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Background and purposeMutations in the glucocerebrosidase (GBA) gene are known to be a risk factor for Parkinson's disease (PD). Data on clinicopathological correlation are limited. The purpose of this study was to determine the clinicopathological findings that might distinguish PD cases with and without mutations in the GBA gene.MethodsData from the Arizona Study of Aging and Neurodegenerative Disorders were used to identify autopsied PD cases that did or did not have a GBA gene mutation. Clinical and neuropathological data were compared.ResultsTwelve PD cases had a GBA mutation and 102 did not. The GBA mutation cases died younger (76 vs. 81 years of age) but there was no difference in disease duration or clinical examination findings. No neuropathological differences were found in total or regional semi-quantitative scores for Lewy-type synucleinopathy, senile plaques, neurofibrillary tangles, white matter rarefaction or cerebral amyloid angiopathy scores.ConclusionsIn longitudinally assessed, autopsied PD cases, those with GBA mutations had a younger age at death but there was no evidence for clinical or neuropathological differences compared to cases without GBA mutations. Due to the small GBA group size, small differences cannot be excluded.

Background: While preclinical studies have shown that alpha-synuclein can spread through cell-to-cell transmission whether it can be transmitted between humans is unknown., Objectives: The aim was to assess the presence of a synucleinopathy in autopsied conjugal couples., Methods: Neuropathological findings in conjugal couples were categorized as Parkinson's disease (PD), dementia with Lewy bodies (DLB), Alzheimer's disease with Lewy bodies (ADLB), incidental Lewy body disease (ILBD), or no Lewy bodies., Results: Ninety conjugal couples were included; the mean age of death was 88.3 years; 32 couples had no Lewy bodies; 42 couples had 1 spouse with a synucleinopathy: 10 PD, 3 DLB, 13 ADLB, and 16 ILBD; 16 couples had both spouses with a synucleinopathy: in 4 couples both spouses had PD, 1 couple had PD and DLB, 4 couples had PD and ADLB, 2 couples had PD and ILBD, 1 couple had DLB and ADLB, in 3 couples both had ADLB, and 1 couple had ADLB and ILBD. No couples had both spouses with ILBD., Conclusions: This large series of 90 autopsied conjugal couples found 16 conjugal couples with synucleinopathies, suggesting transmission of synucleinopathy between spouses is unlikely. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer's disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease., (© 2024. The Author(s).)

The olfactory bulb is involved early in the pathophysiology of Parkinson's disease (PD), which is consistent with the early onset of olfactory dysfunction. Identifying the molecular mechanisms through which PD affects the olfactory bulb could lead to a better understanding of the pathophysiology and etiology of olfactory dysfunction in PD. We specifically aimed to assess gene expression changes, affected pathways and co-expression network by whole transcriptomic profiling of the olfactory bulb in subjects with clinicopathologically defined PD. Bulk RNA sequencing was performed on frozen human olfactory bulbs of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative disorders and the Brain and Body Donation Program. Differential expression analysis (19 PD vs 19 controls) revealed 2164 significantly differentially expressed genes (1090 upregulated and 1074 downregulated) in PD. Pathways enriched in downregulated genes included oxidative phosphorylation, olfactory transduction, metabolic pathways, and neurotransmitters synapses while immune and inflammatory responses as well as cellular death related pathways were enriched within upregulated genes. An overrepresentation of microglial and astrocyte-related genes was observed amongst upregulated genes, and excitatory neuron-related genes were overrepresented amongst downregulated genes. Co-expression network analysis revealed significant modules highly correlated with PD and olfactory dysfunction that were found to be involved in the MAPK signaling pathway, cytokine-cytokine receptor interaction, cholinergic synapse, and metabolic pathways. LAIR1 (leukocyte associated immunoglobulin like receptor 1) and PPARA (peroxisome proliferator activated receptor alpha) were identified as hub genes with a high discriminative power between PD and controls reinforcing an important role of neuroinflammation in the olfactory bulb of PD subjects. Olfactory identification test score positively correlated with expression of genes coding for G-coupled protein, glutamatergic, GABAergic, and cholinergic receptor proteins and negatively correlated with genes for proteins expressed in glial olfactory ensheathing cells. In conclusion, this study reveals gene alterations associated with neuroinflammation, neurotransmitter dysfunction, and disruptions of factors involved in the initiation of olfactory transduction signaling that may be involved in PD-related olfactory dysfunction., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: We examined services to facilitate access to entering substance use disorder (SUD) treatment among a national sample of SUD treatment facilities., Methods: We analyzed data from the National Survey of Substance Abuse Treatment Services (N-SSATS) 2020. Facilities were included in the sample based on criteria such as SUD treatment provision and being in the U.S. Cluster analysis was conducted using variables including ownership, levels of care, and whether facilities provide services or accept payment options aimed at reducing treatment barriers. National and state-level data on the percentage of facilities in each cluster were presented., Results: Among N = 15,788 SUD treatment facilities four distinct clusters were identified: Cluster 1 consisted of for-profit and government outpatient facilities with high proportions of services to reduce barriers (22.2%). Cluster 2, comprised of non-profit outpatient facilities, offered the most comprehensive array of services to minimize barriers to treatment among all four clusters (25.2%). Cluster 3 included facilities with diverse ownership and care levels and provided a moderate to high degree of services aimed at reducing entry barriers to treatment (26.0%). Cluster 4 was primarily for-profit outpatient facilities with a low proportion of these services (26.6%)., Conclusions: This study revealed facility-level groupings with different services to reduce barriers to SUD treatment across various clusters of SUD treatment facilities. While some facilities offered extensive services, others provided fewer. Differences in cluster distributions point to possible facilitators to treatment access for some persons seeking admission to specific treatment facilities. Efforts should be made to ensure that individuals seeking SUD treatment can access these services, and facilities should be adequately equipped to meet their diverse needs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Amoako et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Robotic extended totally extraperitoneal hernia (eTEP) repair is a novel technique for minimally invasive ventral hernia repair with retromuscular placement of mesh. This study aimed to evaluate the learning curve for robotic eTEP hernia repair using risk-adjusted cumulative sum (RA-CUSUM) analysis for two general surgeons-one with dedicated fellowship training in robotic eTEP technique (surgeon 2) and another without robotic eTEP-specific training (surgeon 1)., Methods: We conducted a retrospective analysis of 98 patients undergoing robotic eTEP hernia repair from July 2020 to February 2022 for two surgeons. RA-CUSUM method was applied to the overall operative time (OT) in minutes, adjusting for transversus abdominis release (TAR)., Results: Figures 3 (surgeon 1) and 4 (surgeon 2) illustrate the three phases in the RA-CUSUM graphs of OT. For surgeon 1, the cases for each phase were determined: phase 1 (1 to 12), phase 2 (13 to 24), and phase 3 (25 to 51). For surgeon 2, the three phases were similarly determined as 1 to 8, 9 to 32, and 33 to 47, respectively. A significant (p = 0.017) difference existed for the OTs between phases 1 (262 ± 69) and 3 (192 ± 63.0) for surgeon 1. OT compared to the risk-adjusted value stabilized after case 12 and decreased after case 24 for surgeon 1; it began to decrease after case 8 for surgeon 2., Conclusions: The initial learning curve for surgeon 1 reached its plateau after 12 cases, shorter than comparable studies. This was likely due to the surgeon's intentional focus on learning this technique through courses, proctoring, and active mentorship. The flat learning curve seen in surgeon 2's series illustrates the value of experience gained during fellowship training. Our data support that, given the right resources and support, a short learning curve for eTEP is attainable for community surgeons without prior training in the technique., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as "small vessel disease" or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Sex differences in Alzheimer's disease (AD) may contribute to disease heterogeneity and affect prevalence, risk factors, disease trajectories and outcomes. Depression impacts a large number of patients with AD and has been reported to be more prevalent in women. We aimed to better understand the interaction between sex, depression and AD neuropathology, which could have implications for detection of symptoms, earlier diagnosis, therapeutic management, and enhanced quality of life., Methods: We compared 338 cases with clinicopathologically confirmed AD (46% women) to 258 control cases (50% women), without dementia, parkinsonism or a significant pathological diagnosis. Depression was assessed both, using the Hamilton Depression Scale (HAM-D), and as being reported in their medical history combined with treatment with antidepressant medication., Results: In the control group, women showed a higher depression severity, and a higher proportion of women were found to meet the cut-off score for depression on the HAM-D (32 vs. 16%) and having an history of depression (33 vs. 21%), while these sex differences were not observed in AD. Further, in both groups, female sex independently predicted the presence of depression, with covariates for age and cognitive status. AD subjects had higher mean HAM-D scores, were more likely to meet cutoff scores for depression (41 vs. 24%) and have a history of depression than controls (47 vs. 27%). When comparing the increase in frequency of depression in controls versus AD, the difference was significantly greater in men (AD men - control men: 24%) than in women (AD women - control women: 9%). Although subjects with depression were more likely to have higher levels of AD neuropathology, these differences were not observed when investigating the control or AD group separately., Discussion: Control women had a higher likelihood and severity of depression than control men, but this sex difference was not noted when considering only those with pathologically defined AD, emphasizing the importance of considering sex in aging studies. AD was associated with higher rates of depression and men may be more likely to report or be diagnosed with depression once they develop AD indicating the importance of more frequent depression screenings in men., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tremblay, Choudhury, Belden, Goldfarb, Lorenzini, Beach and Serrano.)

Purpose: Rural areas throughout the US continue to see closures of maternity wards and decreasing access to prenatal and intrapartum care. Studies examining closure's impacts have demonstrated both positive and negative effects on maternal and neonatal outcomes of mortality and morbidity. Our study aims to build on growing evidence from Canada and Scandinavia that suggests increased travel time to give birth is associated with increased emotional and financial stress for rural pregnant women., Methods: Pregnant patients at 7 clinic sites in western North Carolina were invited to complete the Rural Pregnancy Experience Scale (RPES) while waiting for their prenatal appointments. Results were analyzed using adjusted linear regressions to examine the correlation between RPES scores and self-reported distance to anticipated birth location as well as RPES scores with recent local labor and delivery closure., Findings: A total of 174 participants completed the survey and met inclusion criteria. For every 10 min increase in travel distance to the patient's anticipated place of delivery, RPES scores increased by an average of 0.72 points. Participants who reported a recent labor and delivery unit closure near them saw average increases of 2.52 on the RPES., Conclusions: Our findings are consistent with the growing body of literature internationally that demonstrates the distance required to travel to delivery location is associated with increased stress among rural pregnant women., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication. This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The Alzheimer's Questionnaire (AQ) is an informant-based screening tool with good diagnostic accuracy for Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). The aim of this study is to validate the AQ with AD-associated neuritic plaque (NP) and neurofibrillary tangle (NFT) pathology. Data from 205 prospectively followed autopsy cases clinically classified as AD (n = 90), aMCI (n = 42), or cognitively unimpaired (CU, n = 73) were used. Semi-quantitative measures of NP and NFT pathology were correlated with the AQ, Clinical Dementia Rating Sum of Boxes (CDR-SOB), and the Mini-Mental State Exam (MMSE). The AQ correlated significantly (p < 0.001) with NP load (r = 0.37) and NFT load (r = 0.57). The MMSE and CDR-SOB showed similar correlations with NP load (r = - 0.37, r = 0.35, respectively) and NFT load (r = - 0.58, r = 0.55, respectively). The AQ correlates well with NP and NFT pathology of AD, which provides additional confidence to clinicians using the AQ to screen for AD-related cognitive impairment., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The Alzheimer disease (AD) neuropathological hallmarks amyloid β (Aβ) and tau neurofibrillary (NF) pathology have been reported in the olfactory bulb (OB) in aging and in different neurodegenerative diseases, which coincides with frequently reported olfactory dysfunction in these conditions. To better understand when the OB is affected in relation to the hierarchical progression of Aβ throughout the brain and whether OB pathology might be an indicator of AD severity, we assessed the presence of OB Aβ and tau NF pathology in an autopsy cohort of 158 non demented control and 173 AD dementia cases. OB Aβ was found in less than 5% of cases in lower Thal phases 0 and 1, in 20% of cases in phase 2, in 60% of cases in phase 3 and in more than 80% of cases in higher Thal phases 4 and 5. OB Aβ and tau pathology significantly predicted a Thal phase greater than 3, a Braak NF stage greater than 4, and an MMSE score lower than 24. While OB tau pathology is almost universal in the elderly and therefore is not a good predictor of AD severity, OB Aβ pathology coincides with clinically-manifest AD and might prove to be a useful biomarker of the extent of brain spread of both amyloid and tau pathology., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Psychiatric advance directives (PADs) are used to document a person's treatment preferences for a future mental health crisis. Peer support specialists have been proposed to facilitate PADs, but little is known about the quality of peer versus clinician facilitated PADs., Aims: This study examined whether PAD documents facilitated by peer specialists and non-peer clinicians differed in the mix of treatment requests and refusals and expert ratings of feasibility and consistency., Methods: Analyses were conducted of content and expert ratings of 72 PAD documents from a randomized trial of PAD facilitation by peers and clinicians on Assertive Community Treatment (ACT) teams. A count of treatment refusals and requests was used to classify documents as predominantly prescriptive, proscriptive, or balanced. Regression was used to estimate relationships between PAD facilitator type and content., Results: Peer-facilitated PADs were significantly more likely to be predominantly prescriptive than were PADs facilitated by non-peer clinicians. Prescriptive PADs were more likely to receive expert ratings of high feasibility and consistency., Conclusions: Results should alleviate some clinicians' apprehensions regarding the appropriateness of peer-facilitated PADs, such as the concern that people with lived experience with mental illness might encourage other consumers to use their PAD primarily for treatment refusals.

Objective: The Uniform Data Set 3.0 neuropsychological battery (UDS3NB) is well developed for research with Alzheimer's disease and related dementias, and may serve as a common set of measures of cognitive decline across neurodegenerative diseases. However, the battery has not been formally assessed in persons with Parkinson's disease (PD). The current research provides initial information on the convergent and ecological validity of the UDS3NB in individuals with PD., Methods: Participants included 75 individuals diagnosed with PD from the Arizona Study of Aging and Neurodegenerative Disorders. Clinical dementia ratings, administered independently from the cognitive measures, identified individuals as having normal cognition ( n = 38), Mild Cognitive Impairment (MCI; n = 25) and dementia ( n = 12). UDS3NB measures were compared between these groups, and correlations between UDS3NB measures, gold standard neuropsychological measures, and informant rated activities of daily living ability (ADL) were evaluated., Results: At the group-level, UDS3NB scores followed the expected pattern with higher scores in participants with PD but no cognitive diagnosis and lower in those with dementia; scores in the MCI group were between these extremes. Convergent validity was suggested by moderate correlations between UDS specific measures (i.e., Craft story) and measures such as the RAVLT. Ecological validity was suggested by statistically significant correlations between UDS3NB performance and caregiver ratings of ADLs, with speed and executive functioning measures (Trailmaking A; r = -.51, p < .01; Trailmaking B; r = -.51, p < .01) most strongly related to reported daily functioning., Conclusions: Findings provide initial support for the convergent and ecological validity of the UDS3NB in individuals with PD. Implications and future directions for this battery are discussed.

Objective: To update data for diagnostic accuracy of a clinical diagnosis of Parkinson disease (PD) using neuropathologic diagnosis as the gold standard., Methods: Data from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) were used to determine the predictive value of a clinical PD diagnosis. Two clinical diagnostic confidence levels were used, possible PD (PossPD, never treated or not responsive) and probable PD (ProbPD, 2/3 cardinal clinical signs and responsive to dopaminergic medications). Neuropathologic diagnosis was the gold standard., Results: Based on the first visit to AZSAND, 15/54 (27.8%) PossPD participants and 138/163 (84.7%) ProbPD participants had confirmed PD. PD was confirmed in 24/34 (70.6%) ProbPD with <5 years and 114/128 (89.1%) with ≥5 years disease duration. Using the consensus final clinical diagnosis following death, 161/187 (86.1%) ProbPD had neuropathologically confirmed PD. Diagnostic accuracy for ProbPD improved if included motor fluctuations, dyskinesias, and hyposmia, and hyposmia for PossPD., Conclusions: This updated study confirmed lower clinical diagnostic accuracy for elderly, untreated or poorly responsive PossPD participants and for ProbPD with <5 years of disease duration, even when medication responsive. Caution continues to be needed when interpreting clinical studies of PD, especially studies of early disease, that do not have autopsy confirmation., Classification of Evidence: This study provides Class II evidence that a clinical diagnosis of ProbPD at the first visit identifies participants who will have pathologically confirmed PD with a sensitivity of 82.6% and a specificity of 86.0%., (© 2021 American Academy of Neurology.)

Perioperative music decreases pain, anxiety, and analgesia requirements while increasing patient satisfaction. We investigated the acceptability of perioperative music at a women's and children's hospital in Singapore, seeking to uncover barriers and facilitators to implementation in routine practice over a 12-week period. We used an undergraduate-led Rapid Qualitative Inquiry approach that includes data collection from multiple sources, iterative analysis, and additional data collection when necessary. Participants consisted of anesthesiologists and nurses working in the preoperative area, operating room, and postoperative recovery areas. In Stage 1, nurses and anesthesiologists answered a survey assessing attitudes and knowledge about perioperative music and attended a presentation introducing the intervention. In Stage 2, the results of the Stage 1 survey were disclosed, and nurses and anesthesiologists completed a second survey (Stage 1 survey questions with an additional query about implementation). Twenty-nine nurses were interviewed with semi-structured questions on barriers and facilitators to implementation. In Stage 3, nurses retook the Stage 2 survey after one month of implementation. The implementation of perioperative music was both acceptable and feasible in Singapore. The nurses' and anesthesiologists' acceptability increased over time with mostly positive qualitative feedback. Implementation barriers, including patient interest, timing of patient turnover, and added staff workload, appeared minor and could potentially be overcome by utilizing the intervention in the preoperative instead of postoperative area, deploying music in operating rooms with slower turnover, and evenly distributing staff workload. Local implementation stakeholders may make additional recommendations for scaling-up perioperative music interventions to fit other workflows while improving the patient experience., (© The Author(s) 2020. Published by Oxford University Press on behalf of American Music Therapy Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid™) is selective for the neuritic plaque amyloid of Alzheimer's disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker., Objective: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND)., Methods: Three subjects who had PET imaging with both AV-133 and AV-45 as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared., Results: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD., Conclusion: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed.

Worldwide, Brazil has the highest prevalence of violence and hate crimes against sexual and gender minorities (SGMs) among countries with available data. To explore the impact of this scenario, we conducted a qualitative study with 50 SGMs from Rio de Janeiro, Brazil. Among the participants, 66% screened positive for generalised anxiety disorder, 46% for major depressive disorder and 39% for PTSD. A third reported low self-esteem (32%) and one quarter low social support (26%). Experiences of interpersonal discrimination were highly prevalent (>60%), while institutional discrimination related to employment or healthcare was reported by 46% of participants. Verbal abuse is very common (80%), followed by physical assault (40%). Sexual violence is highly frequent among women. Focus groups analysis highlighted three major domains: (1) stigma and discrimination (family, friends and partners, in schools and health services, influencing social isolation); (2) violence (bullying, harassment, physical and sexual violence); and (3) mental suffering (alcohol and drug abuse, depression, suicidality, anxiety). Our findings suggest a close synergy between experiences of discrimination and violence with selected mental disorders. This complex synergy might be better addressed by longer-term individual and group-level interventions that could foster social solidarity among the different groups that comprise SGMs.

Background : Transgender women from low- and middle-income countries (LMICs) are understudied, their coping strategies and struggles underrecognised. Aims : This study aimed to explore the lived experiences of transgender women from two major cities located in Brazil and India, LMICs with high rates of transphobia and gender-based violence. Methods : We conducted a mixed-methods, exploratory study, including focus group discussions (FGDs) and brief survey interviews with 23 transgender women from Hyderabad, India and 12 transgender women from Rio de Janeiro, Brazil. Herein we present the combined (qualitative and quantitative) results related to discrimination, stigma, violence, and suicidality in transgender women's lives. Results : Three major themes emerged from FGDs: stigma and discrimination; violence, and suicidality. Lack of education and working opportunities influence high levels of poverty and engagement in survival sex work by transgender women in both cities. Study participants live in large cities with more than 6 million inhabitants, but transgender women reported chronic social isolation. Participants disclosed frequent suicide ideation and suicide attempts. Brief surveys corroborate FGD findings, identifying high prevalence of discrimination, intimate partner violence, suicidality and low social support. Discussion : Multiple layers of stigma, discrimination, violence and social isolation affect transgender women's quality of life in Hyderabad and Rio de Janeiro. Strategies sensitive to gender and culture should be implemented to tackle entrenched prejudice and social exclusion reported by transgender women. Additional social support strategies, better access to education and employment opportunities are also urgently needed. Improving the availability of evidence-based mental health interventions addressing the high prevalence of suicidality among transgender women from Hyderabad, India and Rio de Janeiro, Brazil should be prioritized., (© 2020 Taylor & Francis Group, LLC.)

Objective: Subjective excessive daytime sleepiness, commonly measured with the Epworth Sleepiness Scale (ESS), is associated with cognitive impairment in Parkinson disease (PD). Significant correlation between subject and informant responses has been reported in neurologically healthy individuals. We sought to assess this correlation in patients with PD., Patients and Methods: 854 individuals in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) had subject as well as informant-completed ESS completed within one year of a movement disorder exam and cognitive assessment. Correlations were evaluated using Spearman's rank correlation coefficients., Results: Overall, 397/854(46.5 %) were female with mean age of 77.5 (SD 8.3). 572 (67 %) were cognitively normal (CogNL), 135 (15.8 %) had mild cognitive impairment (MCI) and 147 (17.2 %) dementia. Spearman R correlations (all with p < 0.001) between subject and informant ESS responses were 0.73 overall, 0.67 for the CogNL group, 0.79 for the MCI group, 0.79 for those with dementia. Of 175 with clinically probable PD, 115 (65.7 %) were CogNL, 38 had MCI, and 22 (12.6 %) dementia. For subjects with PD correlations (all with p < 0.001) were 0.65 for PD-CogNL, 0.83 for PD-MCI, and 0.70 for those with PD-dementia., Conclusion: These significant correlations between subject and informant-completed ESS can be useful in guiding clinical trials designed to assess efficacy of potential treatments for excessive daytime sleepiness for the general population and for patients with PD, even those having cognitive impairment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Many subjects with neuropathologically-confirmed dementia with Lewy bodies (DLB) are never diagnosed during life, instead being categorized as Alzheimer's disease dementia (ADD) or unspecified dementia. Unrecognized DLB therefore is a critical impediment to clinical studies and treatment trials of both ADD and DLB. There are studies that suggest that olfactory function tests may be able to distinguish DLB from ADD, but few of these had neuropathological confirmation of diagnosis. We compared University of Pennsylvania Smell Identification Test (UPSIT) results in 257 subjects that went on to autopsy and neuropathological examination. Consensus clinicopathological diagnostic criteria were used to define ADD and DLB, as well as Parkinson's disease with dementia (PDD), with (PDD+AD) or without (PDD-AD) concurrent AD; a group with ADD and Lewy body disease (LBD) not meeting criteria for DLB (ADLB) and a clinically normal control group were also included. The subjects with DLB, PDD+AD and PDD-AD all had lower (one-way ANOVA p < 0.0001, pairwise Bonferroni p < 0.05) first and mean UPSIT scores than the ADD, ADLB or control groups. For DLB subjects with first and mean UPSIT scores less than 20 and 17, respectively, Firth logistic regression analysis, adjusted for age, gender and mean MMSE score, conferred statistically significant odds ratios of 17.5 and 18.0 for the diagnosis, vs ADD. For other group comparisons (PDD+AD and PDD-AD vs ADD) and UPSIT cutoffs of 17, the same analyses resulted in odds ratios ranging from 16.3 to 31.6 (p < 0.0001). To our knowledge, this is the largest study to date comparing olfactory function in subjects with neuropathologically-confirmed LBD and ADD. Olfactory function testing may be a convenient and inexpensive strategy for enriching dementia studies or clinical trials with DLB subjects, or conversely, reducing the inclusion of DLB subjects in ADD studies or trials., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: research funding from the National Institutes of Health, State of Arizona, Michael J Fox Foundation, Novartis, Eli Lilly, Pharma2B, Cala Health, Biogen, Intec Pharma, US World Meds, Neurocrine, Teva, Eisai, Acadia, Enterin, Sunovion, MagQu, Dong-A, and Avid Radiopharmaceuticals; consulting for AbbVie, Accorda, Amneal, Sunovion, Abbott, Adamas, Allergan, Biogen, Bracket, Grifois, vTv Therapeutics, Sanofi, Neurotrope, Neurocrine, Teva, Cortexyme, Roche-Genentech, Acadia, Acorda, Adamas, Cyapsus, Jazz, Lundbeck, Minerva, Neurocrine, Revance, Scion, Prothena and Vivid Genomics; Scientific advisory board for Roche, Alkahest Alzheon, Aural Analytics, Denali, Green Valley, MagQu, United Neuroscience and Vivid Genomics; ownership interests (stock, stock options) in Versanum Brain Health, Optimal Cognitive Health, Neurotrope and Vivid Genomics; intellectual property rights (royalties or patent sales) in Harper Collins; honoraria from Abbvie, Biogen, Mitsubishi Tanabe Pharma, Cello Health and Acadia Pharmaceuticals. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The effect of perioperative music listening has been proven to relieve preoperative anxiety and depression, while improving patient satisfaction. However, music listening has not been extensively studied in Singapore. Therefore, the primary aim of our study is to investigate the patient satisfaction towards perioperative music listening in the local setting. The secondary aim is to investigate the effect of perioperative music listening in reducing patient surgery-related anxiety and depression., Methods: After obtaining ethics board approval, we conducted a quasiexperimental study on a cohort of female patients who were undergoing elective minor gynaecological surgeries. Apple iPod Touch™ devices containing playlists of selected music genres and noise-cancelling earphones were given to patients to listen during the preoperative and postoperative periods. Hospital Anxiety and Depression Scale (HADS), EQ-5D-3L questionnaire, music listening preferences, and patient satisfaction surveys were administered. Wilcoxon signed-rank and McNemar's tests for paired data were used for analysis., Results: 83 patients were analysed with 97.6% of patients in the preoperative period and 98.8% of patients in the postoperative period were satisfied with music listening. The median (IQR [range]) score for preintervention HADS anxiety was 7.0 (6.0 [0-17]), significantly higher than that in postintervention at 2.0 (4.0 [0-12]) ( P < 0.001). Similarly, there was a significant reduction in preintervention HADS depression as compared to postintervention ( P < 0.001). Similarly, there was a significant reduction in preintervention HADS depression as compared to postintervention (., Conclusion: Perioperative music listening improved patient satisfaction and can reduce patient anxiety and depression. We hope to further investigate on how wider implementation of perioperative music listening could improve patient care., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2020 Daryl Jian An Tan et al.)

Background: The mental health treatment gap-the difference between those with mental health need and those who receive treatment-is high in low- and middle-income countries. Task-shifting has been used to address the shortage of mental health professionals, with a growing body of research demonstrating the effectiveness of mental health interventions delivered through task-shifting. However, very little research has focused on how to embed, support, and sustain task-shifting in government-funded systems with potential for scale up. The goal of the Building and Sustaining Interventions for Children (BASIC) study is to examine implementation policies and practices that predict adoption, fidelity, and sustainment of a mental health intervention in the education sector via teacher delivery and the health sector via community health volunteer delivery., Methods: BASIC is a Hybrid Type II Implementation-Effectiveness trial. The study design is a stepped wedge, cluster randomized trial involving 7 sequences of 40 schools and 40 communities surrounding the schools. Enrollment consists of 120 teachers, 120 community health volunteers, up to 80 site leaders, and up to 1280 youth and one of their primary guardians. The evidence-based mental health intervention is a locally adapted version of Trauma-focused Cognitive Behavioral Therapy, called Pamoja Tunaweza. Lay counselors are trained and supervised in Pamoja Tunaweza by local trainers who are experienced in delivering the intervention and who participated in a Train-the-Trainer model of skills transfer. After the first sequence completes implementation, in-depth interviews are conducted with initial implementing sites' counselors and leaders. Findings are used to inform delivery of implementation facilitation for subsequent sequences' sites. We use a mixed methods approach including qualitative comparative analysis to identify necessary and sufficient implementation policies and practices that predict 3 implementation outcomes of interest: adoption, fidelity, and sustainment. We also examine child mental health outcomes and cost of the intervention in both the education and health sectors., Discussion: The BASIC study will provide knowledge about how implementation of task-shifted mental health care can be supported in government systems that already serve children and adolescents. Knowledge about implementation policies and practices from BASIC can advance the science of implementation in low-resource contexts., Trial Registration: Trial Registration: ClinicalTrials.gov Identifier: NCT03243396. Registered 9th August 2017, https://clinicaltrials.gov/ct2/show/NCT03243396.

Comorbid Lewy body pathology is very common in Alzheimer's disease and may confound clinical trial design, yet there is no in vivo test to identify patients with this. Tissue (and/or radioligand imaging) studies have shown cardiac sympathetic denervation in Parkinson's disease and dementia with Lewy bodies, but this has not been explored in Alzheimer's subjects with Lewy bodies not meeting dementia with Lewy bodies clinicopathological criteria. To determine if Alzheimer's disease with Lewy bodies subjects show sympathetic cardiac denervation, we analysed epicardial and myocardial tissue from autopsy-confirmed cases using tyrosine hydroxylase and neurofilament immunostaining. Comparison of tyrosine hydroxylase fibre density in 19 subjects with Alzheimer's disease/dementia with Lewy bodies, 20 Alzheimer's disease with Lewy bodies, 12 Alzheimer's disease subjects without Lewy body disease, 19 Parkinson's disease, 30 incidental Lewy body disease and 22 cognitively normal without Alzheimer's disease or Lewy body disease indicated a significant group difference ( P  < 0.01; Kruskal-Wallis analysis of variance) and subsequent pair-wise Mann-Whitney U tests showed that Parkinson's disease ( P  < 0.05) and Alzheimer's disease/dementia with Lewy bodies ( P  < 0.01) subjects, but not Alzheimer's disease with Lewy bodies subjects, had significantly reduced tyrosine hydroxylase fibre density as compared with cognitively normal. Both Parkinson's disease and Alzheimer's disease/dementia with Lewy bodies subjects also showed significant epicardial losses of neurofilament protein-immunoreactive nerve fibre densities within the fibre bundles as compared with cognitively normal subjects ( P  < 0.01) and both groups showed high pathologic alpha-synuclein densities ( P  < 0.0001). Cardiac alpha-synuclein densities correlated significantly with brain alpha-synuclein ( P  < 0.001), while cardiac tyrosine hydroxylase and neurofilament immunoreactive nerve fibre densities were negatively correlated with the densities of both brain and cardiac alpha-synuclein, as well as Unified Parkinson's Disease Rating Scale scores ( P  < 0.05). The clear separation of Alzheimer's disease/dementia with Lewy bodies subjects from Alzheimer's disease and cognitively normal, based on cardiac tyrosine hydroxylase fibre density, is the first report of a statistically significant difference between these groups. Our data do not show significant sympathetic cardiac denervation in Alzheimer's disease with Lewy bodies, but strongly confirm that cardiac nuclear imaging with a noradrenergic radioligand is worthy of further study as a potential means to separate Alzheimer's disease from Alzheimer's disease/dementia with Lewy bodies during life., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

This study was designed to correlate clinical findings with the extent of pathologic a-synuclein (aSyn) in the brain using the Unified Staging System for Lewy Body disorders (USSLB). Data from 280 cases from the Arizona Study of Aging and Neurodegenerative Disorders are presented. Each case had a complete USSLB staging and at least 1 full research clinical assessment, including subspecialty neurologist-administered movement and cognitive evaluation. Of the 280, 25.7% were cognitively normal, 8.6% had mild cognitive impairment, and 65.7% had dementia. All cases could be categorized into 1 of 5 USSLB stages (8.6% stage I-olfactory bulb only; 15.4% IIa-brainstem predominant; 13.6% IIb-limbic predominant; 31.8% III-brainstem and limbic; and 30.7% IV-neocortical) yet using the Braak staging system 70 cases (25.3%) could not be classified. Those with USSLB stages III and IV died at a younger age. Multiple measures of motor parkinsonism, cognitive impairment, hyposmia, and probable RBD were significantly correlated with increasing USSLB stage. We conclude that the USSLB is the most comprehensive staging system for all Lewy body disorders and allows for categorization and ranking of all brains with significant correlations to many motor and nonmotor clinical signs and symptoms., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)

Background: The Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDSUPDRS), Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT), Mayo Sleep Questionnaire, Epworth Sleepiness Scale, and Neuropsychiatric Inventory Questionnaire (NPI-Q) are validated instruments for assessing signs and symptoms of Parkinson's disease (PD). Objective: We sought to determine whether responses on the MDS-UPDRS correlate with responses to other scales used in patients with PD. Design: Study subjects were enrolled in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Participants were selected if they had completed all scales within a one-month window. Spearman's rank correlation coefficients were calculated. Results: A total of 96 eligible subjects were identified. High correlation ( r -values) was found between the SCOPA-AUT and MDS-UPDRS excessive saliva (0.73; p <0.001), constipation (0.62; p <0.001), and swallowing (0.59; p <0.001) questions. The r -values for the NPI-Q and MDS-UPDRS depression and anxiety questions were 0.53 ( p <0.001), and 0.67 ( p <0.001). Conclusion: MDS-UPDRS correlates well with some but not all questions from the SCOPA-AUT and NPI-Q. This work emphasizes the importance of employing multiple methods for assessing nonmotor symptoms in patients with PD., Competing Interests: FUNDING:The Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (no. U24 NS072026, National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders); the National Institute on Aging (no. P30 AG19610, Arizona Alzheimer’s Disease Core Center); the Arizona Department of Health Services (contract no. 211002, Arizona Alzheimer’s Research Center); the Arizona Biomedical Research Commission (contract nos. 4001, 0011, 05-901, and 1001, the Arizona Parkinson’s Disease Consortium); and the Michael J. Fox Foundation for Parkinson’s Research. DISCLOSURES:The authors have no conflicts of interest relevant to the content of this article., (Copyright © 2019. Matrix Medical Communications. All rights reserved.)

Background: Verbal fluency deficits are common in patients with Parkinson's disease. The association of these impairments with regional neuropathological changes is unexplored., Objectives: Determine if patients with verbal fluency impairments have greater neuropathological burden in frontal, temporal, and limbic regions and if Lewy bodies or neurofibrillary tangles were associated with verbal fluency impairments., Methods: Data was derived from the Arizona Study of Aging and Neurodegenerative Disorders. 47 individuals who completed phonemic and semantic verbal fluency tasks and met clinicopathological criteria for Parkinson's disease (with and without comorbid Alzheimer's disease) were included. Impairment on fluency tasks was defined by normative data, and the density of neuropathology in temporal, limbic, and frontal regions was compared between groups., Results: Individuals with semantic fluency impairments had greater total pathology (Lewy bodies + neurofibrillary tangles) in limbic structures (W = 320.0, p = .033, r pb  = .33), while those who had phonemic fluency impairments had increased total neuropathology in frontal (W = 364.5, p = .011, r pb  = .37), temporal (W = 356.5, p = .022, r pb  = .34), and limbic regions (W = 357.0, p = .024, r pb  = .34). Greater Lewy body density was found in those with verbal fluency impairments, though trends for greater neurofibrillary tangle density were noted as well., Conclusions: Impaired phonemic fluency was associated with higher Lewy body and tangle burden in frontal, temporal, and limbic regions, while impaired semantic fluency was associated with greater limbic pathology. Though neurofibrillary tangles trended higher in several regions in those with impaired verbal fluency, higher Lewy body density in general was associated with verbal fluency deficits. Implications for research and clinical practice are discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Neuropathology has demonstrated a high rate of comorbid pathology in dementia due to Alzheimer's disease (ADD). The most common major comorbidity is Lewy body disease (LBD), either as dementia with Lewy bodies (AD-DLB) or Alzheimer's disease with Lewy bodies (AD-LB), the latter representing subjects with ADD and LBD not meeting neuropathological distribution and density thresholds for DLB. Although it has been established that ADD subjects with undifferentiated LBD have a more rapid cognitive decline than those with ADD alone, it is still unknown whether AD-LB subjects, who represent the majority of LBD and approximately one-third of all those with ADD, have a different clinical course., Methods: Subjects with dementia included those with "pure" ADD (n = 137), AD-DLB (n = 64) and AD-LB (n = 114), all with two or more complete Mini Mental State Examinations (MMSE) and a full neuropathological examination., Results: Linear mixed models assessing MMSE change showed that the AD-LB group had significantly greater decline compared to the ADD group (β = -0.69, 95% CI: -1.05, -0.33, p<0.001) while the AD-DLB group did not (β = -0.30, 95% CI: -0.73, 0.14, p = 0.18). Of those with AD-DLB and AD-LB, only 66% and 2.1%, respectively, had been diagnosed with LBD at any point during their clinical course. Compared with clinically-diagnosed AD-DLB subjects, those that were clinically undetected had significantly lower prevalences of parkinsonism (p = 0.046), visual hallucinations (p = 0.0008) and dream enactment behavior (0.013)., Conclusions: The probable cause of LBD clinical detection failure is the lack of a sufficient set of characteristic core clinical features. Core DLB clinical features were not more common in AD-LB as compared to ADD. Clinical identification of ADD with LBD would allow stratified analyses of ADD clinical trials, potentially improving the probability of trial success., Competing Interests: We have the following interests: Dr. Kewei Chen is employed by Shanghai Green Valley Pharmaceutical. Dr. Malek-Ahmadi is a consultant to Shanghai Green Valley Pharmaceutical. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

This article examines the application and effectiveness of a 2006 Indiana law designed to prevent gun violence by authorizing police officers to separate firearms from persons who present imminent or future risk of injury to self or others, or display a propensity for violent or emotionally unstable conduct. A court hearing is held to determine ongoing risk in these cases; a judge decides whether to return the seized firearms or retain them for up to five years. The study examines the frequency of criminal arrest as well as suicide outcomes for 395 gun-removal actions in Indiana. Fourteen individuals (3.5%) died from suicide, seven (1.8%) using a firearm. The study population's annualized suicide rate was about 31 times higher than that of the general adult population in Indiana, demonstrating that the law is being applied to a population genuinely at high risk. By extrapolating information on the case fatality rate for different methods of suicide, we calculated that one life was saved for every 10 gun-removal actions, similar to results of a previous study in Connecticut. Perspectives from key stakeholders are also presented along with implications for gun policy reform and implementation., (© 2019 American Academy of Psychiatry and the Law.)

Many studies have been directed at understanding mechanisms of tau aggregation and therapeutics, nearly all focusing on the brain. It is critical to understand the presence of tau in peripheral tissues since this may provide new insights into disease progression and selective vulnerability. The current study sought to determine the presence of select tau species in peripheral tissues in elderly individuals and across an array of tauopathies. Using formalin fixed paraffin embedded sections, we examined abdominal skin, submandibular gland, and sigmoid colon among 69 clinicopathologically defined cases: 19 lacking a clinical neuropathological diagnosis (normal controls), 26 progressive supranuclear palsy (PSP), 21 Alzheimer's disease (AD), and 3 with corticobasal degeneration (CBD). Immunohistochemistry was performed using antibodies for "total" tau (HT7) and two phosphorylated tau species (AT8 and pT231). HT7 staining of abdominal skin revealed immunoreactivity of potential nerve elements in 5% of cases (1 AD, 1 AD/PSP, and 1 CBD out of 55 cases examined); skin sections lacked AT8 and pT231 immunoreactive nerve elements. Submandibular glands from all cases had HT7 immunoreactive nerve elements; while pT231 was present in 92% of cases, and AT8 in only 3 cases (2 AD and one AD/PSP case). In sigmoid colon, HT7 immunoreactivity was present in all but 2 cases (97%), pT231 in 54%, and AT8 was present in only 5/62 cases (8%). These data suggest select tau species in CNS tauopathies do not have a high propensity to spread to the periphery and this may hold clues for the understanding of CNS tau pathogenicity and vulnerability., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Identify clinical features predictive of Lewy body pathology in Alzheimer's disease (AD) patients in an ongoing longitudinal clinicopathologic study., Material and Methods: We queried the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) database for dementia cases with AD pathology (1997-2015). Subjects received longitudinal comprehensive clinical evaluations including motor/neuropsychological assessment and Apo-E4 genotyping. All cases were autopsied and had standard neuropathological assessments for AD and Lewy-type synucleinopathy (LTS). Subjects were categorized based on standardized pathological criteria with AD cases that had LTS but did not meet DLB pathologic criteria being categorized as ADLB. We performed pairwise comparison between the different diagnoses and multivariable modelling to identify clinical symptoms that predict the pathological diagnosis., Results: We identified 32 DLB/AD, 54 ADLB, 70 AD only and 41 PDD/AD cases. AD subjects with LTS pathology had higher UPDRS II and III total scores as well as generally higher individual scores compared to AD alone. While depression scales and Trail-making Test A correlated significantly with LTS, other neuropsychological variables were not significantly different. Apo E4 occurrence was similar in all groups (40%-49%)., Conclusions: Our study suggests that the presence (or absence) of LTS influences motor and non-motor clinical findings in AD patients. These findings may lead to biomarkers that allow for more targeted treatment of AD., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Some epidemiology studies suggest that atherosclerotic cardiovascular disease (ASCVD) risk factors increase the risk of developing Parkinson's disease (PD). However, conflicting data suggest lower rates of ASCVD in PD., Objective: The objective of this study is to determine, with data from a longitudinal clinicopathological study, whether ASCVD risk factors are associated with a PD diagnosis and/or increased brain or peripheral load of Lewy-type synucleinopathy (LTS)., Methods: All subjects were followed to autopsy and neuropathological examination in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Multivariable regression models, including age, gender, and smoking history, were used to investigate the association of a PD diagnosis or brain or submandibular gland LTS load with ASCVD risk factors., Results: 150 subjects were included (PD n = 60, controls n = 90). Univariable comparisons and regression models showed a general trend to inverse associations. The multivariable odds ratio (OR) of brain LTS load for carotid artery disease was 0.93 (95% CI: 0.86 to 0.98; p = 0.02), for anticoagulant use 0.95 (95% CI: 0.90 to 0.99; p = 0.04) and for abnormal heart weight 0.96 (95% CI: 0.92 to 0.99; p = 0.01). Composite clinical and overall (clinical + pathology composite risk scores) composite risk scores were also significantly lower in the PD subjects (p = 0.0164 and 0.0187, respectively). Submandibular gland LTS load was not significantly related to ASCVD conditions., Conclusions: This study shows associations of higher brain LTS with lower prevalence of both clinical and pathological indices of ASCVD in PD subjects versus age-similar controls. We suggest that this is due to α-synuclein pathology-induced sympathetic denervation in PD.

Inability to accurately diagnose Lewy type alpha-synucleinopathy (LTS) pre-mortem has been a major obstacle to clinical care and research. Probable REM sleep behavior disorder (PRBD) diagnosed with support of instruments such as the Mayo Sleep Questionnaire (MSQ) may provide a cost effective means of predicting LTS. Since 2007, 602 subjects in the Arizona Study of Aging and Neurodegenerative Disorders had clinician assessment for PRBD (298 with, 304 without support of the MSQ), completed cognitive and movement examinations, and had neuropathological assessment. Mean age at death was 84.8 years. Histological evidence of LTS was found in 80/101(79.2%) cases with PRBD and 198/501 (39.5%) without PRBD (p < 0.001). Overall sensitivity for predicting LTS by PRBD diagnosis was 28.8%, specificity 93.5%, positive predictive value (PPV) 79.2%, negative predictive value (NPV) 60.5%. Diagnosis of PRBD was less frequently present in subjects without LTS [4/105 (3.8%) of healthy controls, 42/255 (16.5%) AD, 2/33 (6.1%) progressive supranuclear palsy (PSP) without LTS] than in subjects with LTS [11/46 (23.9%) DLB, 58/104 (55.8%) PD, and 4/16 (25.0%) PSP with LTS.] PRBD was not present in any of 46 subjects with incidental Lewy body disease (ILBD). MSQ-supported diagnosis of PRBD appears useful for predicting LTS in manifest neurodegenerative disease, but not necessarily ILBD. Additional prospective autopsy research, including well-characterized polysomnogram-confirmed RBD subjects, is needed to elucidate the earliest tissue abnormalities in the "idiopathic" (premotor/pre-dementia) stage of RBD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Complementary integrative health therapies have a perioperative role in the reduction of pain, analgesic use, and anxiety, and increasing patient satisfaction. However, long implementation lags have been quantified. The Consolidated Framework for Implementation Research (CFIR) can help mitigate this translational problem., Methods: We reviewed evidence for several nonpharmacological treatments (CFIR domain: characteristics of interventions) and studied external context and organizational readiness for change by surveying providers at 11 Veterans Affairs (VA) hospitals (domains: outer and inner settings). We asked patients about their willingness to receive music and studied the association between this and known risk factors for opioid use (domain: characteristics of individuals). We implemented a protocol for the perioperative use of digital music players loaded with veteran-preferred playlists and evaluated its penetration in a subgroup of patients undergoing joint replacements over a 6-month period (domain: process of implementation). We then extracted data on postoperative recovery time and other outcomes, comparing them with historic and contemporary cohorts., Results: Evidence varied from strong and direct for perioperative music and acupuncture, to modest or weak and indirect for mindfulness, yoga, and tai chi, respectively. Readiness for change surveys completed by 97 perioperative providers showed overall positive scores (mean >0 on a scale from -2 to +2, equivalent to >2.5 on the 5-point Likert scale). Readiness was higher at Durham (+0.47) versus most other VA hospitals (range +0.05 to +0.63). Of 3307 veterans asked about willingness to receive music, approximately 68% (n = 2252) answered "yes." In multivariable analyses, a positive response (acceptability) was independently predicted by younger age and higher mean preoperative pain scores (>4 out of 10 over 90 days before admission), factors associated with opioid overuse. Penetration was modest in the targeted subset (39 received music out of a possible 81 recipients), potentially reduced by device nonavailability due to diffusion into nontargeted populations. Postoperative recovery time was not changed, suggesting smooth integration into workflow., Conclusions: CFIR-guided implementation of perioperative music was feasible at a tertiary VA hospital, with moderate penetration in a high-risk subset of patients. Use of digital music players with preferred playlists was supported by strong evidence, tension for change, modest readiness among providers, good acceptability among patients (especially those at risk for opioid overuse), and a protocolized approach. Further study is needed to identify similar frameworks for effective knowledge-translation activities.

Background: Clinical diagnostic criteria for PD rely on rest tremor, bradykinesia, and rigidity. These features are non-specific and neuropathological confirmation remains the gold standard for diagnosis. This study presents data on clinical certainty ratings in autopsy-proven PD., Methods: Subjects were assessed annually by a movement disorders specialist and assigned to a clinical certainty group for PD based on multiple clinical features before autopsy. The three groups considered for analysis are as follows: Group I 0-49% certainty, Group II 50-89% certainty, and Group III 90-100% certainty. All subjects were autopsied and had a standardized neuropathological assessment., Results: 275 subjects were assigned a PD certainty at their last visit before death. Group I had 80 subjects, Group II 56 subjects, and Group III 139 subjects. The clinical features recorded in Group I, II, and III, were as follows: rest tremor, bradykinesia, rigidity, postural instability, asymmetric onset, persistent asymmetry, current response to dopaminergic treatment, motor fluctuations, and dyskinesia. Rigidity, postural instability, asymmetric onset, current response to dopaminergic treatment, motor fluctuation, and dyskinesia were more likely to be present in the group which was rated with higher certainty. The final diagnosis of PD was confirmed by neuropathological assessment in 85% of the patients in Group III as compared to 30% in Group II and 5% in Group I., Conclusions: High certainty (90-100%) had strong positive predictive value (85%) for autopsy-proven PD as compared to either lower certainty groups (0-49% and 50-89%) which had lower predictive value (5% and 30% respectively).

The utility of plasma amyloid beta (Aβ) and tau levels for the clinical diagnosis of Alzheimer's disease (AD) dementia has been controversial. The main objective of this study was to compare Aβ42 and tau levels measured by the ultra-sensitive immunomagnetic reduction (IMR) assays in plasma samples collected at the Banner Sun Health Institute (BSHRI) (United States) with those from the National Taiwan University Hospital (NTUH) (Taiwan). Significant increase in tau levels were detected in AD subjects from both cohorts, while Aβ42 levels were increased only in the NTUH cohort. A regression model incorporating age showed that tau levels identified probable ADs with 81 and 96% accuracy in the BSHRI and NTUH cohorts, respectively, while computed products of Aβ42 and tau increased the accuracy to 84% in the BSHRI cohorts. Using 382.68 (pg/ml) 2 as the cut-off value, the product achieved 92% accuracy in identifying AD in the combined cohorts. Overall findings support that plasma Aβ42 and tau assayed by IMR technology can be used to assist in the clinical diagnosis of AD.

Multiple studies suggest that females are affected by Alzheimer disease (AD) more severely and more frequently than males. Other studies have failed to confirm this and the issue remains controversial. Difficulties include differences in study methods and male versus female life expectancy. Another element of uncertainty is that the majority of studies have lacked neuropathological confirmation of the AD diagnosis. We compared clinical and pathological AD severity in 1028 deceased subjects with full neuropathological examinations. The age of dementia onset did not differ by gender but females were more likely to proceed to very severe clinical and pathological disease, with significantly higher proportions having a Mini-Mental State Examination score of 5 or less and Braak stage VI neurofibrillary degeneration. Median neuritic plaque densities were similar in females and males with AD but females had significantly greater tangle density scores. In addition, we found that AD-control brain weight differences were significantly greater for females, even after adjustment for age, disease duration, and comorbid conditions. These findings suggest that when they are affected by AD, females progress more often to severe cognitive dysfunction, due to more severe neurofibrillary degeneration, and greater loss of brain parenchyma., (© 2016 American Association of Neuropathologists, Inc. All rights reserved.)

Background: Although champions are commonly employed in health information technology (HIT) implementations, the state of empirical literature on HIT champions' is unclear. The purpose of our review was to synthesize quantitative and qualitative studies to identify the extent of research on the characteristics, behaviors, and impacts of HIT champions. Ultimately, our goal was to identify gaps in the literature and inform implementation science., Methods: Our review employed a broad search strategy using multiple databases-Embase, Pubmed, Cinahl, PsychInfo, Web of Science, and the Cochrane library. We identified 1728 candidate articles, of which 42 were retained for full-text review., Results: Of the 42 studies included, fourteen studies employed a multiple-case study design (33 %), 12 additional articles employed a single-case study design (29 %), five used quantitative methods (12 %), two used mixed-methods (5 %), and one used a Delphi methodology (2 %). Our review revealed multiple categories and characteristics of champions as well as influence tactics they used to promote an HIT project. Furthermore, studies have assessed three general types of HIT champion impacts: (1) impacts on the implementation process of a specific HIT; (2) impacts on usage behavior or overall success of a specific HIT; and (3) impacts on general organizational-level innovativeness. However the extent to which HIT projects fail even with a champion and why such failures occur is not clear. Also unclear is whether all organizations require a champion for successful HIT project implementation. In other words, we currently do not know enough about the conditions under which (1) a health IT champion is needed, (2) multiple champions are needed, and (3) an appointed champion-as opposed to an emergent champion-can be successful., Conclusions: Although champions appear to have contributed to successful implementation of HIT projects, simply measuring the presence or absence of a champion is not sufficient for assessing impacts. Future research should aim for answers to questions about who champions should be, when they should be engaged, what they should do, how management can support their efforts, and what their impact is given the organizational context.

Background: Clinical misdiagnosis, particularly at early disease stages, is a roadblock to finding new therapies for Lewy body disorders. Biopsy of a peripheral site might provide improved diagnostic accuracy. Previously, we reported, from both autopsy and needle biopsy, a high prevalence of submandibular gland synucleinopathy in Parkinson's disease (PD). Here, we report on an extension of these studies to subjects with dementia with Lewy bodies (DLB) and other Lewy body disorders in 228 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders., Objective: To provide an estimate of the prevalence of histological synucleinopathy in the submandibular glands of subjects with PD and other Lewy body disorders., Methods: Submandibular gland sections from autopsied subjects were stained with an immunohistochemical method for α-synuclein phosphorylated at serine 129. Included were 146 cases with CNS Lewy-type synucleinopathy (LTS), composed of 46 PD, 28 DLB, 14 incidental Lewy body disease (ILBD), 33 Alzheimer's disease with Lewy bodies (ADLB) and 2 with progressive supranuclear palsy and Lewy bodies (PSPLB). Control subjects included 79 normal elderly, 15 AD, 12 PSP, 2 conticobasal degeneration (CBD) and 2 multiple system atrophy (MSA)., Results: Submandibular gland LTS was found in 42/47 (89%) of the PD subjects, 20/28 (71%) DLB, 4/33 (12%) ADLB and 1/9 (11%) ILBD subjects but none of the 110 control subjects., Conclusions: These results provide support for further clinical trials of in vivo submandibular gland diagnostic biopsy for PD and DLB. An accurate peripheral biopsy diagnosis would assist subject selection for clinical trials and could also be used to verify other biomarkers.

Introduction: Rapid eye movement (REM) sleep behavior disorder (RBD) in Parkinson's disease (PD) is associated with differences in clinical phenotype, including dementia, autonomic loss, and gait dysfunction. The pathological basis for this remains unclear., Methods: Parkinson's disease subjects in a longitudinal clinicopathologic study were screened for probable RBD with the Mayo Sleep Questionnaire. After death, semiquantitative analyses were conducted for synuclein, amyloid, neurofibrillary tangles, and cerebrovascular lesions., Results: Forty cases had probable RBD (PD+RBD), and 41 did not (PD-RBD). Despite similar age at death (∼80 y) and disease duration (∼14.5 y), PD+RBD had increased synuclein deposition in all regions examined, with nine of 10 regions significantly different. The Lewy body 10-region total score (scale = 0-40) was 29.5 in PD+RBD versus 24.5 in PD-RBD (Cohen-d effect size = 0.79, P = 0.002). Cerebrovascular lesion burden was slightly higher in PD-RBD., Conclusions: Although overlap occurs between groups, PD patients with probable RBD may have greater density and range of synuclein pathology on autopsy., (© 2015 International Parkinson and Movement Disorder Society.)

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects., (© 2015 Japanese Society of Neuropathology.)

Limited information regarding the specificity of mild cognitive impairment (MCI) as it relates to dementia with Lewy bodies (DLB) exists. Here, we summarize the clinical phenotype of MCI in clinically suspect DLB. Ten patients with a primary diagnosis of MCI and secondary diagnoses of DLB were identified. Patients underwent clinical neurological and neuropsychological evaluation that included application of McKeith criteria. We found parkinsonism and gait abnormality in 9 of the 10 patients; fluctuations in 8 of the 10; and hallucinations and dream enactment behavior in 5 of the 10. Of the 10 cases, 4 were classified as nonamnestic MCI and 6 were amnestic MCI. Of the 10 cases, 9 displayed executive and/or visuospatial dysfunction. Of the 10 cases, 6 have progressed to DLB. Progression of MCI to DLB is not dependent on memory impairment. The presence of core clinical features-parkinsonism and cognitive fluctuations-and predominant executive and visuospatial dysfunction ± memory impairment is suggestive of a prodromal DLB presentation., (© The Author(s) 2014.)

Background: Fibromyalgia (FM) has been understudied in the elderly population, a group with particular vulnerabilities to pain, reduced mobility, and sleep disruption., Aims: To characterize FM symptoms and treatments in a cohort of older subjects examined over time to determine the extent to which current, community-based treatment for older FM patients is in accord with published guidelines, and effective in reducing symptoms., Methods: A longitudinal, observational study of 51 subjects with FM (range 55-95 years) and 81 control subjects (58-95 years) performed at Banner Sun Health Research Institute in Sun City, AZ, USA. Serial history and examination data were obtained over a 6-year period. FM data included medical history, medications, physical examination, tender point examination, neuropsychological testing, sleep and pain ratings, the Physical Function Subscale of the Fibromyalgia Impact Questionnaire, and other standardized scales to evaluate depression and other psychiatric symptoms, and cognitive and functional impairment., Results: Pain and stiffness that interfered with physical activity, sleep, and mood were reported by 80 % or more of subjects. Over time, pain involved an increasing number of body areas. Over half of subjects were treated with NSAIDs, one-quarter with opioids, and one-quarter with estrogen. Few were treated with dual-acting antidepressants or pregabalin., Discussion: In this cohort of elders with suboptimally treated FM, substantial persistence of symptoms was seen over time. In general, recommended treatments were either not used or not tolerated., Conclusions: Age-appropriate treatments as well as education of primary care providers are needed to improve treatment of FM in the older population.

Introduction: Longitudinal assessment of cognitive decline in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) often involves the use of both informant-based and objective cognitive assessments. As efforts have focused on identifying individuals in pre-clinical stages, instruments that are sensitive to subtle cognitive changes are needed. The Alzheimer's Questionnaire (AQ) has demonstrated high sensitivity and specificity in identifying aMCI and AD; however its ability to measure longitudinal change has not been assessed. The aims of this study are to assess the sensitivity to change of the AQ and to determine whether the AQ predicts change in global cognition and function in cognitively normal (CN), aMCI, and AD subjects., Methods: Data from 202 individuals participating in a brain and body donation program were utilized for this study (101 CN, 62 aMCI, 39 AD). AD and aMCI individuals were matched on age, education, and gender to CN individuals. Sensitivity to change of the AQ was assessed in addition to the AQ's ability to predict change in global cognition and function. The Mini Mental State Exam (MMSE) and Functional Activities Questionnaire (FAQ) were used as gold standard comparisons of cognition and function. Sample size calculations for a 25% treatment effect were also carried out for all three groups., Results: The AQ demonstrated small sensitivity to change in the aMCI and CN groups (d = 0.33, d = 0.23, respectively) and moderate sensitivity to change in the AD group (d = 0.43). The AQ was associated with increases in the Clinical Dementia Rating Global Score (OR = 1.20 (1.09, 1.32), P <0.001). Sample size calculations found that the AQ would require substantially fewer subjects than the MMSE given a 25% treatment effect., Conclusions: Although the AQ demonstrated small sensitivity to change in aMCI and CN individuals in terms of effect size, the AQ may be superior to objective cognitive tests in terms of required sample size for a clinical trial. As clinicians and researchers continue to identify and treat individuals in earlier stages of AD, there is a need for instruments that are sensitive to cognitive changes in these earlier stages.