Publications by authors named "Irene Litvan"

208 Publications

Semantic Recollection in Parkinson's Disease: Functional Reconfiguration and MAPT Variants.

Front Aging Neurosci 2021 20;13:727057. Epub 2021 Sep 20.

Research and Radiology Services, VA San Diego Healthcare System, San Diego, CA, United States.

Decline in semantic cognition in early stages of Parkinson's disease (PD) is a leading risk factor for future dementia, yet the underlying neural mechanisms are not understood. The present study addressed this gap by investigating the functional connectivity of regions involved in semantic recollection. We further examined whether microtubule-associated protein tau (MAPT) risk variants, which may accelerate cognitive decline, altered the strength of regional functional connections. Cognitively normal PD and healthy elder controls underwent fMRI while performing a fame-discrimination task, which activates the semantic network. Analyses focused on disturbances in fame-modulated functional connectivity in PD for regions that govern semantic recollection and interrelated processes. Group differences were found in multiple connectivity features, which were reduced into principal components that reflected the strength of fame-modulated regional couplings with other brain areas. Despite the absence of group differences in semantic cognition, two aberrant connectivity patterns were uncovered in PD. One pattern was related to a loss in frontal, parietal, and temporal connection topologies that governed semantic recollection in older controls. Another pattern was characterized by functional reconfiguration, wherein frontal, parietal, temporal and caudate couplings were strengthened with areas that were not recruited by controls. Correlations between principal component scores and cognitive measures suggested that reconfigured frontal coupling topologies in PD supported compensatory routes for accessing semantic content, whereas reconfigured parietal, temporal, and caudate connection topologies were detrimental or unrelated to cognition. Increased tau transcription diminished recruitment of compensatory frontal topologies but amplified recruitment of parietal topologies that were unfavorable for cognition. Collectively, the findings provide a new understanding of early vulnerabilities in the functional architecture of regional connectivity during semantic recollection in cognitively normal PD. The findings also have implications for tracking cognitive progression and selecting patients who stand to benefit from therapeutic interventions.
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http://dx.doi.org/10.3389/fnagi.2021.727057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489380PMC
September 2021

Current directions in tau research: Highlights from Tau 2020.

Alzheimers Dement 2021 Sep 28. Epub 2021 Sep 28.

Neurodegeneration Development Unit, Biogen, Boston, Massachusetts, USA.

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.
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http://dx.doi.org/10.1002/alz.12452DOI Listing
September 2021

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

JAMA 2021 09;326(10):926-939

University of Cincinnati, Cincinnati, Ohio.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data.

Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression.

Design, Participants, And Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019.

Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years.

Main Outcomes And Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity.

Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years).

Conclusions And Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD.

Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.
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http://dx.doi.org/10.1001/jama.2021.10207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441591PMC
September 2021

Reply to: "Laryngeal Movement Disorders in Multiple System Atrophy: A Diagnostic Biomarker?"

Mov Disord 2021 08;36(8):1999-2000

Department of Neurosciences, University of California San Diego, La Jolla, California, USA.

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http://dx.doi.org/10.1002/mds.28697DOI Listing
August 2021

Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial.

Nat Med 2021 08 12;27(8):1451-1457. Epub 2021 Aug 12.

Biogen, Cambridge, MA, USA.

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P < 0.0001). Incidences of adverse events and deaths were similar between groups. This well-powered study suggests that N-terminal tau neutralization does not translate into clinical efficacy.
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http://dx.doi.org/10.1038/s41591-021-01455-xDOI Listing
August 2021

Best Practices in the Clinical Management of Progressive Supranuclear Palsy and Corticobasal Syndrome: A Consensus Statement of the CurePSP Centers of Care.

Front Neurol 2021 1;12:694872. Epub 2021 Jul 1.

Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.
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http://dx.doi.org/10.3389/fneur.2021.694872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284317PMC
July 2021

Clinical Features of Patients With Progressive Supranuclear Palsy in an US Insurance Claims Database.

Front Neurol 2021 17;12:571800. Epub 2021 Jun 17.

Department of Neurology, Technische Universität München, Munich, Germany.

Progressive supranuclear palsy is a rare neurodegenerative movement disorder and little is known about its epidemiology. Estimate age-adjusted prevalence of progressive supranuclear palsy and describe antecedent diagnoses and progressive supranuclear palsy patient features in the 5 years before first diagnostic code. In a nested case-control study in the IBM MarketScan Commercial and Medicare Supplemental Databases, a large set of US insurance databases containing medical service and prescription drug claims from employer-based commercial and Medicare supplemental health insurance plans, progressive supranuclear palsy cases (identified via International Statistical Classification of Diseases 9th/10th revision codes) and controls were included if enrollment was ≥1 month in the study period (October 1, 2015-October 31, 2017). Two controls with no diagnosis codes for PSP were matched to cases on birth year, sex, enrollment time in the database, and pharmacy benefit eligibility. Controls were assigned a randomly selected index date from their eligibility period. Prevalence of progressive supranuclear palsy was estimated in 2016 among patients with ≥1 month of continuous enrollment in that year. Prevalence ratios for comorbidities (claim/diagnosis codes) were examined in the ≤ 5 years before index date (first progressive supranuclear palsy claim date). Age-adjusted progressive supranuclear palsy prevalence was 2.95/100,000 in 2016. The most common diagnosis codes in cases vs. controls in the 5 years pre-index were gait abnormalities (79.3 vs. 21.8%), pain in joint (54.9 vs. 36.0%), Parkinson's disease (54.6 vs. 1.0%), fatigue (49.8 vs. 21.6%), and cerebrovascular disease (45.6 vs. 16.4%). In this large database analysis, based on preliminary analyses, the prevalence of diagnosed progressive supranuclear palsy was 2.95/100,000, which is lower than many prior studies. Typical symptoms suggestive of progressive supranuclear palsy were present before index date, indicating a potential delay in time to diagnosis. The identification of diagnostic codes for clinical features of progressive supranuclear palsy that occurred before index date may be used to develop predictive models to identify potential progressive supranuclear palsy patients earlier in their disease course.
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http://dx.doi.org/10.3389/fneur.2021.571800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245849PMC
June 2021

A Microstirring Pill Enhances Bioavailability of Orally Administered Drugs.

Adv Sci (Weinh) 2021 06 18;8(12):2100389. Epub 2021 May 18.

Department of Nanoengineering and Chemical Engineering Program University of California San Diego La Jolla CA 92093 USA.

Majority of drugs are administered orally, yet their efficient absorption is often difficult to achieve, with a low dose fraction reaching the blood compartment. Here, a microstirring pill technology is reported with built-in mixing capability for oral drug delivery that greatly enhances bioavailability of its therapeutic payload. Embedding microscopic stirrers into a pill matrix enables faster disintegration and dissolution, leading to improved release profiles of three widely used model drugs, aspirin, levodopa, and acetaminophen, without compromising their loading. Unlike recently developed drug-carrying nanomotors, drug molecules are not associated with the microstirrers, and hence there is no limitation on the loading capacity. These embedded microstirrers are fabricated through the asymmetric coating of titanium dioxide thin film onto magnesium microparticles. In vitro tests illustrate that the embedded microstirrers lead to substantial enhancement of local fluid transport. In vivo studies using murine and porcine models demonstrate that the localized stirring capability of microstirrers leads to enhanced bioavailability of drug payloads. Such improvements are of considerable importance in clinical scenarios where fast absorption and high bioavailability of therapeutics are critical. The encouraging results obtained in porcine model suggest that the microstirring pill technology has translational potential and can be developed toward practical biomedical applications.
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http://dx.doi.org/10.1002/advs.202100389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224427PMC
June 2021

Non-Invasive Sweat-Based Tracking of L-Dopa Pharmacokinetic Profiles Following an Oral Tablet Administration.

Angew Chem Int Ed Engl 2021 08 19;60(35):19074-19078. Epub 2021 Jul 19.

Department of Nanoengineering, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.

Levodopa (L-Dopa) is the "gold-standard" medication for symptomatic therapy of Parkinson disease (PD). However, L-Dopa long-term use is associated with the development of motor and non-motor complications, primarily due to its fluctuating plasma levels in combination with the disease progression. Herein, we present the first example of individualized therapeutic drug monitoring for subjects upon intake of standard L-Dopa oral pill, centered on dynamic tracking of the drug concentration in naturally secreted fingertip sweat. The touch-based non-invasive detection method relies on instantaneous collection of fingertip sweat on a highly permeable hydrogel that transports the sweat to a biocatalytic tyrosinase-modified electrode, where sweat L-Dopa is measured by reduction of the dopaquinone enzymatic product. Personalized dose-response relationship is demonstrated within a group of human subjects, along with close pharmacokinetic correlation between the finger touch-based fingertip sweat and capillary blood samples.
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http://dx.doi.org/10.1002/anie.202106674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373796PMC
August 2021

Association of Orthostatic Hypotension With Cerebral Atrophy in Patients With Lewy Body Disorders.

Neurology 2021 08 7;97(8):e814-e824. Epub 2021 Jun 7.

From the Neurology Unit (A. Pilotto, A.S., B.B., A.L., A. Padovani), Department of Clinical and Experimental Sciences, and Neuroradiology Unit (R.G.), Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia; Parkinson's Disease Rehabilitation Centre (A. Pilotto, M.C.R.), FERB ONLUS-S. Isidoro Hospital, Trescore Balneario, Bergamo; Department of Neuroscience "Rita Levi Montalcini" (A.R., E.M., L.L.) and Autonomic Unit (S.M.), Department of Medical Sciences, University of Turin, Italy; Department of Medicine (Neurology) (M.M., C.O.-L., S.E.B.), University of Toronto; Hurvitz Brain Sciences Program (M.M., C.O.-L., S.E.B.), Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Neurology (Y.S., R.T., K.Y., T.H., N.H.), Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Neuroscience Imaging and Clinical Sciences (L.B., S.D.P.), University G. d'Annunzio of Chieti-Pescara, Chieti, Italy; Department of Medicine and Neuroscience and Mental Health Institute (R.C., M.G.), University of Alberta, Edmonton, Canada; Department of Radiology (L.L.W.), and Gardner Family Center for Parkinson's Disease and Movement Disorders (A.J.E.), Department of Neurology, University of Cincinnati, OH; Department of Molecular and Translational Medicine (A.K.D.), Texas Tech University Health Sciences Center, El Paso; Parkinson and Other Movement Disorders Center (K.L., I.L.), Department of Neurosciences, University of California, San Diego, La Jolla; Department of Neurology (F.R.-P.), Medical University of South Carolina, Charleston; Imaging Research Center (M.D), Department of Radiology, Cincinnati Children's Hospital Medical Center; University of Cincinnati College of Medicine (M.D.), OH; Department of Neurology (J.A.V.), Emory University, Atlanta, GA; ASST Spedali Civili Hospital (R.G.), Brescia, Italy; and Department of Neurology (A.M.), The Ohio State University, Columbus .

Objective: To evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB).

Methods: Supine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales.

Results: A total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy ( = 0.004) and regional atrophy involving the anterior-temporal ( = 0.001) and mediotemporal ( = 0.001) regions, greater in severe vs nonsevere OH ( = 0.001). The WMH burden was similar in those with and without OH ( = 0.49). SH was not associated with brain atrophy ( = 0.59) or WMH ( = 0.72).

Conclusions: OH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH.
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http://dx.doi.org/10.1212/WNL.0000000000012342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397588PMC
August 2021

Cognitive Impairment in Parkinson's Disease: Epidemiology, Clinical Profile, Protective and Risk Factors.

Behav Sci (Basel) 2021 May 13;11(5). Epub 2021 May 13.

Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, ON M5T2S8, Canada.

Cognitive impairment is a common non-motor symptom in Parkinson's Disease (PD) and an important source of patient disability and caregiver burden. The timing, profile and rate of cognitive decline varies widely among individuals with PD and can range from normal cognition to mild cognitive impairment (PD-MCI) and dementia (PDD). Beta-amyloid and tau brain accumulation, oxidative stress and neuroinflammation are reported risk factors for cognitive impairment. Traumatic brain injury and pesticide and tobacco exposure have also been described. Genetic risk factors including genes such as , and may also play a role. Less is known about protective factors, although the Mediterranean diet and exercise may fall in this category. Nonetheless, there is conflicting evidence for most of the factors that have been studied. The use of inconsistent criteria and lack of comprehensive assessment in many studies are important methodological issues. Timing of exposure also plays a crucial role, although identification of the correct time window has been historically difficult in PD. Our understanding of the mechanism behind these factors, as well as the interactions between gene and environment as determinants of disease phenotype and the identification of modifiable risk factors will be paramount, as this will allow for potential interventions even in established PD.
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http://dx.doi.org/10.3390/bs11050074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152515PMC
May 2021

Environmental Risk Factors for Progressive Supranuclear Palsy.

J Mov Disord 2021 May 26;14(2):103-113. Epub 2021 May 26.

Parkinson and Other Movement Disorders Center, Department of Neurosciences, University of California San Diego, La Jolla, CA, USA.

Typically, progressive supranuclear palsy (PSP) is clinically characterized by slow vertical saccades or supranuclear gaze palsy, levodopa-resistant parkinsonism with predominant axial symptoms, and cognitive executive impairment. Over the past decades, various PSP phenotypes, including PSP with predominant parkinsonism, PSP with corticobasal syndrome, PSP with progressive gait freezing, and PSP with predominant frontal dysfunction, have been identified from pathologically confirmed cases. Expanding knowledge led to new diagnostic criteria for PSP that with increased disease awareness led to increased PSP prevalence estimates. The identification of environmental and modifiable risk factors creates an opportunity to intervene and delay the onset of PSP or slow disease progression. To date, despite the increasing number of publications assessing risk factors for PSP, few articles have focused on environmental and lifestyle risk factors for this disorder. In this article, we reviewed the literature investigating the relationship between PSP and several environmental and other modifiable lifestyle risk factors. In our review, we found that exposures to toxins related to diet, metals, well water, and hypertension were associated with increased PSP risk. In contrast, higher education and statins may be protective. Further case-control studies are encouraged to determine the exact role of these factors in the etiopathogenesis of PSP, which in turn would inform strategies to prevent and reduce the burden of PSP.
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http://dx.doi.org/10.14802/jmd.20173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175813PMC
May 2021

Gene-Environment Interactions in Progressive Supranuclear Palsy.

Front Neurol 2021 9;12:664796. Epub 2021 Apr 9.

Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, United States.

Several genetic and environmental factors have been reported in progressive supranuclear palsy (PSP), although none were identified as a definitive cause. We aimed to explore potential gene-environment interactions in PSP. Two hundred and ninety two PSP cases and 292 controls matched for age, sex, and race from the ENGENE-PSP were analyzed to determine the association between PSP and minor alleles of 5 single nucleotide polymorphisms (SNPs) in 4 genes (MAPT, MOBP, EIF2AK3, and STX6), which were previously associated with PSP risk. Interactions between these SNPs and environmental factors, including previously reported occupational and agricultural risk factors for PSP, were assessed for PSP odds and age of symptom onset. Minor alleles of MAPTrs242557 and EIF2AK3rs7571971 were individually associated with increased odds; MAPTrs8070723 minor alleles were associated with lower PSP odds. There were several gene-environment interactions for PSP odds and age of symptom onset, however, they did not remain significant after FDR-correction. Larger scale studies are required to determine potential interactions.
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http://dx.doi.org/10.3389/fneur.2021.664796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062875PMC
April 2021

TRANSCENDS: A Career Development Program for Underrepresented in Medicine Scholars in Academic Neurology.

Neurology 2021 Apr 23. Epub 2021 Apr 23.

Department of Neurology, University of California, San Francisco

Background: The Training in Research for Academic Neurologists to Sustain Careers and Enhance the Numbers of Diverse Scholars (TRANSCENDS) program is a career advancement opportunity for individuals underrepresented in biomedical research, funded by the National Institute and Neurological Disorders and Stroke; and American Academy of Neurology (AAN).

Objective: To report on qualitative and quantitative outcomes in TRANSCENDS.

Design: Early career individuals (neurology fellows and junior faculty) from groups underrepresented in medicine were competitively selected from a national pool of applicants (2016-2019). TRANSCENDS activities comprised an online Clinical Research degree program, monthly webinars, AAN meeting activities, and mentoring. Participants were surveyed during and after completion of TRANSCENDS to evaluate program components.

Outcomes: Of 23 accepted scholars (comprising four successive cohorts), 56% were women; 61% Hispanic/Latinx, 30% Black/African American, 30% assistant professors. To date, 48% have graduated the TRANSCENDS program and participants have published 180 peer-reviewed articles. Mentees' feedback noted that professional skills development (i.e., manuscript and grant writing), networking opportunities, and mentoring were the most beneficial elements of the program. Stated opportunities for improvement included: incorporating a mentor-the-mentor workshop, providing more transitional support for mentees in the next stage of their careers, and requiring mentees to provide quarterly reports.

Conclusions: TRANSCENDS is a feasible program for supporting underrepresented in medicine neurologists towards careers in research and faculty academic appointments attained thus far have been sustained. While longer term outcomes and process enhancements are warranted, programs like this may help increase the numbers of diverse academic neurologists, and further drive neurological innovation.
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http://dx.doi.org/10.1212/WNL.0000000000012058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302150PMC
April 2021

Gene Therapy in Movement Disorders: A Systematic Review of Ongoing and Completed Clinical Trials.

Front Neurol 2021 6;12:648532. Epub 2021 Apr 6.

Department of Neurological Surgery, College of Medicine, The Ohio State University, Columbus, OH, United States.

We sought to provide an overview of the published and currently ongoing movement disorders clinical trials employing gene therapy, defined as a technology aiming to modulate the expression of one or more genes to achieve a therapeutic benefit. We systematically reviewed movement disorders gene therapy clinical trials from PubMed and ClinicalTrials.gov using a searching strategy that included Parkinson disease (PD), Huntington disease (HD), amino acid decarboxylase (AADC) deficiency, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dystonia, tremor, ataxia, and other movement disorders. Data extracted included study characteristics, investigational product, route of administration, safety/tolerability, motor endpoints, and secondary outcomes (i.e., neuroimaging, biomarkers). We identified a total of 46 studies focusing on PD (21 published and nine ongoing), HD (2 published and 5 ongoing), AADC deficiency (4 published and 2 ongoing), MSA (2 ongoing), and PSP (1 ongoing). In PD, intraparenchymal infusion of viral vector-mediated gene therapies demonstrated to be safe and showed promising preliminary data in trials aiming at restoring the synthesis of dopamine, enhancing the production of neurotrophic factors, or modifying the functional interaction between different nodes of the basal ganglia. In HD, monthly intrathecal delivery of an antisense oligonucleotide (ASO) targeting the huntingtin protein (HTT) mRNA proved to be safe and tolerable, and demonstrated a dose-dependent reduction of the cerebrospinal fluid levels of mutated HTT, while a small phase-I study testing implantable capsules of cells engineered to synthesize ciliary neurotrophic factor failed to show consistent drug delivery. In AADC deficiency, gene replacement studies demonstrated to be relatively safe in restoring catecholamine and serotonin synthesis, with promising outcomes. Ongoing movement disorders clinical trials are focusing on a variety of gene therapy approaches including alternative viral vector serotypes, novel recombinant genes, novel delivery techniques, and ASOs for the treatment of HD, MSA, and distinct subtypes of PD (LRRK2 mutation or GBA1 mutation carriers). Initial phase-I and -II studies tested the safety and feasibility of gene therapy in PD, HD, and AADC deficiency. The ongoing generation of clinical trials aims to test the efficacy of these approaches and explore additional applications for gene therapy in movement disorders.
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http://dx.doi.org/10.3389/fneur.2021.648532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056023PMC
April 2021

Association of Stress-Health Factors among Parkinson's Disease Patient/Caregiving-Partner Dyads.

Arch Clin Neuropsychol 2021 Apr 19. Epub 2021 Apr 19.

Department of Psychological and Brain Sciences, University of Louisville, Louisville, KY, USA.

Objective: Few studies have explored the shared effects of Parkinson's disease (PD) within patient/caregiver dyads. To fill this gap, we compared stress-health outcomes of patients with those of caregiving-partners, examined individual stress-health associations, and explored stress-health associations within dyads.

Method: A total of 18 PD patient/caregiving-partner dyads (N = 36) reported on disease-specific distress, anxiety, quality of life (QOL), and provided saliva samples for cortisol assessment. This cross-sectional, secondary analysis of a prospective pilot study used Actor-Partner Interdependence Models to test aims.

Results: Patients reported greater anxiety, poorer QOL, and demonstrated flatter cortisol slopes and higher mean bedtime cortisol compared to caregiving-partners. Both patients and caregiving-partners with greater anxiety had elevated bedtime cortisol and poorer QOL. Greater disease-specific distress in an individual was associated with higher diurnal mean cortisol in their partner.

Conclusions: Findings highlight the potential for psychosocial interventions at the dyadic level to reduce shared burden and promote coping among PD patient/caregiving-partner dyads.
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http://dx.doi.org/10.1093/arclin/acab024DOI Listing
April 2021

Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia.

Cortex 2021 06 19;139:99-115. Epub 2021 Mar 19.

Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, USA.

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.
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http://dx.doi.org/10.1016/j.cortex.2021.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119343PMC
June 2021

Hispanic Perspectives on Parkinson's Disease Care and Research Participation.

J Alzheimers Dis 2021 ;81(2):809-819

Barrow Neurological Institute, Phoenix, AZ, USA.

Background: Hispanics are under-represented in Parkinson's disease (PD) research despite the importance of diversity for results to apply to a wide range of patients.

Objective: To investigate the perspective of Hispanic persons with Parkinson disease (PWP) regarding awareness, interest, and barriers to participation in research.

Methods: We developed and administered a survey and qualitative interview in English and Spanish. For the survey, 62 Hispanic and 38 non-Hispanic PWP linked to a tertiary center were recruited in Arizona. For interviews, 20 Hispanic PWP, 20 caregivers, and six physicians providing service to Hispanic PWP in the community were recruited in California. Survey responses of Hispanic and non-Hispanic PWP were compared. Major survey themes were identified by applying grounded theory and open coding.

Results: The survey found roughly half (Q1 54%, Q2 55%) of Hispanic PWP linked to a tertiary center knew about research; there was unawareness among community Hispanic PWP. Most preferred having physician recommendations for research participation and were willing to participate. Hispanics preferred teams who speak their native language and include family. Research engagement, PD knowledge, role of family, living with PD, PD care, pre-diagnosis/diagnosis emerged as themes from the interview.

Conclusion: Barriers exist for participation of Hispanic PWP in research, primarily lack of awareness of PD research opportunities. Educating physicians of the need to encourage research participation of Hispanic PWP can address this. Physicians need to be aware of ongoing research and should not assume PWP disinterest. Including family members and providing research opportunities in their native language can increase research recruitment.
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http://dx.doi.org/10.3233/JAD-210231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203231PMC
September 2021

Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.

Neurology 2021 05 7;96(18):e2296-e2312. Epub 2021 Apr 7.

From the University of California, San Francisco (J.C.R., P.W., A.M.S., Y.C., A.W., S.-Y.M.G., P.A.L., H.W.H., J.C.F., J.B.T., A.M.K., L.L.M., J.K., J.H.K., B.L.M., H.J.S., A.L.B.); UK Dementia Research Centre (C.H., D.M.C., R.S.C., M.B., M.F., C.V.G., G.P., L.R., I.S., E.T., J.D.R.), UCL Institute of Neurology, Queen Square, London; Quanterix Corp (E.V., L.S., A.J., D.H.), Lexington; Novartis Institutes for Biomedical Research Inc (L.Y., A. Khinikar, R.S.), Cambridge, MA; Novartis Pharma AG (A. Kieloch, M.-A.V.), Basel, Switzerland; Bluefield Project to Cure Frontotemporal Dementia (L.L.M., R.P.), San Francisco, CA; Mayo Clinic (K.K., D.S.K., B.F.B.), Rochester, MN; Mayo Clinic (N.G.-R., L.P., R.R.), Jacksonville, FL; University of Pennsylvania (D.J.I., M.G.), Philadelphia; University of California, Los Angeles (E.M.R., G.C., M.F.M., Y.B.); Harvard University/Massachusetts General Hospital (B.D.C.), Boston, MA; Washington University (N.G.), St. Louis, MO; Columbia University (E.D.H.), New York, NY; University of British Columbia (I.R.M., G.-Y.R.H.), Vancouver, Canada; Case Western Reserve University (B.S.A.), Cleveland, OH; University of Washington (K.D.-R.), Seattle; Laboratory of Neuroimaging (A.W.T.), University of Southern California, Los Angeles; Northwestern University (S.W.), Chicago, IL; University of North Carolina (D.I.K.), Chapel Hill; Texas Health Presbyterian Hospital Dallas (D.K.); University of California, San Diego (I.L.); Johns Hopkins Hospital (C.U.O., A.P.), Baltimore, MD; University of Alabama at Birmingham (E.D.R.); University of Toronto (M.C.T., M.M.), Ontario, Canada; Indiana University School of Medicine (T.F.), Indianapolis; Biogen Inc (W.C., J.C., D.L.G.), Cambridge, MA; Erasmus Medical Centre (J.C.v.S.), Rotterdam, the Netherlands; University of Brescia (B.B.), Italy; University of Barcelona (R.S.-V.); Donostia University Hospital (F.M.), San Sebastian, Gipuzkoa, Spain; Clinique Interdisciplinaire de Mémoire (R.L.), Département des Sciences Neurologiques, CHU de Québec; Faculté de Médecine (R.L.), Université Laval, Quebec, Canada; Center for Alzheimer Research (C.G.), Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Solna, Sweden; University of Tübingen (M.S.); Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Fondazione IRCCS Ospedale Policlinico (D.G.); University of Milan (D.G.), Centro Dino Ferrari, Italy; Department of Clinical Neurosciences and Cambridge University Hospital (J.B.R.), University of Cambridge, UK; University of Western Ontario (E.F.), London, Canada; KU Leuven (R.V.), Belgium; Neurology Service (R.V.), University Hospitals Leuven, Belgium; University of Lisbon (A.d.M.), Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (F.T.), Milan, Italy; University of Coimbra (I.S.), Portugal; McGill University (S.D.), Montreal, Québec, Canada; University of Oxford (C.R.B.); Wolfson Molecular Imaging Centre (A.G.), University of Manchester, UK; University of Duisburg-Essen (A.G.), Duisberg; Ludwig-Maximilians-Universität München (J.L., A.D.); German Center for Neurodegenerative Diseases (J.L.), Munich Cluster for Systems Neurology (SyNergy); University of Ulm (M.O.), Germany; and Department of Neuroscience, Psychology, Drug Research and Child Health (S.S.), University of Florence, and IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.

Methods: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. , , and mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables.

Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.

Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.

Classification Of Evidence: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
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http://dx.doi.org/10.1212/WNL.0000000000011848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166434PMC
May 2021

Assessment of Motor Dysfunction with Virtual Reality in Patients Undergoing [I]FP-CIT SPECT/CT Brain Imaging.

Tomography 2021 03 26;7(2):95-106. Epub 2021 Mar 26.

Department of Radiology, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.

[I]FP-CIT SPECT has been valuable for distinguishing Parkinson disease (PD) from essential tremor. However, its performance for quantitative assessment of motor dysfunction has not been established. A virtual reality (VR) application was developed and compared with [I]FP-CIT SPECT/CT for detection of severity of motor dysfunction. Forty-four patients (21 males, 23 females, age 64.5 ± 12.4) with abnormal [I]FP-CIT SPECT/CT underwent assessment of bradykinesia, activities of daily living, and tremor with VR. Support vector machines (SVM) machine learning models were applied to VR and SPECT data. Receiver operating characteristic (ROC) analysis demonstrated greater area under the curve (AUC) for VR (0.8418, 95% CI 0.6071-0.9617) compared with brain SPECT (0.5357, 95% CI 0.3373-0.7357, = 0.029) for detection of motor dysfunction. Logistic regression identified VR as an independent predictor of motor dysfunction (Odds Ratio 326.4, SE 2.17, = 0.008). SVM for prediction of the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) demonstrated greater R-squared of 0.713 ( = 0.008) for VR, compared with 0.0764 ( = 0.361) for brain SPECT. This study demonstrates that VR can be safely used in patients prior to [I]FP-CIT SPECT imaging and may improve prediction of motor dysfunction. This test has the potential to provide a simple, objective, quantitative analysis of motor symptoms in PD patients.
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http://dx.doi.org/10.3390/tomography7020009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103274PMC
March 2021

The TOPAZ study: a home-based trial of zoledronic acid to prevent fractures in neurodegenerative parkinsonism.

NPJ Parkinsons Dis 2021 Mar 1;7(1):16. Epub 2021 Mar 1.

Department of Medicine, Duke University School of Medicine, VA Medical Center, Durham, NC, USA.

The Trial of Parkinson's And Zoledronic acid (TOPAZ, https://clinicaltrials.gov/ct2/show/NCT03924414 ) is a unique collaboration between experts in movement disorders and osteoporosis to test the efficacy of zoledronic acid, an FDA-approved parenteral treatment for osteoporosis, for fracture prevention in people with neurodegenerative parkinsonism. Aiming to enroll 3,500 participants age 65 years or older, TOPAZ is one of the largest randomized, placebo-controlled clinical trials ever attempted in parkinsonism. The feasibility of TOPAZ is enhanced by its design as a U.S.- wide home-based trial without geographical limits. Participants receive information from multiple sources, including specialty practices, support groups and websites. Conducting TOPAZ in participants' homes takes advantage of online consent technology, the capacity to confirm diagnosis using telemedicine and the availability of research nursing to provide screening and parenteral therapy in homes. Home-based clinical research may provide an efficient, convenient, less expensive method that opens participation in clinical trials to almost anyone with parkinsonism.
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http://dx.doi.org/10.1038/s41531-021-00162-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921548PMC
March 2021

Medication Management Performance in Parkinson's Disease: Examination of Process Errors.

Arch Clin Neuropsychol 2021 Oct;36(7):1307-1315

Research Service, Veterans Administration San Diego Healthcare System, San Diego, CA, 92161, USA.

Objective: Individuals with Parkinson's disease (PD) are at risk for increased medication mismanagement, which can lead to worse clinical outcomes. However, the nature of the errors (i.e., undertaking or overtaking medications) contributing to mismanagement and their relationship to cognition in PD is unknown. Therefore, this study sought to examine errors committed on the Medication Management Ability Assessment (MMAA) between PD participants with normal cognition (PD-NC) or mild cognitive impairment (PD-MCI) relative to healthy adults (HA).

Method: HA (n = 74), PD-NC (n = 102), and PD-MCI (n = 45) participants were administered the MMAA to assess undertaking, overtaking, and overall errors as well as overall performance (total score). Additionally, participants were administered a comprehensive neuropsychological battery from which cognitive composites of Attention, Learning, Memory, Language, Visuospatial, and Executive Functioning were derived.

Results: Separate negative binomial regression analyses indicated the PD-MCI group performed significantly worse overall on the MMAA (total score) and committed more undertaking and overall errors relative to HA and PD-NC. In the PD-MCI group, poorer MMAA performance was associated with worse delayed memory performance, whereas cognitive performance was not related to MMAA in HA or PC-NC.

Conclusion: Compared to PD and healthy adults with normal cognition, PD-MCI patients exhibited greater difficulty with medication management, particularly with undertaking medications. Poorer medication management in PD-MCI was associated with worse delayed recall. Thus, PD-MCI patients experiencing memory problems may require additional assistance with their medications. Findings have clinical relevance suggesting that objective measures of medication errors may assist clinicians in identifying PD patients needing adherence strategies.
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http://dx.doi.org/10.1093/arclin/acab004DOI Listing
October 2021

The Second NINDS/NIBIB Consensus Meeting to Define Neuropathological Criteria for the Diagnosis of Chronic Traumatic Encephalopathy.

J Neuropathol Exp Neurol 2021 Feb;80(3):210-219

VA Boston Healthcare System, Boston, Massachusetts.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder associated with exposure to head trauma. In 2015, a panel of neuropathologists funded by the NINDS/NIBIB defined preliminary consensus neuropathological criteria for CTE, including the pathognomonic lesion of CTE as "an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern," based on review of 25 tauopathy cases. In 2016, the consensus panel met again to review and refine the preliminary criteria, with consideration around the minimum threshold for diagnosis and the reproducibility of a proposed pathological staging scheme. Eight neuropathologists evaluated 27 cases of tauopathies (17 CTE cases), blinded to clinical and demographic information. Generalized estimating equation analyses showed a statistically significant association between the raters and CTE diagnosis for both the blinded (OR = 72.11, 95% CI = 19.5-267.0) and unblinded rounds (OR = 256.91, 95% CI = 63.6-1558.6). Based on the challenges in assigning CTE stage, the panel proposed a working protocol including a minimum threshold for CTE diagnosis and an algorithm for the assessment of CTE severity as "Low CTE" or "High CTE" for use in future clinical, pathological, and molecular studies.
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http://dx.doi.org/10.1093/jnen/nlab001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899277PMC
February 2021

Safety and efficacy of tilavonemab in progressive supranuclear palsy: a phase 2, randomised, placebo-controlled trial.

Lancet Neurol 2021 03;20(3):182-192

Neuroscience, AbbVie Inc, North Chicago, IL, USA.

Background: Progressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy.

Methods: We did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics in Australia, Canada, France, Germany, Italy, Japan, Spain, and the USA. Participants (aged ≥40 years) diagnosed with possible or probable progressive supranuclear palsy who were symptomatic for less than 5 years, had a reliable study partner, and were able to walk five steps with minimal assistance, were randomly assigned (1:1:1) by interactive response technology to tilavonemab 2000 mg, tilavonemab 4000 mg, or matching placebo administered intravenously on days 1, 15, and 29, then every 28 days through to the end of the 52-week treatment period. Randomisation was done by the randomisation specialist of the study sponsor, who did not otherwise participate in the study. The sponsor, investigators, and participants were unaware of treatment allocations. The primary endpoint was the change from baseline to week 52 in the Progressive Supranuclear Palsy Rating Scale (PSPRS) total score in the intention-to-treat population. Adverse events were monitored in participants who received at least one dose of study drug. Prespecified interim futility criteria were based on a model-based effect size of 0 or lower when 60 participants had completed the 52-week treatment period and 0·12 or lower when 120 participants had completed the 52-week treatment period. This study is registered at ClinicalTrials.gov, number NCT02985879.

Findings: Between Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised. The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis. A total of 377 participants received at least one dose of study drug and were included in the efficacy and safety analyses (2000 mg, n=126; 4000 mg, n=125; placebo, n=126). Least squares mean change from baseline to week 52 in PSPRS was similar in all groups (between-group difference vs placebo: 2000 mg, 0·0 [95% CI -2·6 to 2·6], effect size 0·000, p>0·99; 4000 mg, 1·0 [-1·6 to 3·6], -0·105, p=0·46). Most participants reported at least one adverse event (2000 mg, 111 [88%]; 4000 mg, 111 [89%]; placebo, 108 [86%]). Fall was the most common adverse event (2000 mg, 42 [33%]; 4000 mg, 54 [43%]; placebo, 49 [39%]). Proportions of patients with serious adverse events were similar among groups (2000 mg, 29 [23%]; 4000 mg, 34 [27%]; placebo, 33 [26%]). Fall was the most common treatment-emergent serious adverse event (2000 mg, five [4%]; 4000 mg, six [5%]; placebo, six [5%]). 26 deaths occurred during the study (2000 mg, nine [7%]; 4000 mg, nine [7%]; placebo, eight [6%]) but none was drug related.

Interpretation: A similar safety profile was seen in all treatment groups. No beneficial treatment effects were recorded. Although this study did not provide evidence of efficacy in progressive supranuclear palsy, the findings provide potentially useful information for future investigations of passive immunisation using tau antibodies for progressive supranuclear palsy.

Funding: AbbVie Inc.
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http://dx.doi.org/10.1016/S1474-4422(20)30489-0DOI Listing
March 2021

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

J Neurol Neurosurg Psychiatry 2021 Jul 9;92(7):745-750. Epub 2021 Feb 9.

Neurosciences, University of California San Diego, La Jolla, California, USA.

Introduction: Sex differences in dementia with Lewy bodies (DLB) have been reported in clinically defined cohorts; however, clinical diagnostic accuracy in DLB is suboptimal and phenotypic differences have not been assessed in pathologically confirmed participants.

Methods: Core DLB features were compared across 55 women and 156 men with pathologically defined DLB in the National Alzheimer's Coordinating Center. These analyses were repeated for 55 women and 55 men matched for age, education and tau burden.

Results: In the total sample, women died older, had fewer years of education, had higher tau burden but were less likely to be diagnosed with dementia and clinical DLB. In the matched sample, visual hallucinations continued to be less common in women, and fewer women met clinical DLB criteria.

Discussion: Sex impacts clinical manifestations of underlying pathologies in DLB. Despite similar underlying Lewy body pathology, women are less likely to manifest core DLB features and may be clinically underdiagnosed.
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http://dx.doi.org/10.1136/jnnp-2020-325668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530264PMC
July 2021

Progressive Supranuclear Palsy and Corticobasal Degeneration.

Adv Exp Med Biol 2021 ;1281:151-176

UC San Diego Department of Neurosciences, La Jolla, CA, USA.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative tauopathies with neuronal and glial lesions composed of tau that is composed predominantly of isomers with four repeats in the microtubule-binding domain (4R tau). The brain regions vulnerable to pathology in PSP and CBD overlap, but there are differences, particularly with respect to distribution of neuronal loss, the relative abundance of neuronal and glial lesions, the morphologic features of glial lesions, and the frequency of comorbid pathology. Both PSP and CBD have a wide spectrum of clinical manifestations, including disorders of movement and cognition. Recognition of phenotypic diversity in PSP and CBD may improve antemortem diagnostic accuracy, which tends to be very good for the most common presentation of PSP (Richardson syndrome), but poor for the most characteristic presentation of CBD (corticobasal syndrome: CBS). Development of molecular and imaging biomarkers may improve antemortem diagnostic accuracy. Currently, multidisciplinary symptomatic and supportive treatment with pharmacological and non-pharmacological strategies remains the standard of care. In the future, experimental therapeutic trials will be important to slow disease progression.
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http://dx.doi.org/10.1007/978-3-030-51140-1_11DOI Listing
February 2021

Delineation of Apathy Subgroups in Parkinson's Disease: Differences in Clinical Presentation, Functional Ability, Health-related Quality of Life, and Caregiver Burden.

Mov Disord Clin Pract 2021 Jan 10;8(1):92-99. Epub 2020 Dec 10.

Department of Psychiatry University of California San Diego La Jolla California USA.

Background: Apathy is a prevalent, multidimensional neuropsychiatric condition in Parkinson's disease (PD). Several authors have proposed apathy subtypes in PD, but no study has examined the classification of PD patients into distinct apathy subtypes, nor has any study examined the clinical utility of doing so.

Objectives: The current study used a data-driven approach to explore the existence and associated clinical characteristics of apathy subtypes in PD.

Method: The Apathy Scale (AS) was administered to 157 non-demented individuals with PD. Participants were classified into apathy subgroups through cluster analysis. Differences among apathy subtypes on external clinical indicators were explored across apathy subgroups.

Results: Individuals with PD were classified into three subgroups: a Non-Apathetic group with low levels of apathy symptoms, a Low Interest/Energy group, characterized by elevated symptoms of low interest/energy and minimal low initiation/emotional indifference symptoms, and a Low Initiation group, characterized by an absence of low interest/energy symptoms and elevated levels of low initiation/emotional indifference symptoms. Both Low Interest/Energy and Low Initiation groups exhibited worse depression, fatigue, anxiety, health-related quality of life, and caregiver burden than the Non-Apathetic subgroup. The Low Initiation group exhibited worse overall cognition, emotional well-being, state anxiety, communicative ability, and functional ability than the Low Interest/Energy group. Importantly, disease-related characteristics did not differ across apathy symptom subgroups.

Conclusions: Non-demented PD patients can be separated into distinct apathy symptom subgroups, which are differentially associated with important clinical variables. Apathy subgroup membership may reflect disruption to different neural systems independent of disease progression.
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http://dx.doi.org/10.1002/mdc3.13127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780962PMC
January 2021

Informant-Reported Cognitive Decline is Associated with Objective Cognitive Performance in Parkinson's Disease.

J Int Neuropsychol Soc 2021 05 9;27(5):439-449. Epub 2020 Dec 9.

Research Service, VA San Diego Healthcare System, La Jolla, California, 3350 La Jolla Village Dr, San Diego, CA92161, USA.

Objective: The utility of informant-based measures of cognitive decline to accurately describe objective cognitive performance in Parkinson's disease (PD) without dementia is uncertain. Due to the clinical relevance of this information, the purpose of this study was to examine the relationship between informant-based reports of patient cognitive decline via the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE) and objective cognition in non-demented PD controlling for cognitive status (i.e., mild cognitive impairment; PD-MCI and normal cognition; PD-NC).

Method: One-hundred and thirty-nine non-demented PD participants (PD-MCI n = 38; PD-NC n = 101) were administered measures of language, executive function, attention, learning, delayed recall, visuospatial function, mood, and motor function. Each participant identified an informant to complete the IQCODE and a mood questionnaire.

Results: Greater levels of informant-based responses of patient cognitive decline on the IQCODE were significantly associated with worse objective performance on measures of global cognition, attention, learning, delayed recall, and executive function in the overall sample, above and beyond covariates and cognitive status. However, the IQCODE was not significantly associated with language or visuospatial function.

Conclusions: Results indicate that informant responses, as measured by the IQCODE, may provide adequate information on a wide range of cognitive abilities in non-demented PD, including those with MCI and normal cognition. Findings have important clinical implications for the utility of the IQCODE in the identification of PD patients in need of further evaluation, monitoring, and treatment.
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http://dx.doi.org/10.1017/S1355617720001137DOI Listing
May 2021

Brain volumetric deficits in MAPT mutation carriers: a multisite study.

Ann Clin Transl Neurol 2021 01 28;8(1):95-110. Epub 2020 Nov 28.

Mayo Clinic, Jacksonville, Florida, USA.

Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.

Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.

Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.

Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.
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http://dx.doi.org/10.1002/acn3.51249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818091PMC
January 2021

Two Patients with Niemann Pick Disease Type C Diagnosed in the Seventh Decade of Life.

Mov Disord Clin Pract 2020 Nov 18;7(8):961-964. Epub 2020 Sep 18.

University of California San Diego Department of Neurosciences Movement Disorders Center La Jolla California USA.

Background: Niemann-Pick disease type C (NPC) is a rare, autosomal recessive lysosomal lipid storage disorder. It may present with cerebellar ataxia, vertical supranuclear gaze palsy, and cognitive impairment, and the age of symptom onset in adult-onset NPC is usually earlier than the fourth decade.

Cases: We present 2 patients with adult-onset NPC diagnosed in the seventh decade of life. The slow motor progression and subtle findings of supranuclear vertical gaze palsy and ataxia can lead to a delayed diagnosis and misdiagnosis with parkinsonian disorders, particularly progressive supranuclear palsy.

Conclusion: This report highlights and differentiates key clinical characteristics between NPC and parkinsonian disorders. It is important to consider NPC in the differential diagnosis when patients present with slowed vertical saccades, vertical supranuclear gaze palsy, ataxia, and cognitive impairment present at any age. This will allow appropriate and prompt treatment with miglustat and novel experimental therapies.
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http://dx.doi.org/10.1002/mdc3.13085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604695PMC
November 2020
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