Promoting Growth in Behavioral Neurology: A Path Forward.

Behavioral neurology & neuropsychiatry (BNNP) is a field that seeks to understand brain-behavior relationships, including fundamental brain organization principles and the many ways that brain structures and connectivity can be disrupted, leading to abnormalities of behavior, cognition, emotion, perception, and social cognition. In North America, BNNP has existed as an integrated subspecialty through the United Council for Neurologic Subspecialties since 2006. Nonetheless, the number of behavioral neurologists across academic medical centers and community settings is not keeping pace with increasing clinical and research demand. In this commentary, we provide a brief history of BNNP followed by an outline of the current challenges and opportunities for BNNP from the behavioral neurologist's perspective across clinical, research, and educational spheres. We provide a practical guide for promoting BNNP and addressing the shortage of behavioral neurologists to facilitate the continued growth and development of the subspecialty. We also urge a greater commitment to recruit trainees from diverse backgrounds so as to dismantle persistent obstacles that hinder inclusivity in BNNP-efforts that will further enhance the growth and impact of the subspecialty. With rapidly expanding diagnostic and therapeutic approaches across a range of conditions at the intersection of neurology and psychiatry, BNNP is well positioned to attract new trainees and expand its reach across clinical, research, and educational activities.

Contributions of rare and common variation to early-onset and atypical dementia risk.

We collected and analyzed genomic sequencing data from individuals with clinician-diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with 68 newly described in this report. Of those 68, 62 patients self-reported white, non-Hispanic ethnicity and 6 reported as African-American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria for pathogenicity. A polygenic risk score (PRS) was calculated for Alzheimer's patients in the total cohort and compared to the scores of a late-onset Alzheimer's cohort and a control set. Patients with early-onset Alzheimer's had higher non-APOE PRSs than patients with late-onset Alzheimer's, supporting the conclusion that both rare and common genetic variation associate with early-onset neurodegenerative disease risk.

Contributions of rare and common variation to early-onset and atypical dementia risk.

We collected and analyzed genomic sequencing data from individuals with clinician- diagnosed early-onset or atypical dementia. Thirty-two patients were previously described, with sixty-eight newly described in this report. Of those sixty-eight, sixty-two patients reported Caucasian, non-Hispanic ethnicity and six reported as African American, non-Hispanic. Fifty-three percent of patients had a returnable variant. Five patients harbored a pathogenic variant as defined by the American College of Medical Genetics criteria for pathogenicity. A polygenic risk score was calculated for Alzheimer's patients in the total cohort and compared to the scores of a late-onset Alzheimer's cohort and a control set. Patients with early-onset Alzheimer's had higher non- APOE polygenic risk scores than patients with late onset Alzheimer's, supporting the conclusion that both rare and common genetic variation associate with early-onset neurodegenerative disease risk.

Imaging spectrum of amyloid-related imaging abnormalities associated with aducanumab immunotherapy.

Alzheimer's Disease (AD) is a leading cause of morbidity. Management of AD has traditionally been aimed at symptom relief rather than disease modification. Recently, AD research has begun to shift focus towards disease-modifying therapies that can alter the progression of AD. In this context, a class of immunotherapy agents known as monoclonal antibodies target diverse cerebral amyloid-beta (Aß) epitopes to inhibit disease progression. Aducanumab was authorized by the US Food and Drug Administration (FDA) to treat AD on June 7, 2021. Aducanumab has shown promising clinical and biomarker efficacy but is associated with amyloid-related imaging abnormalities (ARIA). Neuroradiologists play a critical role in diagnosing ARIA, necessitating familiarity with this condition. This pictorial review will appraise the radiologic presentation of ARIA in patients on aducanumab.

Electronic Cigarettes and Vaping in Allergic and Asthmatic Disease.

Electronic nicotine delivery systems (ENDS) were introduced in 2006, offering alternatives to combustible cigarettes. There is significant controversy regarding their sale and regulation, particularly with youth and high-risk patient populations. They were deemed a "major public health concern" by the United States (US) Surgeon General in 2016 . Already associated with health consequences, recently e-cig or vaping product use-associated lung injury (EVALI) has exposed their potential to cause life-threatening complications. This publication aims to educate readers on the the immediate and long-term health consequences of ENDS, so they may provide patient counseling on utilization focusing on the asthmatic population.

Taking the Time to Assess Cognition in Parkinson's Disease: The Clock Drawing Test.

BACKGROUND: Cognitive impairment is common and disabling in Parkinson's disease (PD). Cognitive testing can be time consuming in the clinical setting. One rapid test to detect cognitive impairment in non-PD populations is the Clock Drawing Test (CDT), which calls upon the brain's executive and visuospatial abilities to draw a clock designating a certain time. OBJECTIVE: Test the hypothesis that PD participants would perform worse on CDT compared to controls and that CDT would correlate with other measures of cognition. METHODS: This study evaluated two independent CDT scoring systems and differences in CDT performance between PD (N = 97) and control (N = 54) participants using a two-sample t-test. Pearson's correlations were conducted between the CDT and tests of sleepiness (Epworth Sleepiness Scale) and vigilance (Psychomotor Vigilance Test); executive function (Trails B-A); and global cognition (Montreal Cognitive Assessment). Receiver operating characteristic curves were used to determine cut points on the CDT that identify individuals who need additional cognitive testing. RESULTS: PD participants had worse performance on CDT compared to controls. The CDT was correlated with executive function (Trails B-A) and global cognition (Montreal Cognitive Assessment). The CDT correlated with vigilance (Psychomotor Vigilance Task) only in healthy controls. However, the CDT was not correlated with measures of sleepiness (Epworth Sleepiness Scale) in either group. A cut point of 9 on the Rouleau scale and 18 on the Mendez scale identified PD participants with cognitive impairment. CONCLUSION: The CDT is a rapid clinical cognitive assessment that is feasible in PD and correlates with other measures of cognition.

A rise in social media utilization by U.S. neurology residency programs in the era of COVID-19.

OBJECTIVE: To determine how neurology departments and residency programs in the United States used virtual communication to adapt to the COVID-19 pandemic, we investigated the presence and use of social media pages, virtual outreach events, and virtual internship opportunities. METHODS: Twitter, Instagram, and Facebook accounts were identified (or noted as nonexistent) for 159 accredited neurology departments and residency programs. Google searches and social media site specific searches were performed. For existing pages, the date of creation was determined and all posts on and after March 1st, 2020, were assessed to investigate the presence of virtual open house advertisements. Each program was also assessed for virtual sub-internship and elective opportunities on the Visiting Student Application Service (VSAS). RESULTS: A majority of neurology residency programs (110) had a social media presence, particularly on Twitter and Instagram. Most residency program Twitter and Instagram accounts were created after March 1st, 2020, and this was not the case on Facebook. Twitter and Instagram were used most to advertise virtual opportunities. A correlation was observed between presence and number of social media accounts and program prestige. Few programs offered virtual opportunities on VSAS for the 2020-2021 year. CONCLUSION: Neurology residency programs adapted to the COVID-19 pandemic by creating residency social media accounts, primarily on Instagram and Twitter, and hosting virtual informational events. We recommend that neurology residency applicants create professional Instagram and Twitter accounts to network with programs and receive updates about virtual events. Similarly, going forward, we recommend continued social media use by neurology residency programs for applicant outreach.

Addressing the social needs of individuals with food allergy and celiac disease during COVID-19: A new practice model for sustained social care.

COVID-19 has led to high rates of food insecurity. Food insecure patients with food allergy and celiac disease are especially vulnerable during the pandemic when foods become limited. This paper describes a practice innovation implemented by a community-based organization, Food Equality Initiative (FEI), whose mission is improving health and ending hunger among individuals with food allergy and celiac disease. FEI responded to the pandemic by converting their in-person pantries to a contactless delivery of safe foods. The practice innovation is discussed in relation to three system-level elements necessary to sustain the integration of social care into the delivery of healthcare.

Reactions to Multiple Ascending Doses of the Microtubule Stabilizer TPI-287 in Patients With Alzheimer Disease, Progressive Supranuclear Palsy, and Corticobasal Syndrome: A Randomized Clinical Trial.

Importance: Basket-design clinical trials that allow investigation of treatment effects on different clinical syndromes that share the same molecular pathophysiology have not previously been attempted in neurodegenerative disease. Objective: To assess the safety, tolerability, and pharmacodynamics of the microtubule stabilizer TPI-287 (abeotaxane) in Alzheimer disease (AD) or the 4-repeat tauopathies (4RT) progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Design, Setting, and Participants: Two parallel-design, double-blind, placebo-controlled phase 1 randomized clinical trials in AD and 4RT were conducted from December 20, 2013, through May 4, 2017, at the University of California, San Francisco, and University of Alabama at Birmingham. A total of 94 patients with clinically diagnosed AD (n = 39) and 4RT (n = 55) were screened; of these, 3 refused to participate, and 10 with AD and 11 with 4RT did not meet inclusion criteria. A total of 29 patients with AD, 14 with PSP, and 30 with ß-amyloid-negative CBS (determined on positron emission tomography findings) were enrolled. Data were analyzed from December 20, 2013, through May 4, 2017, based on modified intention to treat. Interventions: Randomization was 8:3 drug to placebo in 3 sequential dose cohorts receiving 2.0, 6.3, or 20.0 mg/m2 of intravenous TPI-287 once every 3 weeks for 9 weeks, with an optional 6-week open-label extension. Main Outcomes and Measures: Primary end points were safety and tolerability (maximal tolerated dose) of TPI-287. Secondary and exploratory end points included TPI-287 levels in cerebrospinal fluid (CSF) and changes on biomarker, clinical, and neuropsychology measures. Results: A total of 68 participants (38 men [56%]; median age, 65 [range, 50-85] years) were included in the modified intention-to-treat analysis, of whom 26 had AD (14 women [54%]; median age, 63 [range, 50-76] years), and 42 had 4RT (16 women [38%]; median age, 69 [range, 54-83] years). Three severe anaphylactoid reactions occurred in TPI-287-treated patients with AD, whereas none were seen in patients with 4RT, leading to a maximal tolerated dose of 6.3 mg/m2 for AD and 20.0 mg/m2 for 4RT. More falls (3 in the placebo group vs 11 in the TPI-287 group) and a dose-related worsening of dementia symptoms (mean [SD] in the CDR plus NACC FTLD-SB [Clinical Dementia Rating scale sum of boxes with frontotemporal dementia measures], 0.5 [1.8] in the placebo group vs 0.7 [1.6] in the TPI-287 group; median difference, 1.5 [95% CI, 0-2.5]; P = .03) were seen in patients with 4RT. Despite undetectable TPI-287 levels in CSF, CSF biomarkers demonstrated decreased chitinase-3-like protein-1 (YKL-40) levels in the 4RT treatment arm (mean [SD], -8.4 [26.0] ng/mL) compared with placebo (mean [SD], 10.4 [42.3] ng/mL; median difference, -14.6 [95% CI, -30.0 to 0.2] ng/mL; P = .048, Mann-Whitney test). Conclusions and Relevance: In this randomized clinical trial, TPI-287 was less tolerated in patients with AD than in those with 4RT owing to the presence of anaphylactoid reactions. The ability to reveal different tau therapeutic effects in various tauopathy syndromes suggests that basket trials are a valuable approach to tau therapeutic early clinical development. Trial Registration: ClinicalTrials.gov identifiers: NCT019666666 and NCT02133846.

Genome sequencing for early-onset or atypical dementia: high diagnostic yield and frequent observation of multiple contributory alleles.

We assessed the results of genome sequencing for early-onset dementia. Participants were selected from a memory disorders clinic. Genome sequencing was performed along with C9orf72 repeat expansion testing. All returned sequencing results were Sanger-validated. Prior clinical diagnoses included Alzheimer's disease, frontotemporal dementia, and unspecified dementia. The mean age of onset was 54 (41-76). Fifty percent of patients had a strong family history, 37.5% had some, and 12.5% had no known family history. Nine of 32 patients (28%) had a variant defined as pathogenic or likely pathogenic (P/LP) by American College of Medical Genetics and Genomics standards, including variants in APP, C9orf72, CSF1R, and MAPT Nine patients (including three with P/LP variants) harbored established risk alleles with moderate penetrance (odds ratios of ∼2-5) in ABCA7, AKAP9, GBA, PLD3, SORL1, and TREM2 All six patients harboring these moderate penetrance variants but not P/LP variants also had one or two APOE ε4 alleles. One patient had two APOE ε4 alleles with no other established contributors. In total, 16 patients (50%) harbored one or more genetic variants likely to explain symptoms. We identified variants of uncertain significance (VUSs) in ABI3, ADAM10, ARSA, GRID2IP, MME, NOTCH3, PLCD1, PSEN1, TM2D3, TNK1, TTC3, and VPS13C, also often along with other variants. In summary, genome sequencing for early-onset dementia frequently identified multiple established or possible contributory alleles. These observations add support for an oligogenic model for early-onset dementia.

Alabama Brief Cognitive Screener: Utility of a New Cognitive Screening Instrument in a Memory Disorders Clinic.

Objective: We assessed the clinical utility of the Alabama Brief Cognitive Screener (ABCs), an alternative to the Mini-Mental State Examination (MMSE), for cognitive screening in a new electronic medical record. Other available nonproprietary instruments were determined to be more tuned to milder deficits than the MMSE. Methods: The ABCs was administered as part of routine clinical assessment in the University of Alabama at Birmingham memory disorders clinics from April 30, 2012, to April 30, 2015. Outpatients (N = 1,589) with clinician diagnoses (ICD-9-CM) of memory loss, mild cognitive impairment, neurodegenerative cognitive impairment, Alzheimer's dementia, or dementia not otherwise specified were included in the analysis. Memory disorder clinicians used multiple sources of information for assignment of diagnoses, including interviews with patients and caregivers, the ABCs, figure copy, semantic fluencies, phonemic fluencies, ratings of daily function, imaging, laboratory tests, and medical records. Results: Scoring distribution by diagnosis was mild cognitive impairment (n = 310): mean (SD) = 25.47 (3.37), median = 26; Alzheimer's dementia (n = 208): mean (SD) = 16.42 (6.33), median = 17; cerebral degeneration (n = 371): mean (SD) = 20.61 (5.90), median = 21; memory loss (n = 583): mean (SD) = 24.90 (5.09), median = 27; and dementia (n = 117): mean (SD) = 15.18 (6.34), median = 15. Mean ABCs scores differed by diagnosis (Wilcoxon signed-ranks Z = 483.5, P < .001). This finding was consistent with a meta-analysis of MMSE performance between groups. Conclusions: ABCs scores vary appropriately by diagnosis and resemble MMSE scoring distributions. The ABCs provides a nonproprietary alternative to the MMSE to assess the severity of cognitive deficits.

Clinical, imaging, pathological, and biochemical characterization of a novel presenilin 1 mutation (N135Y) causing Alzheimer's disease.

We present 2 cases of early-onset Alzheimer's disease due to a novel N135Y mutation in PSEN1. The proband presented with memory and other cognitive symptoms at age 32. Detailed clinical characterization revealed initial deficits in memory with associated dysarthria, progressing to involve executive dysfunction, spastic gait, and episodic confusion with polyspike discharges on long-term electroencephalography. Amyloid- and FDG-PET scans showed typical results of Alzheimer's disease. By history, the proband's father had developed cognitive symptoms at age 42 and died at age 48. Neuropathological evaluation confirmed Alzheimer's disease, with moderate to severe amyloid angiopathy. Skeletal muscle showed type 2 fiber-predominant atrophy with pale central clearing. Genetic testing of the proband revealed an N135Y missense mutation in PSEN1. This mutation was predicted to be pathogenic by in silico analysis. Biochemical analysis confirmed that the mutation caused an increased Aß42/Aß40 ratio, consistent with other PSEN1 mutations and with a loss of presenilin function.

Normal cognitive aging.

Even those who do not experience dementia or mild cognitive impairment may experience subtle cognitive changes associated with aging. Normal cognitive changes can affect an older adult's everyday function and quality of life, and a better understanding of this process may help clinicians distinguish normal from disease states. This article describes the neurocognitive changes observed in normal aging, followed by a description of the structural and functional alterations seen in aging brains. Practical implications of normal cognitive aging are then discussed, followed by a discussion of what is known about factors that may mitigate age-associated cognitive decline.