Publications by authors named "Matthew J Barrett"

58 Publications

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

Clin Neuropsychol 2022 Apr 21:1-19. Epub 2022 Apr 21.

Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA.

The generation and maintenance of goal-directed behavior is subserved by multiple brain regions that receive cholinergic inputs from the cholinergic nucleus 4 (Ch4). It is unknown if Ch4 degeneration contributes to apathy in Parkinson's disease (PD). We analyzed data from 106 pre-surgical patients with PD who had brain MRIs and completed the Frontal Systems Behavior Scales (FrSBe). Eighty-eight patients also completed the Beck Depression Inventory-2nd Edition. Cholinergic basal forebrain grey matter densities (GMD) were measured by applying probabilistic maps to T1 MPRAGE sequences processed using voxel-based morphometry methods. We used linear and hierarchical regression modelling to examine the association between Ch4 GMD and the FrSBe Apathy subscale scores. We used similar methods to assess the specificity of this association and potential associations between Ch4 target regions and apathy. Ch4 GMD ( = .021) and Ch123 GMD ( = .032) were significantly associated with Apathy subscale scores on univariate analysis. Ch4 GMD, but not Ch123 GMD, remained significantly associated with apathy when adjusting for age, sex, levodopa equivalent doses, and disease duration. Centromedial amygdala GMD, which receives cholinergic inputs from Ch4, was also associated with apathy. Ch4 GMD was not associated with depression or disinhibition, nor was it associated with executive dysfunction when adjusting for clinical and demographic variables. Ch4 GMD is specifically associated with apathy in PD. Ch4 degeneration results in cholinergic denervation of multiple cortical and limbic regions, which may contribute to the cognitive and emotional-affective processing deficits that underlie the behavioral symptoms of apathy.
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http://dx.doi.org/10.1080/13854046.2022.2065362DOI Listing
April 2022

Anticholinergic Medication Burden in Parkinson's Disease Outpatients.

J Parkinsons Dis 2022 ;12(2):599-606

Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA.

Background: Individuals with Parkinson's disease (PD) may be especially vulnerable to future cognitive decline from anticholinergic medications.

Objective: To characterize anticholinergic medication burden, determine the co-occurrence of anticholinergic and cholinesterase inhibitors, and to assess the correlations among anticholinergic burden scales in PD outpatients.

Methods: We studied 670 PD outpatients enrolled in a clinic registry between 2012 and 2020. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Drug Burden Index-Anticholinergic component (DBI-Ach). Correlations between scales were assessed with weighted kappa coefficients.

Results: Between 31.5 to 46.3% of PD patients were taking medications with anticholinergic properties. Among the scales applied, the ACB produced the highest prevalence of medications with anticholinergic properties (46.3%). Considering only medications with definite anticholinergic activity (scores of 2 or 3 on ACB, ADS, or ARS), the most common anticholinergic drug classes were antiparkinsonian (8.2%), antipsychotic (6.4%), and urological (3.3%) medications. Cholinesterase inhibitors and medications with anticholinergic properties were co-prescribed to 5.4% of the total cohort. The most highly correlated scales were ACB and ADS (κ= 0.71), ACB and ARS (κ= 0.67), and ADS and ARS (κ= 0.55).

Conclusion: A high proportion of PD patients (20%) were either taking antiparkinsonian, urological, or antipsychotic anticholinergic medications or were co-prescribed anticholinergic medications and cholinesterase inhibitors. By virtue of its detection of a high prevalence of anticholinergic medication usage and its high correlation with other scales, our data support use of the ACB scale to assess anticholinergic burden in PD patients.
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http://dx.doi.org/10.3233/JPD-212769DOI Listing
April 2022

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

Mov Disord Clin Pract 2021 Nov 8;8(8):1181-1188. Epub 2021 Oct 8.

Department of Neurology University of Pennsylvania School of Medicine Philadelphia Pennsylvania USA.

The relative importance of antimuscarinic anticholinergic medications for Parkinson's disease (PD) declined after the introduction of levodopa, such that anticholinergic medications are now much more likely to be prescribed for clinical indications other than parkinsonism. Recent studies have found an association between anticholinergic medication exposure and future risk of dementia in older individuals and those with PD. These findings provide a further reason to avoid the use of anticholinergic medications to treat motor symptoms of PD. More importantly, they raise the question of whether one of the goals of PD treatment should be to deprescribe all medications with anticholinergic properties, regardless of their indication, to reduce dementia risk. In this review, we discuss the use of anticholinergic medications in PD, the evidence supporting the association between anticholinergic medications and future dementia risk, and the potential implications of these findings for clinical care in PD.
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http://dx.doi.org/10.1002/mdc3.13347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8564829PMC
November 2021

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

Parkinsonism Relat Disord 2021 09 27;90:27-32. Epub 2021 Jul 27.

Department of Radiology and Medical Imaging, Division of Neuroradiology, University of Virginia Health System, Charlottesville, VA, USA.

Introduction: Impaired olfaction and reduced cholinergic nucleus 4 (Ch4) volume both predict greater cognitive decline in Parkinson's disease (PD). We examined the relationship between olfaction, longitudinal change in cholinergic basal forebrain nuclei and their target regions, and cognition in early PD.

Methods: We analyzed a cohort of 97 PD participants from the Parkinson's Progression Markers Initiative with brain MRIs at baseline, 1 year, 2 years, and 4 years. Using probabilistic maps, regional grey matter density (GMD) was calculated for Ch4, cholinergic nuclei 1, 2, and 3 (Ch123), and their target regions.

Results: Baseline University of Pennsylvania Smell Identification Test score correlated with change in GMD of all regions of interest (all p < 0.05). Rate of change of Ch4 GMD was correlated with rate of change of Ch123 (p = 0.034), cortex (p = 0.001), and amygdala GMD (p < 0.001), but not hippocampus GMD (p = 0.38). Rate of change of Ch123 GMD was correlated with rate of change of cortex (p = 0.001) and hippocampus (p < 0.001), but not amygdala GMD (p = 0.133). In a linear regression model including change in GMD of all regions of interest and age as predictors, change in cortex GMD (βˆ= 38.2; 95 % CI: [0.47, 75.9]) and change in hippocampus GMD (βˆ= 24.8; 95 % CI: [0.80, 48.8]) were significant predictors of Montreal Cognitive Assessment score change over time.

Conclusion: Impaired olfaction is associated with degeneration of the cholinergic basal forebrain and bilateral cortex, amygdala, and hippocampus in PD. The relationship between impaired olfaction and cognitive decline may be mediated by greater atrophy of the cortex and hippocampus.
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http://dx.doi.org/10.1016/j.parkreldis.2021.07.024DOI Listing
September 2021

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

J Geriatr Psychiatry Neurol 2022 Jul 11;35(4):527-534. Epub 2021 Jun 11.

6886Virginia Commonwealth University, Richmond, VA, USA.

Background: Research criteria for prodromal dementia with Lewy bodies (DLB) were published in 2020, but little is known regarding prodromal DLB in clinical settings.

Methods: We identified non-demented participants without neurodegenerative disease from the National Alzheimer's Coordinating Center Uniform Data Set who converted to DLB at a subsequent visit. Prevalence of neuropsychiatric and motor symptoms were examined up to 5 years prior to DLB diagnosis.

Results: The sample included 116 participants clinically diagnosed with DLB and 348 age and sex-matched (1:3) Healthy Controls. Motor slowing was present in approximately 70% of participants 3 years prior to DLB diagnosis. In the prodromal phase, 50% of DLB participants demonstrated gait disorder, 70% had rigidity, 20% endorsed visual hallucinations, and over 50% of participants endorsed REM sleep behavior disorder. Apathy, depression, and anxiety were common prodromal neuropsychiatric symptoms. The presence of 1+ core clinical features of DLB in combination with apathy, depression, or anxiety resulted in the greatest AUC (0.815; 95% CI: 0.767, 0.865) for distinguishing HC from prodromal DLB 1 year prior to diagnosis. The presence of 2+ core clinical features was also accurate in differentiating between groups (AUC = 0.806; 95% CI: 0.756, 0.855).

Conclusion: A wide range of motor, neuropsychiatric and other core clinical symptoms are common in prodromal DLB. A combination of core clinical features, neuropsychiatric symptoms and cognitive impairment can accurately differentiate DLB from normal aging prior to dementia onset.
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http://dx.doi.org/10.1177/08919887211023586DOI Listing
July 2022

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

Mov Disord Clin Pract 2021 May 30;8(4):555-562. Epub 2021 Mar 30.

Department of Neurology Virginia Commonwealth University Richmond Virginia USA.

Background: Huntington disease (HD) is an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. Little is known about the effects of environmental factors on HD symptom onset and severity.

Objective: To evaluate the relationship between education level and age of diagnosis, symptom onset, and symptom severity in HD.

Methods: This study evaluated 4537 adult-onset, motor-manifest HD participants from the Enroll-HD global registry. Education level was assessed using International Standard Classification of Education categories, stratified into three education groups corresponding to pre-secondary, secondary, and post-secondary educational attainment. Motor and behavioral symptoms of HD, cognition, and functional capacity were measured using baseline Unified Huntington's Disease Rating Scale (UHDRS), Mini-Mental State Exam (MMSE), Symbol Digit Modalities Test (SDMT), verbal fluency, and Stroop assessments.

Results: After adjusting for CAG repeats, higher level of education predicted lower age of onset of motor symptoms, depression, irritability, and cognitive impairment (all -values < 0.001). After adjusting for age of enrollment and CAG repeats, the highest education level predicted the lowest UHDRS motor scores, higher UHDRS total functional capacity and functional assessment scores, and higher SDMT, MMSE, verbal fluency, and Stroop assessment scores (all -values < 0.001).

Conclusions: HD participants with higher education levels have earlier age of diagnosis and age of symptom onset, but lower motor exam scores and higher functional assessment scores. Earlier recognition of symptoms in more highly educated participants may explain earlier symptom onset and diagnosis. Better performance on motor and functional assessments may be explained by higher cognitive reserve in those with greater education.
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http://dx.doi.org/10.1002/mdc3.13195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088098PMC
May 2021

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

Neuropsychology 2021 Jul 29;35(5):540-546. Epub 2021 Apr 29.

Center for Neurological Restoration, Neurological Institute, Cleveland Clinic.

Objective: There is substantial heterogeneity in depressive symptomology for individuals with Parkinson's disease (PD). It is unknown whether the Beck Depression Inventory-Second Edition (BDI-II) is capable of identifying such phenotypic variations of depression.

Method: We investigated the factor structure of the BDI-II and its associations with demographic characteristics and other nonmotor symptoms in PD. We reviewed the cases of 236 patients with a confirmed PD diagnosis. Evaluations included the BDI-II, Montreal Cognitive Assessment (MoCA), Apathy Scale (AS), and Geriatric Anxiety Inventory (GAI). We used exploratory structural equation modeling (ESEM) with target rotations as this method integrates aspects of exploratory and confirmatory factor analysis. We conducted hierarchical regressions to assess for associations between the BDI-II factors and gender, age, education, disease duration, cognition, anxiety, and apathy.

Results: ESEM supported the retention of a Somatic factor and an Affective factor that accounted for 53% of the model variance. Model goodness-of-fit measures were within normal limits. Higher AS scores were positively associated with the Somatic and Affective factors. Higher GAI scores were positively associated only with the Affective factor. There were no other significant relationships with factor scores.

Conclusions: This study supports the retention of a two-factor model of the BDI-II in PD. These unique clusters of depressive symptoms in PD can be used to guide clinical decisions about the need for further psychiatric evaluation and the appropriateness of different therapeutic interventions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/neu0000739DOI Listing
July 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.

J Clin Med 2020 Nov 16;9(11). Epub 2020 Nov 16.

Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington's disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington's Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.
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http://dx.doi.org/10.3390/jcm9113682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696926PMC
November 2020

Refractory CIDP: Clinical characteristics, antibodies and response to alternative treatment.

J Neurol Sci 2020 Nov 15;418:117098. Epub 2020 Aug 15.

Department of Neurology, Oregon Health & Science University, Portland, OR, USA. Electronic address:

Objective: To review the clinical characteristics, antibodies, and response to alternative treatments in a cohort of patients with refractory CIDP.

Methods: We reviewed the charts of all CIDP patients seen at the Oregon Health & Science University neuromuscular clinic between 2017 and 2019. We collected demographics, clinical characteristics, antibodies, and response to treatments.

Results: Among 45 CIDP patients studied, 34 (76%) showed improvement with first-line therapy (steroids, IVIG and/or plasmapheresis) and 11 (24%) were considered refractory to first line therapy. Of the latter, 7 of 11 patients (64%) responded to alternative treatment (cyclophosphamide or rituximab). Three were refractory to all treatment. Most patients were ambulatory without aid and a few were in remission. One patient died from complications of alcoholic liver cirrhosis. Thrombosis was seen in three patients receiving IVIG. Six patients (13%) tested positive for Neurofascin (NF) antibodies. Four tested positive for NF155 IgM antibodies only and of those, one responded to IVIG, two partially responded to IVIG and one was refractory. One patient tested positive for NF155 IgG4. Another tested positive for NF155 IgG4 and NF155 IgM. Both patients with IgG4 antibodies were refractory to IVIG, one responded to rituximab and one was refractory to all treatment.

Conclusion: Less than a quarter of our CIDP patients did not respond to steroids, IVIG, and/or plasmapheresis. Most of the refractory patients responded to rituximab or cyclophosphamide. Patients with IgG4 NF antibodies were resistant to IVIG. The majority of refractory CIDP patients were seronegative and disease management relied on clinical judgement.
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http://dx.doi.org/10.1016/j.jns.2020.117098DOI Listing
November 2020

Cholinergic nucleus 4 atrophy and gait impairment in Parkinson's disease.

J Neurol 2021 Jan 28;268(1):95-101. Epub 2020 Jul 28.

Department of Neurology, University of Virginia, 1221 Lee St 4th Floor, Charlottesville, VA, 22908, USA.

Background: There is evidence that cortical cholinergic denervation contributes to gait and balance impairment in Parkinson's Disease (PD), especially reduced gait speed.

Objectives: The objective of this study was to determine the relationship between cholinergic basal forebrain gray matter density (GMD) and gait in PD patients.

Methods: We investigated 66 PD patients who underwent a pre-surgical evaluation for a neurosurgical procedure to treat motor symptoms of PD. As part of this evaluation patients had a brain MRI and formal gait assessments. By applying probabilistic maps of the cholinergic basal forebrain to voxel-based morphometry of brain MRI, we calculated gray matter density (GMD) for cholinergic nucleus 4 (Ch4), cholinergic nucleus 1, 2, and 3 (Ch123), and the entire cortex.

Results: Reduced Ch4 GMD was associated with reduced Fast Walking Speed in the "on" medication state (FWSON, p = 0.004). Bilateral cortical GMD was also associated with FWSON (p = 0.009), but Ch123 GMD was not (p = 0.1). Bilateral cortical GMD was not associated with FWSON after adjusting for Ch4 GMD (p = 0.44). While Ch4 GMD was not associated with improvement in Timed Up and Go (TUG) or Cognitive TUG in the "on" medication state, reduced Ch4 GMD was associated with greater percent worsening based on dual tasks (p = 0.021).

Conclusions: Reduced Ch4 GMD is associated with slower gait speed in PD and greater percent worsening in TUG during dual tasks in patients with PD. These findings have implications for planning of future clinical trials investigating cholinergic therapies to improve gait impairment in PD.
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http://dx.doi.org/10.1007/s00415-020-10111-2DOI Listing
January 2021

Cytoarchitectonic Mapping of MRI Detects Rapid Changes in Alzheimer's Disease.

Front Neurol 2020 30;11:241. Epub 2020 Apr 30.

Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, VA, United States.

The clinical and pathological progression of Alzheimer's disease often proceeds rapidly, but little is understood about its structural characteristics over short intervals. This study evaluated the short temporal characteristics of the brain structure in Alzheimer's disease through the application of cytoarchitectonic probabilistic brain mapping to measurements of gray matter density, a technique which may provide advantages over standard volumetric MRI techniques. Gray matter density was calculated using voxel-based morphometry of T1-weighted MRI obtained from Alzheimer's disease patients and healthy controls evaluated at intervals of 0.5, 1.5, 3.5, 6.5, 9.5, 12, 18, and 24 months by the MIRIAD study. The Alzheimer's disease patients had 19.1% less gray matter at 1st MRI, and this declined 81.6% faster than in healthy controls. Atrophy in the hippocampus, amygdala, and basal forebrain distinguished the Alzheimer's disease patients. Notably, the CA2 of the hippocampus was found to have atrophied significantly within 1 month. Gray matter density measurements were reliable, with intraclass correlation coefficients exceeding 0.8. Comparative atrophy in the Alzheimer's disease group agreed with manual tracing MRI studies of Alzheimer's disease while identifying atrophy on a shorter time scale than has previously been reported. Cytoarchitectonic mapping of gray matter density is reliable and sensitive to small-scale neurodegeneration, indicating its use in the future study of Alzheimer's disease.
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http://dx.doi.org/10.3389/fneur.2020.00241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203491PMC
April 2020

Neuropsychiatric symptoms and cognitive abilities over the initial quinquennium of Parkinson disease.

Ann Clin Transl Neurol 2020 04 13;7(4):449-461. Epub 2020 Apr 13.

Departments of Neurology and Psychiatry & Behavioral Sciences, Baylor College of Medicine, Houston, Texas.

Objective: To determine the evolution of numerous neuropsychiatric symptoms and cognitive abilities in Parkinson disease from disease onset.

Methods: Prospectively collected, longitudinal (untreated, disease onset to year 5), observational data from Parkinson's Progression Markers Initiative annual visits was used to evaluate prevalence, correlates, and treatment of 10 neuropsychiatric symptoms and cognitive impairment in Parkinson disease participants and matched healthy controls.

Results: Of 423 Parkinson disease participants evaluated at baseline, 315 (74.5%) were assessed at year 5. Eight neuropsychiatric symptoms studied increased in absolute prevalence by 6.2-20.9% at year 5 relative to baseline, and cognitive impairment increased by 2.7-6.2%. In comparison, the frequency of neuropsychiatric symptoms in healthy controls remained stable or declined over time. Antidepressant and anxiolytic/hypnotic use in Parkinson disease were common at baseline and increased over time (18% to 27% for the former; 13% to 24% for the latter); antipsychotic and cognitive-enhancing medication use was uncommon throughout (2% and 5% of patients at year 5); and potentially harmful anticholinergic medication use was common and increased over time. At year 5 the cross-sectional prevalence for having three or more neuropsychiatric disorders/cognitive impairment was 56% for Parkinson disease participants versus 13% for healthy controls, and by then seven of the examined disorders had either occurred or been treated at some time point in the majority of Parkinson disease patients. Principal component analysis suggested an affective disorder subtype only.

Interpretation: Neuropsychiatric features in Parkinson disease are common from the onset, increase over time, are frequently comorbid, and fluctuate in severity.
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http://dx.doi.org/10.1002/acn3.51022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187707PMC
April 2020

Randomized, Controlled Trial of Exercise on Objective and Subjective Sleep in Parkinson's Disease.

Mov Disord 2020 06 24;35(6):947-958. Epub 2020 Feb 24.

Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Background: Sleep dysfunction is common and disabling in persons with Parkinson's Disease (PD). Exercise improves motor symptoms and subjective sleep quality in PD, but there are no published studies evaluating the impact of exercise on objective sleep outcomes. The goal of this study was to to determine if high-intensity exercise rehabilitation combining resistance training and body-weight interval training, compared with a sleep hygiene control improved objective sleep outcomes in PD.

Methods: Persons with PD (Hoehn & Yahr stages 2-3; aged ≥45 years, not in a regular exercise program) were randomized to exercise (supervised 3 times a week for 16 weeks; n = 27) or a sleep hygiene, no-exercise control (in-person discussion and monthly phone calls; n = 28). Participants underwent polysomnography at baseline and post-intervention. Change in sleep efficiency was the primary outcome, measured from baseline to post-intervention. Intervention effects were evaluated with general linear models with measurement of group × time interaction. As secondary outcomes, we evaluated changes in other aspects of sleep architecture and compared the effects of acute and chronic training on objective sleep outcomes.

Results: The exercise group showed significant improvement in sleep efficiency compared with the sleep hygiene group (group × time interaction: F = 16.0, P < 0.001, d = 1.08). Other parameters of sleep architecture also improved in exercise compared with sleep hygiene, including total sleep time, wake after sleep onset, and slow-wave sleep. Chronic but not acute exercise improved sleep efficiency compared with baseline.

Conclusions: High-intensity exercise rehabilitation improves objective sleep outcomes in PD. Exercise is an effective nonpharmacological intervention to improve this disabling nonmotor symptom in PD. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8826749PMC
June 2020

Brain MRI Reveals Ascending Atrophy in Parkinson's Disease Across Severity.

Front Neurol 2019 18;10:1329. Epub 2019 Dec 18.

Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, VA, United States.

Models which assess the progression of Lewy pathology in Parkinson's disease have proposed ascending spread in a caudal-rostral pattern. human evidence for this theory is limited, in part because there are no biomarkers that allow for direct assessment of Lewy pathology. Here, we measured neurodegeneration via MRI, an outcome which may serve as a proxy for a more direct assessment of ascending models using a combination of (1) MRI-based measures of gray matter density and (2) regions of interest (ROIs) corresponding to cortical and subcortical loci implicated in past MRI and stereological studies of Parkinson's disease. Gray matter density was measured using brain MRI voxel-based morphometry from three cohorts: (1) early Parkinson's disease, (2) more advanced Parkinson's disease and (3) healthy controls. Early Parkinson's disease patients ( = 228, mean age = 61.9 years, mean disease duration = 0.6 years) were newly diagnosed by the Parkinson's Progression Markers Initiative (PPMI). Advanced Parkinson's disease patients ( = 136, mean age = 63.5 years, mean disease duration = 8.0 years) were collected retrospectively from a local cohort undergoing evaluation for functional neurosurgery. Control subjects ( = 103, mean age = 60.2 years) were from PPMI. Comparative analyses focused on gray matter regions ranging from deep gray subcortical structures to the neocortex. ROIs were defined with existing probabilistic cytoarchitectonic brain maps. For subcortical regions of the basal forebrain, amygdala, and entorhinal cortex, advanced Parkinson's disease patients had significantly lower gray matter density when compared to both early Parkinson's disease and healthy controls. No differences were seen in neocortical regions that are "higher" in any proposed ascending pattern. Across early and advanced Parkinson's disease, gray matter density from nearly all subcortical regions significantly decreased with disease duration; no neocortical regions showed this effect. These results demonstrate that atrophy in advanced Parkinson's patients compared to early patients and healthy controls is largely confined to subcortical gray matter structures. The degree of atrophy in subcortical brain regions was linked to overall disease duration, suggesting an organized pattern of atrophy across severity.
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http://dx.doi.org/10.3389/fneur.2019.01329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930693PMC
December 2019

Therapeutic approaches to cholinergic deficiency in Lewy body diseases.

Expert Rev Neurother 2020 01 12;20(1):41-53. Epub 2019 Oct 12.

Department of Neurosurgery, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.

: Cortical cholinergic denervation resulting from degeneration of the nucleus basalis of Meynert (NBM) is a primary contributor to cognitive impairment and neuropsychiatric symptoms in the Lewy body diseases Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB). Considering the morbidity associated with cognitive impairment and neuropsychiatric symptoms in these diseases, it is important to investigate all potential therapies to improve these symptoms.: The authors review the current landscape of pharmacological and surgical therapies for mitigating the cortical cholinergic deficiency in PD, PDD, and DLB.: The cholinesterase inhibitors rivastigmine, donepezil, and galantamine are currently the primary pharmacological treatments available to improve cognition and associated neuropsychiatric symptoms in Lewy body diseases. Other possible pharmacological strategies include increasing acetylcholine release with 5-HT agonists or directly stimulating cholinergic receptors with muscarinic and nicotinic agonists. The side effect profile of muscarinic agonists is a deterrent to their future study, but 5-HT and nicotinic agonists deserve further investigation. Targeting the basal forebrain with either deep brain stimulation (DBS)- or cell-based therapies is another strategy to mitigate cortical cholinergic deficiency. Before NBM DBS studies continue, it will be important to resolve issues related to targeting, stimulation pattern, and duration.
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http://dx.doi.org/10.1080/14737175.2020.1676152DOI Listing
January 2020

Comparison of Parkinson's Disease Patients' Characteristics by Indication for Deep Brain Stimulation: Men Are More Likely to Have DBS for Tremor.

Tremor Other Hyperkinet Mov (N Y) 2019 17;9. Epub 2019 Sep 17.

Department of Neurology, University of Virginia, Charlottesville, VA, USA.

Background: We investigated whether the characteristics of Parkinson's disease (PD) patients differ based on the primary indication for deep brain stimulation (DBS).

Methods: We reviewed data for 149 consecutive PD patients who underwent DBS at the University of Virginia. Patients were categorized based on primary surgical indication, and clinical characteristics were compared between groups.

Results: Twenty-nine (93.5%) of 31 PD patients who underwent DBS for medication refractory tremor were men, and 66 (62.3%) of 106 PD patients who underwent DBS for motor fluctuations were men (p = 0.001). Other primary indications for DBS were tremor and fluctuations ( = 5), medication intolerance ( = 5), and dystonia ( = 2).

Discussion: Patients who underwent DBS for medication refractory tremor were predominantly men, while patients who had DBS for motor fluctuations approximated the gender distribution of PD. Possible explanations are that men with PD are more likely to develop medication refractory tremor or undergo surgery for medication refractory tremor in PD compared to women.
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http://dx.doi.org/10.7916/tohm.v0.676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749750PMC
March 2020

Red blood cells stabilize flow in brain microvascular networks.

PLoS Comput Biol 2019 08 30;15(8):e1007231. Epub 2019 Aug 30.

Institute of Fluid Dynamics, ETH Zurich, Sonneggstrasse 3, Zurich, Switzerland.

Capillaries are the prime location for oxygen and nutrient exchange in all tissues. Despite their fundamental role, our knowledge of perfusion and flow regulation in cortical capillary beds is still limited. Here, we use in vivo measurements and blood flow simulations in anatomically accurate microvascular network to investigate the impact of red blood cells (RBCs) on microvascular flow. Based on these in vivo and in silico experiments, we show that the impact of RBCs leads to a bias toward equating the values of the outflow velocities at divergent capillary bifurcations, for which we coin the term "well-balanced bifurcations". Our simulation results further reveal that hematocrit heterogeneity is directly caused by the RBC dynamics, i.e. by their unequal partitioning at bifurcations and their effect on vessel resistance. These results provide the first in vivo evidence of the impact of RBC dynamics on the flow field in the cortical microvasculature. By structural and functional analyses of our blood flow simulations we show that capillary diameter changes locally alter flow and RBC distribution. A dilation of 10% along a vessel length of 100 μm increases the flow on average by 21% in the dilated vessel downstream a well-balanced bifurcation. The number of RBCs rises on average by 27%. Importantly, RBC up-regulation proves to be more effective the more balanced the outflow velocities at the upstream bifurcation are. Taken together, we conclude that diameter changes at capillary level bear potential to locally change the flow field and the RBC distribution. Moreover, our results suggest that the balancing of outflow velocities contributes to the robustness of perfusion. Based on our in silico results, we anticipate that the bi-phasic nature of blood and small-scale regulations are essential for a well-adjusted oxygen and energy substrate supply.
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http://dx.doi.org/10.1371/journal.pcbi.1007231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750893PMC
August 2019

Lower volume, more impairment: reduced cholinergic basal forebrain grey matter density is associated with impaired cognition in Parkinson disease.

J Neurol Neurosurg Psychiatry 2019 11 7;90(11):1251-1256. Epub 2019 Jun 7.

Radiology and Medical Imaging, University of Virginia, Charlottesville, Virginia, USA.

Objective: A major contributor to dementia in Parkinson disease (PD) is degeneration of the cholinergic basal forebrain. This study determined whether cholinergic nucleus 4 (Ch4) density is associated with cognition in early and more advanced PD.

Methods: We analysed brain MRIs and neuropsychological test scores for 228 newly diagnosed PD participants from the Parkinson's Progression Markers Initiative (PPMI), 101 healthy controls from the PPMI and 125 more advanced PD patients from a local retrospective cohort. Cholinergic basal forebrain nuclei densities were determined by applying probabilistic maps to MPRAGE T1 sequences processed using voxel-based morphometry methods. Relationships between grey matter densities and cognitive scores were analysed using correlations and linear regression models.

Results: In more advanced PD, greater Ch4 density was associated with Montreal Cognitive Assessment (MoCA) score (β=14.2; 95% CI=1.5 to 27.0; p=0.03), attention domain z-score (β=3.2; 95% CI=0.8 to 5.5; p=0.008) and visuospatial domain z-score (β=7.9; 95% CI=2.0 to 13.8; p=0.009). In the PPMI PD cohort, higher Ch4 was associated with higher scores on MoCA (β=9.2; 95% CI=1.9 to 16.5; p=0.01), Judgement of Line Orientation (β=20.4; 95% CI=13.8 to 27.0; p<0.001), Letter Number Sequencing (β=16.5; 95% CI=9.5 to 23.4; p<0.001) and Symbol Digit Modalities Test (β=41.8; 95% CI=18.7 to 65.0; p<0.001). These same relationships were observed in 97 PPMI PD participants at 4 years. There were no significant associations between Ch4 density and cognitive outcomes in healthy controls.

Conclusion: In de novo and more advanced PD, lower Ch4 density is associated with impaired global cognition, attention and visuospatial function.
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http://dx.doi.org/10.1136/jnnp-2019-320450DOI Listing
November 2019

Predictors of health-related quality of life in Parkinson's disease.

Parkinsonism Relat Disord 2019 08 7;65:86-90. Epub 2019 May 7.

Department of Neurology, University of Virginia, Charlottesville, VA, USA.

Background: Health-related quality of life in Parkinson's disease may be affected by a wide range of motor and non-motor symptoms. Identifying which symptoms are significant predictors of health-related quality of life in Parkinson's disease prioritizes symptoms for treatment, therapeutic development, and clinical outcomes.

Objectives: To determine predictors of health-related quality of life in patients with Parkinson's disease.

Methods: We recruited 102 subjects into a prospective study to investigate neuropsychiatric symptoms in Parkinson's disease. Health-related quality of life was measured with the 39-item Parkinson's Disease Questionnaire. Subjects completed the Movement Disorder Society Unified Parkinson's Disease Rating Scale Parts I-IV as well as validated scales to assess anxiety, depression, apathy, cognition, psychosis, impulsive-compulsive disorder, autonomic dysfunction, sleep quality, excessive daytime sleepiness, and rapid eye movement sleep behavior disorder. We used univariate analyses to select clinical predictors to construct a multivariate regression model to determine which predictors were independently associated with worse health-related quality of life.

Results: In a multivariate linear regression model adjusted for age and gender, higher scores for the International Parkinson and Movement Disorder Society Unified Parkinson's Disease Rating Scale part II as well more severe symptoms of depression, anxiety, apathy, and excessive daytime sleepiness were associated with worse health-related quality of life. The model explained 78% of the variance of health-related quality of life, and the non-motor symptoms explained 49% of the variance.

Conclusions: Anxiety, depression, excessive daytime sleepiness, apathy, and impairment in activities of daily living related to motor symptoms were independently associated with worse health-related quality of life.
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http://dx.doi.org/10.1016/j.parkreldis.2019.05.009DOI Listing
August 2019

Oxyphor 2P: A High-Performance Probe for Deep-Tissue Longitudinal Oxygen Imaging.

Cell Metab 2019 03 24;29(3):736-744.e7. Epub 2019 Jan 24.

Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Quantitative imaging of oxygen distributions in tissue can provide invaluable information about metabolism in normal and diseased states. Two-photon phosphorescence lifetime microscopy (2PLM) has been developed to perform measurements of oxygen in vivo with micron-scale resolution in 3D; however, the method's potential has not yet been fully realized due to the limitations of current phosphorescent probe technology. Here, we report a new sensor, Oxyphor 2P, that enables oxygen microscopy twice as deep (up to 600 μm below the tissue surface) and with ∼60 times higher speed than previously possible. Oxyphor 2P allows longitudinal oxygen measurements without having to inject the probe directly into the imaged region. As proof of principle, we monitored oxygen dynamics for days following micro-stroke induced by occlusion of a single capillary in the mouse brain. Oxyphor 2P opens up new possibilities for studies of tissue metabolic states using 2PLM in a wide range of biomedical research areas.
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http://dx.doi.org/10.1016/j.cmet.2018.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402963PMC
March 2019

Clinical and demographic correlates of apathy in Parkinson's disease.

J Neurol 2019 Feb 2;266(2):507-514. Epub 2019 Jan 2.

Department of Neurology, University of Virginia, PO Box 800394, 22908-0394, Charlottesville, VA, USA.

Objective: To better understand the demographic, neuropsychiatric, cognitive, and motor predictors of apathy in Parkinson's disease (PD).

Method: 112 participants (M = 68.53 years; M = 6.17 years) were administered the Apathy Scale (AS), Beck Depression Inventory-II (BDI-II), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Trail Making Test (TMT), Wechsler Adult Intelligence Scale-IV Matrix Reasoning subtest, letter (F-A-S) and category (Animals) fluency, and Hopkins Verbal Learning Test-Revised. Psychosis was assessed. A stepwise logistic regression analysis was performed to investigate the ability of demographic factors and clinical assessments to predict nonapathetic (AS ≤ 13) versus apathetic (AS > 13) group membership.

Results: The regression analysis yielded a robust model in which older age, less education, elevated BDI-II, current psychosis, higher MDS-UPDRS Part III (motor score), and slower TMT-B performance predicted membership in the apathetic group, with a correct classification rate of 77.5% (Nagelkerke R = 0.48, p < .001). Depression (OR = 9.20, p < .001) and education (OR = 0.66, p = 0.002) contributed significantly to the overall model. A linear regression with AS score as the outcome variable was similar, but TMT-B additionally contributed significantly (p = 0.02) to the overall model, F(6, 86) = 12.02, p < .001, adjusted R = 0.42.

Conclusions: Of the factors examined, depression, education, and executive functioning were the strongest correlates of apathy in PD. These results support the idea that common underlying frontosubcortical disruptions in this population contribute to apathy, depression, and executive dysfunction.
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http://dx.doi.org/10.1007/s00415-018-9166-3DOI Listing
February 2019

Accelerated, first-pass cardiac perfusion pulse sequence with radial k-space sampling, compressed sensing, and k-space weighted image contrast reconstruction tailored for visual analysis and quantification of myocardial blood flow.

Magn Reson Med 2019 04 12;81(4):2632-2643. Epub 2018 Nov 12.

Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: To develop an accelerated cardiac perfusion pulse sequence and test whether it is capable of increasing spatial coverage, generating high-quality images, and enabling quantification of myocardial blood flow (MBF).

Methods: We implemented an accelerated first-pass cardiac perfusion pulse sequence by combining radial k-space sampling, compressed sensing (CS), and k-space weighted image contrast (KWIC) filtering. The proposed and clinical standard pulse sequences were evaluated in a randomized order in 13 patients at rest. For visual analysis, 3 readers graded the conspicuity of wall enhancement, artifact, and noise level on a 5-point Likert scale (overall score index = sum of 3 individual scores). Resting MBF was calculated using a Fermi function model with and without KWIC filtering. Mean visual scores and MBF values were compared between sequences using appropriate statistical tests.

Results: The proposed pulse sequence produced greater spatial coverage (6-8 slices) with higher spatial resolution (1.6 × 1.6 × 8 mm ) and shorter readout duration (78 ms) compared to clinical standard (3-4 slices, 3 × 3 × 8 mm , 128 ms, respectively). The overall image score index between accelerated (11.1 ± 1.3) and clinical standard (11.2 ± 1.3) was not significantly different (P = 0.64). Mean resting MBF values with KWIC filtering (0.9-1.2 mL/g/min across different slices) were significantly lower (P < 0.0001) than those without KWIC filtering (3.1-4.3 mL/g/min) and agreed better with values reported in literature.

Conclusion: An accelerated, first-pass cardiac perfusion pulse sequence with radial k-space sampling, CS, and KWIC filtering is capable of increasing spatial coverage, generating high-quality images, and enabling quantification of MBF.
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http://dx.doi.org/10.1002/mrm.27573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372310PMC
April 2019

Intravitreal AAV-Delivery of Genetically Encoded Sensors Enabling Simultaneous Two-Photon Imaging and Electrophysiology of Optic Nerve Axons.

Front Cell Neurosci 2018 23;12:377. Epub 2018 Oct 23.

Institute of Pharmacology & Toxicology, University of Zurich, Zurich, Switzerland.

Myelination of axons by oligodendrocytes is a key feature of the remarkably fast operating CNS. Oligodendrocytes not only tune axonal conduction speed but are also suggested to maintain long-term axonal integrity by providing metabolic support to the axons they ensheath. However, how myelinating oligodendrocytes impact axonal energy homeostasis remains poorly understood and difficult to investigate. Here, we provide a method of how to study electrically active myelinated axons expressing genetically encoded sensors by combining electrophysiology and two-photon imaging of acutely isolated optic nerves. We show that intravitreal adeno-associated viral (AAV) vector delivery is an efficient tool to achieve functional sensor expression in optic nerve axons, which is demonstrated by measuring axonal ATP dynamics following AAV-mediated sensor expression. This novel approach allows for fast expression of any optical sensor of interest to be studied in optic nerve axons without the need to go through the laborious process of producing new transgenic mouse lines. Viral-mediated biosensor expression in myelinated axons and the subsequent combination of nerve recordings and sensor imaging outlines a powerful method to investigate oligodendroglial support functions and to further interrogate cellular mechanisms governing axonal energy homeostasis under physiological and pathological conditions.
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http://dx.doi.org/10.3389/fncel.2018.00377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205974PMC
October 2018

The Relation Between Capillary Transit Times and Hemoglobin Saturation Heterogeneity. Part 2: Capillary Networks.

Front Physiol 2018 21;9:1296. Epub 2018 Sep 21.

Department of Mechanical and Process Engineering, Institute of Fluid Dynamics, ETH Zürich, Zurich, Switzerland.

Brain metabolism is highly dependent on continuous oxygen supply. Cortical microvascular networks exhibit heterogeneous blood flow, leading to non-uniform tissue oxygenation and capillary hemoglobin saturation. We recently proposed capillary outflow saturation heterogeneity (COSH) to represent effects of heterogeneity on oxygen supply to tissue regions most vulnerable to hypoxia, and showed that diffusive oxygen exchange among red blood cells within capillaries and among capillaries (diffusive interaction) significantly reduces COSH in simplified geometrical configurations. Here, numerical simulations of oxygen transport in capillary network geometries derived from mouse somatosensory cortex are presented. Diffusive interaction was found to reduce COSH by 41 to 62% compared to simulations where diffusive interaction was excluded. Hemoglobin saturation drop across the microvascular network is strongly correlated with red blood cell transit time, but the coefficient of variation of saturation drop is approximately one third lower. Unexpectedly, the radius of the tissue cylinder supplied by a capillary correlates weakly with the anatomical tissue cylinder radius, but strongly with hemoglobin saturation. Thus, diffusive interaction contributes greatly to the microcirculation's ability to achieve tissue oxygenation, despite heterogeneous capillary transit time and hematocrit distribution. These findings provide insight into the effects of cerebral small vessel disease on tissue oxygenation and brain function.
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http://dx.doi.org/10.3389/fphys.2018.01296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160581PMC
September 2018

Focused ultrasound thalamotomy in Parkinson disease: Nonmotor outcomes and quality of life.

Neurology 2018 10 29;91(14):e1275-e1284. Epub 2018 Aug 29.

From the Departments of Neurology (S.A.S., B.B.S., M.J.B.), Neurosurgery (A.E.B., W.J.E.), and Physical Therapy (D.S.H.), University of Virginia Health Science Center, Charlottesville; and College of Arts and Sciences (J.A.G.M.), University of Virginia, Charlottesville.

Objective: To examine nonmotor outcomes and correlates of quality of life (QoL) 3 and 12 months after unilateral focused ultrasound thalamotomy in tremor-dominant Parkinson disease (TDPD).

Methods: Twenty-seven patients with TDPD in a double-blind, sham-controlled, randomized clinical trial underwent comprehensive neuropsychological evaluations. These included assessment of mood, behavior, and QoL at baseline, 3 months, 3 months post crossover in the sham group, and 12 months after active treatment. We used Mann-Whitney tests to assess differences between the active (n = 20) and sham (n = 7) groups at 3 months and Friedman tests to assess within-group changes after active treatment. We assessed correlations between disease variables and postoperative QoL using Kendall tau-b tests.

Results: There were no differences in cognition, mood, or behavior between the active and sham groups at 3-month blinded assessment. After active treatment, there were no differences in mood or behavior. Only declines in Stroop Color Naming and phonemic fluency were observed. Patients experienced postoperative improvements in QoL and activities of daily living (ADL). Mood and behavioral symptoms, aspects of cognitive functioning, ADL, and overall motor symptom severity, but not tremor severity specifically, were associated with QoL.

Conclusions: In TDPD, unilateral focused ultrasound thalamotomy appears safe from a cognitive, mood, and behavioral perspective. QoL and ADL significantly improved following surgery. Nonmotor symptoms and ADL were more closely associated with QoL than tremor severity.

Classification Of Evidence: This study provides Class II evidence that for patients with TDPD, unilateral focused ultrasound thalamotomy did not adversely change cognition, mood, or behavior at 3 months.
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http://dx.doi.org/10.1212/WNL.0000000000006279DOI Listing
October 2018

Typical features of Parkinson disease and diagnostic challenges with microdeletion 22q11.2.

Neurology 2018 06 11;90(23):e2059-e2067. Epub 2018 May 11.

From The Dalglish Family 22q Clinic for Adults and Department of Psychiatry (E.B., A.M.F., A.S.B.), Toronto General Research Institute (A.S.B.), and Division of Cardiology, Department of Medicine (A.S.B.), University Health Network, Toronto, Canada; De Hartekamp Groep (E.B.), Centre for People with Intellectual Disability, Haarlem; Department of Nuclear Medicine (E.B., J.B.), Academic Medical Center, Amsterdam, the Netherlands; Clinical Genetics Research Program and Campbell Family Mental Health Research Institute (N.J.B., A.M.F., A.S.B.), Centre for Addiction and Mental Health, Toronto; Institute of Medical Science (N.J.B., M.M., A.E.L., A.S.B.), Division of Neurology, Department of Medicine (C.M., M.M., A.E.L.), and Department of Psychiatry (A.S.B.), University of Toronto; Deer Lodge Movement Disorders Centre (S.U.); Section of Neurology (S.U.), Division of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg; Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease Research (C.M., A.E.L.), Toronto Western Hospital and University of Toronto, Canada; Department of Molecular Neuroscience (K.Y.M., N.W.W.), UCL Institute of Neurology, London, UK; Department of Neurology (S.K.), Kansai Medical University, Osaka, Japan; Department of Neurology (M.J.B.), University of Virginia School of Medicine, Charlottesville; Medical Genetics Unit (P.P.), Perugia University Hospital, Italy; Department of Neurology (B.D.B.), University of Colorado Anschutz Medical Campus, Aurora; Neurology Section (B.D.B.), VA Eastern Colorado Health Care System, Denver; Cognitive & Movement Disorders Clinic and Hurvitz Brain Sciences Research Program (M.M.), Sunnybrook Health Sciences Centre, Toronto, Canada; Departments of Clinical Neurosciences (Movement Disorders) (B.D.) and Genetics (Neurogenetics) (K.N.), Timone University Hospital (AP-HM), Provence-Alpes-Côte d'Azur; Aix-Marseille University (B.D., K.N.), Marseille; Department of Genetics (Neurogenetics) (P.C., A.J.), Pitié-Salpêtrière University Hospital; Sorbonne University (P.C., A.J.), Paris; Department of Neurosciences (Movement Disorders) (E.M.), Lille University Hospital; Lille University (E.M.); Department of Neurology (Movement Disorders) (T.D.), Pierre Wertheimer University Hospital, Lyon; Marc Jeannerod Center for Cognitive Neurosciences (T.D.), Lyon-1 University; Department of Neurology (Movement Disorders) and Clinical Investigation Center (Clinical and Experimental Neurosciences) (O.C.), Poitiers University Hospital; Department of Neurology (Movement Disorders) (S.D.), Rennes University Hospital; Rennes-1 University (S.D.); Department of Clinical Neurosciences (Movement Disorders) (M.B.), Nice University Hospital, France; Department of Psychiatry (A.M.F.), Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, the Netherlands; Center for Human Genetics (E.V., A.S., A.V.), University Hospital Leuven; Department of Human Genetics (A.S.), KU Leuven, Belgium; Department of Neurology (A.P.), University of Munich, Germany; Scientific and Technological Coordination Unit of the ANLIS Directorate (C.P.), National Administration of Laboratories and Institutes of Health, Argentina; Department of Neurodegenerative Diseases (T.G.), Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen; German Center for Neurodegenerative Diseases (DZNE) (T.G.); Department of Neurology (K.C.), AZ Turnhout, Antwerp, Belgium; Neurology Unit and Stroke Center (F.B.), Hôpital Foch, Suresnes, France; Movement Disorder Division (K.M.), Johns Hopkins University, Baltimore, MD; and Psychological Medicine and Clinical Neurosciences (N.M.W.), MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, UK.

Objective: To delineate the natural history, diagnosis, and treatment response of Parkinson disease (PD) in individuals with 22q11.2 deletion syndrome (22q11.2DS), and to determine if these patients differ from those with idiopathic PD.

Methods: In this international observational study, we characterized the clinical and neuroimaging features of 45 individuals with 22q11.2DS and PD (mean follow-up 7.5 ± 4.1 years).

Results: 22q11.2DS PD had a typical male excess (32 male, 71.1%), presentation and progression of hallmark motor symptoms, reduced striatal dopamine transporter binding with molecular imaging, and initial positive response to levodopa (93.3%). Mean age at motor symptom onset was relatively young (39.5 ± 8.5 years); 71.4% of cases had early-onset PD (<45 years). Despite having a similar age at onset, the diagnosis of PD was delayed in patients with a history of antipsychotic treatment compared with antipsychotic-naive patients (median 5 vs 1 year, = 0.001). Preexisting psychotic disorders (24.5%) and mood or anxiety disorders (31.1%) were common, as were early dystonia (19.4%) and a history of seizures (33.3%).

Conclusions: Major clinical characteristics and response to standard treatments appear comparable in 22q11.2DS-associated PD to those in idiopathic PD, although the average age at onset is earlier. Importantly, treatment of preexisting psychotic illness may delay diagnosis of PD in 22q11.DS patients. An index of suspicion and vigilance for complex comorbidity may assist in identifying patients to prioritize for genetic testing.
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http://dx.doi.org/10.1212/WNL.0000000000005660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993183PMC
June 2018

Cortical Circuit Activity Evokes Rapid Astrocyte Calcium Signals on a Similar Timescale to Neurons.

Neuron 2018 05 26;98(4):726-735.e4. Epub 2018 Apr 26.

Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Electronic address:

Sensory stimulation evokes intracellular calcium signals in astrocytes; however, the timing of these signals is disputed. Here, we used novel combinations of genetically encoded calcium indicators for concurrent two-photon imaging of cortical astrocytes and neurons in awake mice during whisker deflection. We identified calcium responses in both astrocyte processes and endfeet that rapidly followed neuronal events (∼120 ms after). These fast astrocyte responses were largely independent of IPR2-mediated signaling and known neuromodulator activity (acetylcholine, serotonin, and norepinephrine), suggesting that they are evoked by local synaptic activity. The existence of such rapid signals implies that astrocytes are fast enough to play a role in synaptic modulation and neurovascular coupling. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.neuron.2018.03.050DOI Listing
May 2018

Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease.

Neurology 2018 05 4;90(18):e1618-e1626. Epub 2018 Apr 4.

From the Departments of Neurology (M.J.B., S.A.S.) and Public Health Sciences (M.E.S.), University of Virginia; and Department of Radiology and Medical Imaging (J.C.B., T.J.D.), Division of Neuroradiology, University of Virginia Health System, Charlottesville.

Objective: Determining baseline predictors of future psychosis in Parkinson disease (PD) may identify those at risk for more rapidly progressive disease, i.e., a more malignant PD subtype.

Methods: This cohort study evaluated 423 patients with newly diagnosed PD collected as part of the Parkinson's Progression Markers Initiative. Psychotic symptoms were assessed with the Movement Disorders Society-Unified Parkinson Disease Rating Scale item 1.2, which assesses hallucinations and psychosis over the past week. At baseline, participants completed the Scales for Outcomes in Parkinson's Disease-Autonomic, the REM Sleep Behavior Disorder (RBD) Screening Questionnaire, and the Epworth Sleepiness Scale. Cholinergic nucleus 4 (Ch4) density was calculated for 228 participants with PD and 101 healthy controls.

Results: Multivariate logistic regression adjusted for age and sex found that greater autonomic symptoms ( = 0.002), RBD ( = 0.021), and excessive daytime sleepiness (EDS) ( = 0.003) at baseline were associated with increased risk of reporting psychotic symptoms on ≥2 occasions. Having 2 or 3 of these baseline symptoms was associated with lower Ch4 density ( = 0.007). In a logistic regression model adjusted for age and sex, higher Ch4 gray matter density was associated with lower risk of reporting psychotic symptoms on ≥2 occasions (odds ratio 0.96 [for an increase in density of 1 unit], = 0.03).

Conclusions: This study confirms that RBD, EDS, and greater autonomic symptom burden are associated with greater risk of future psychotic symptoms in PD. Reduced Ch4 density at baseline is associated with future psychotic symptoms and a greater burden of RBD, EDS, and autonomic symptoms.
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http://dx.doi.org/10.1212/WNL.0000000000005421DOI Listing
May 2018
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