at Parkinson's diagnosis; SGM-M had the lowest PDAQ-15 at baseline (p ≤ .014 for all). Scores declined more for males than females in unadjusted and adjusted models (p < .001 for both). In unadjusted models, SGM-M had a higher impairment risk than PwP identifying as cisgender and heterosexual (p ≤ .018). In adjusted models, females had a lower impairment risk than males (p < .001). Age, education, and discrimination level were significant moderators (p < .001 for all). Conclusions: SGM-M can be at a higher risk for impairment in cognitive IADL, associated with social determinants. Female sex assigned at birth may be associated with a lower level of impairment risk, although this advantage can disappear with social determinants.

Sex differences for clinical correlates of substantia nigra neuron loss in people with Lewy body pathology.

BACKGROUND: Lewy body dementia (LBD) phenotype is associated with the presence and degree of Lewy body, Alzheimer's pathologies, and substantia nigra neuron loss. Nigral neuron loss is associated with parkinsonism in LBD, and females with LBD are less likely than males to have parkinsonism. As sex differences were reported for clinical correlates of Lewy body and Alzheimer's pathologies, we aimed to investigate whether there are also sex differences for correlates of nigral neuron loss. METHODS: Data were obtained from the National Alzheimer's Coordinating Center for females (n = 159) and males (n = 263) with brainstem, limbic, and neocortical Lewy body pathology. Sex differences for the nigral neuron loss' association with Lewy body pathology staging and core clinical LBD features (cognitive fluctuations, visual hallucinations, rapid eye movement sleep behavior disorder, parkinsonism) during follow-up were analyzed with generalized linear models adjusting for age and Alzheimer's pathology staging. Whether any of the core clinical features at the time of dementia onset can predict underlying nigral neuron loss for females and males were also analyzed with generalized linear models. RESULTS: Compared to males, females died older and had higher levels of Braak tau staging, but had similar levels of Lewy body pathology staging and nigral neuron loss. Females were less likely than males to have a clinical Lewy body disease diagnosis during follow-up. More advanced Lewy body pathology staging was associated with more nigral neuron loss, more so for males than females. More nigral neuron loss was associated with parkinsonism and clinical LBD diagnosis during follow-up, more so for males than females. Across the subgroup with dementia (40 females, 58 males), core LBD features at first visit with dementia were not associated with nigral neuron loss. CONCLUSIONS: Nigral neuron loss' association with Lewy body pathology staging and core LBD features can differ by sex. Compared to males, females with Lewy body pathology have a higher risk of underdiagnosis. There is a need to elucidate the mechanisms underlying sex differences for pathology and clinicopathological correlations to advance diagnostic and therapeutic efforts in LBD.

Lewy body dementia (LBD) is the third most common dementia associated with Lewy body pathology, Alzheimer's pathology, and substantia nigra loss. It is often less recognized in females compared to males, because the typical symptoms are less evident in females. In this study, we investigated whether substantia nigra neuron loss plays a role in the atypical presentation of LBD in females, contributing to the underdiagnosis compared to males. We analyzed data from 159 females and 263 males with pathological Lewy body disease obtained from the National Alzheimer's Coordinating Center. Females tended to be older at the time of death and had more tau buildup, but similar levels of Lewy body pathology and substantia nigra neuron loss compared to males. When we compared males and females of similar age with similar levels of Alzheimer's pathology, we observed that females had less substantia nigra neuron loss at less advanced Lewy body pathology stages. Greater nigral neuron loss was associated with parkinsonism and the typical LBD symptoms in males, but not as strongly in females. The extent of nigral loss could not be predicted based on the clinical features at the time of dementia diagnosis. Thus, the relationship between nigral neuron loss and the LBD symptoms seems to vary by sex. Females with underlying Lewy body disease are more likely to be underdiagnosed compared to males. We need further work to understand why these sex differences exist and how we can better identify and treat LBD.

Sexual Orientation, Gender Identity, and Experiences During, Awareness of, and Attitudes Toward Research for People With Parkinson Disease.

Background and Objectives: Presentation, progression, and treatment of Parkinson disease (PD) can differ based on sex and gender. However, knowledge on PD is limited by the characteristics of research participants, and most of the participants are men. In this study, we aimed to identify the attitudes toward and barriers to research participation for people with PD (PwP) based on their sexual orientation and gender identity. Methods: Data were obtained from the Fox Insight on March 16, 2023, for PwP who completed the Attitudes and Beliefs Regarding Research and Genetic Testing for PD. Responses were compared between sexual and gender minorities (SGM) (n = 136), cisgender heterosexual women (n = 1,479), and cisgender heterosexual men (n = 1,445). Associations between age, socioeconomic variables, and the responses that differed between the groups were assessed with linear models. Results: More than 68% of the participants were willing to participate in research; only 43.7% heard about research opportunities, and 52.3% knew where to find a study. Approximately 86.8% of the participants reported hearing about a study from their doctor would make them more likely to participate. A higher percentage of SGM were concerned about transportation and researchers not understanding or respecting their beliefs; a higher percentage of cisgender heterosexual women were concerned about transportation, data privacy, and their family's reaction to genetic results; and a higher percentage of cisgender heterosexual men were concerned about time required for research activities and complex forms. Age and socioeconomic variables were significantly associated with approach toward research that differed between the groups. Discussion: PwP are willing to participate in research, and health care providers can facilitate their participation. Barriers to research participation related to sexual and gender identity exist and must be addressed to increase our understanding of PD in underrepresented populations.

Ethnoracial differences for caregiving burden in Parkinson's disease.

INTRODUCTION: Caregivers play an important role in Parkinson's disease (PD) treatment, especially as the disease progresses. As the symptom profile and needs of people with PD (PwP) differ across ethnoracial groups, whether caregiving needs also differ for different ethnoracial groups should be investigated. METHODS: Data were obtained from the Parkinson's Foundation funded Parkinson's Outcomes Project for PwP identifying as Hispanic (n = 495), non-Hispanic Asian (n = 170), non-Hispanic Black (n = 162), or non-Hispanic White (n = 7687). Cross-sectional and longitudinal total Multidimensional Caregiver Strain Index (MCSI) and domain-specific scores for caregiving burden were compared across the ethnoracial groups. Effect of demographics and clinical variables, interaction of these variables with ethnoracial groups for caregiver burden was assessed. RESULTS: Care partners of PwP identifying as non-Hispanic Asian experienced the most burden. PwP identifying as non-Hispanic White were oldest, yet their care partners experienced the least burden. Care partners of PwP identifying as non-Hispanic Asian experienced more burden in physical and social domains, care partners of PwP identifying as Hispanic experienced more burden in financial and elder demanding/manipulative domains. Over time, burden increased similarly across the ethnoracial groups. Effect of frequency of falls, hospital admission, neuropsychiatric disorder and social support on burden over time differed across the groups. CONCLUSION: PwP from different ethnoracial groups can experience different levels of caregiving burden. Predictors for caregiving burden, such as social support and falls can have different impacts based on ethnicity and race. Caregiver needs should also be assessed and culturally competent support should be provided to benefit all affected by PD.

Genetic analysis of the X chromosome in people with Lewy body dementia nominates new risk loci.

Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequence data from 2591 LBD cases and 4391 controls. We identified a significant risk locus within intron 1 of MAP3K15 (rs141773145, odds ratio = 2.42, 95% confidence interval = 1.65-3.56, p-value = 7.0 × 10-6) in female LBD cases conditioned for APOE ε4 dosage. The locus includes an enhancer region that regulates MAP3K15 expression in ganglionic eminence cells derived from primary cultured neurospheres. Rare variant burden testing showed differential enrichment of missense mutations in TEX13A in female LBD cases, that did not reach significance (p-value = 1.34 × 10-4). These findings support the sex-specific effects of genetic factors and a potential role of Alzheimer's-related risk for females with LBD.