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568


Neuro-Ophthalmic Manifestations of Adult Polyglucosan Body Disease

Dugue, Andrew G; Abreu, Nicolas J; Pillai, Cinthi; Galetta, Steven L; Grossman, Scott N
BACKGROUND:Adult polyglucosan body disease (APBD) is caused by a deficiency in glycogen branching enzyme that leads to polyglucosan accumulation in multiple organs. It has a progressive clinical course with prominent neurologic manifestations. We aim to describe the neuro-ophthalmic manifestations of APBD. METHODS:This is a case series of 3 individuals with genetically proven APBD. Written informed consent was provided by the brothers. We also performed a literature review on the current state of knowledge on APBD through PubMed. RESULTS:Brother 1 developed gait imbalance and length-dependent polyneuropathy in his 40s followed by progressive urinary symptoms in his 50s. He reported diplopia and blurry vision in his 60s. Neuro-ophthalmic assessment revealed bilateral optic neuropathy, convergence insufficiency, and a right fourth nerve palsy. Genetic testing showed a homozygous pathogenic variant in GBE1 c.986A>C p.Tyr329Ser. Brother 2 developed progressive urinary symptoms in his 40s that were followed by cognitive deficits, length-dependent polyneuropathy, and lower extremity weakness in his 50s and 60s. He reported blurred vision, and neuro-ophthalmic evaluation revealed bilateral optic neuropathy. Genetic testing revealed the same variant as Brother 1, GBE1 c.986A>C p.Tyr329Ser. Brother 3 developed progressive urinary urgency and lower extremity weakness in his 50s followed by a length-dependent polyneuropathy in his 60s. He reported diplopia and blurry vision in his 70s. Neuro-ophthalmic assessment revealed bilateral optic neuropathy and convergence insufficiency. Genetic testing revealed the same variant as Brothers 1 and 2, GBE1 c.986A>C p.Tyr329Ser. CONCLUSIONS:There is an array of afferent and efferent neuro-ophthalmic manifestations in APBD. Neuro-ophthalmic evaluation is crucial in evaluating and treating patients with APBD, particularly in those with visual dysfunction.
PMID: 39143664
ISSN: 1536-5166
CID: 5697252

Repetitive Head Impacts and Perivascular Space Volume in Former American Football Players

Jung, Leonard B; Wiegand, Tim L T; Tuz-Zahra, Fatima; Tripodis, Yorghos; Iliff, Jeffrey J; Piantino, Juan; Arciniega, Hector; Kim, Cara L; Pankatz, Lara; Bouix, Sylvain; Lin, Alexander P; Alosco, Michael L; Daneshvar, Daniel H; Mez, Jesse; Sepehrband, Farshid; Rathi, Yogesh; Pasternak, Ofer; Coleman, Michael J; Adler, Charles H; Bernick, Charles; Balcer, Laura; Cummings, Jeffrey L; Reiman, Eric M; Stern, Robert A; Shenton, Martha E; Koerte, Inga K; ,
IMPORTANCE/UNASSIGNED:Exposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role. OBJECTIVE/UNASSIGNED:To investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses. EXPOSURE/UNASSIGNED:Prior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts). MAIN OUTCOMES AND MEASURES/UNASSIGNED:Individual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume. RESULTS/UNASSIGNED:Analyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (β = 2.71 × 10-8 [95% CI, 0.50 × 10-8 to 4.93 × 10-8]; P = .03) and CHII-G (β = 2.24 × 10-6 [95% CI, 0.35 × 10-6 to 4.13 × 10-6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (β = -0.74 [95% CI, -1.35 to -0.13]; P = .04). CONCLUSIONS AND RELEVANCE/UNASSIGNED:These findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.
PMID: 39186275
ISSN: 2574-3805
CID: 5697412

Characterizing Neurobehavioral Dysregulation Among Former American Football Players: Findings From the DIAGNOSE CTE Research Project

Pulukuri, Surya V; Fagle, Tessa R; Trujillo-Rodriguez, Diana; van Amerongen, Suzan; Bernick, Charles; Geda, Yonas E; Wethe, Jennifer V; Peskind, Elaine R; Katz, Douglas I; Alosco, Michael L; Palmisano, Joseph N; Tripodis, Yorghos; Adler, Charles H; Balcer, Laura J; Reiman, Eric M; Shenton, Martha E; Cummings, Jeffrey L; Stern, Robert A; ,
OBJECTIVE/UNASSIGNED:Neurobehavioral dysregulation (NBD), a core clinical feature of traumatic encephalopathy syndrome, encompasses neuropsychiatric symptoms reported among individuals with a history of repetitive head impact exposure, including contact sport athletes. The objective of this study was to examine the construct and subconstructs of NBD through a series of factor and cluster analyses. METHODS/UNASSIGNED:Six clinician-scientists selected self-report questionnaire items relevant to NBD from seven available neuropsychiatric scales through a blinded voting process. These items were subjected to confirmatory factor analyses in a sample of 178 former college and professional American football players and 60 asymptomatic individuals without a history of repetitive head impact exposure. All participants were enrolled in the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Factor scores were generated on the basis of the optimal expert-informed model for NBD. Construct validity was assessed with neuropsychiatric scales not included in generation of the factor scores. Cluster analyses with NBD factor scores were used to examine symptom profiles. RESULTS/UNASSIGNED:Factor analyses confirmed that NBD was composed of four subconstructs: explosivity, emotional dyscontrol, impulsivity, and affective lability. Cluster analyses indicated four distinct symptom profiles of NBD in this group of former football players: asymptomatic (N=80, 45%), short fuse (N=33, 19%), high affective lability (N=34, 19%), and high NBD (N=31, 17%). CONCLUSIONS/UNASSIGNED:These findings characterize NBD as a multifaceted clinical construct with a heterogeneous presentation, providing a foundation for empirical work on the diagnostic criteria for traumatic encephalopathy syndrome and research on the neurobiological underpinnings of NBD.
PMID: 39034669
ISSN: 1545-7222
CID: 5723382

Multiple Cranial Nerve Palsies as the Presenting Sign of GCA

Merati, Melody; Radomski, Shana; Below, Alexandra; Lambert-Cheatham, Nathan; Keating, Ryan; Chang, Howard; Kaufman, David
PMID: 36892944
ISSN: 1536-5166
CID: 5456872

Myelin Oligodendrocyte Glycoprotein Antibody Disease Optic Neuritis: A Structure-Function Paradox?

Ross, Ruby; Kenney, Rachel; Balcer, Laura J; Galetta, Steven L; Krupp, Lauren; O'Neill, Kimberly A; Grossman, Scott N
BACKGROUND:Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is a demyelinating disorder that most commonly presents with optic neuritis (ON) and affects children more often than adults. We report 8 pediatric patients with MOG-associated ON and characterize focal optical coherence tomography (OCT) abnormalities over time that help distinguish this condition from the trajectories of other demyelinating disorders. These OCT findings are examined in the context of longitudinal visual function testing. METHODS:This is a retrospective case series of 8 pediatric patients with MOG-associated ON who were referred for neuro-ophthalmic evaluation. Longitudinal data for demographics, clinical history, physical examination, and OCT obtained in the course of clinical evaluations were collected through retrospective medical record review. RESULTS:Patients demonstrated acute peripapillary retinal nerve fiber layer (RNFL) thickening in one or both eyes, consistent with optic disc swelling. This was followed by steady patterns of average RNFL thinning, with 9 of 16 eyes reaching significantly low RNFL thickness using OCT platform reference databases (P < 0.01), accompanied by paradoxical recovery of high-contrast visual acuity (HCVA) in every patient. There was no correlation between HCVA and any OCT measures, although contrast sensitivity (CS) was associated with global thickness, PMB thickness, and nasal/temporal (N/T) ratio, and color vision was associated with PMB thickness. There was a lower global and papillomacular bundle (PMB) thickness (P < 0.01) in clinically affected eyes compared with unaffected eyes. There was also a significantly higher N:T ratio in clinically affected eyes compared with unaffected eyes in the acute MOG-ON setting (P = 0.03), but not in the long-term setting. CONCLUSIONS:MOG shows a pattern of prominent retinal atrophy, as demonstrated by global RNFL thinning, with remarkable preservation of HCVA but remaining deficits in CS and color vision. These tests may be better clinical markers of vision changes secondary to MOG-ON. Of the OCT parameters measured, PMB thickness demonstrated the most consistent correlation between structural and functional measures. Thus, it may be a more sensitive marker of clinically significant retinal atrophy in MOG-ON. The N:T ratio in acute clinically affected MOG-ON eyes in our study was higher than the N:T ratio of neuromyelitis optica (NMO)-ON eyes and similar to the N:T ratio in multiple sclerosis (MS)-ON eyes as presented in the prior literature. Therefore, MOG may share a more similar pathophysiology to MS compared with NMO.
PMID: 38526582
ISSN: 1536-5166
CID: 5644452

Navigating the U.S. regulatory landscape for neurologic digital health technologies

Busis, Neil A; Marolia, Dilshad; Montgomery, Robert; Balcer, Laura J; Galetta, Steven L; Grossman, Scott N
Digital health technologies (DHTs) can transform neurological assessments, improving quality and continuity of care. In the United States, the Food & Drug Administration (FDA) oversees the safety and efficacy of these technologies, employing a detailed regulatory process that classifies devices based on risk and requires rigorous review and post-market surveillance. Following FDA approval, DHTs enter the Current Procedural Terminology, Relative Value Scale Update Committee, and Centers for Medicare & Medicaid Services coding and valuation processes leading to coverage and payment decisions. DHT adoption is challenged by rapid technologic advancements, an inconsistent evidence base, marketing discrepancies, ambiguous coding guidance, and variable health insurance coverage. Regulators, policymakers, and payers will need to develop better methods to evaluate these promising technologies and guide their deployment. This includes striking a balance between patient safety and clinical effectiveness versus promotion of innovation, especially as DHTs increasingly incorporate artificial intelligence. Data validity, cybersecurity, risk management, societal, and ethical responsibilities should be addressed. Regulatory advances can support adoption of these promising tools by ensuring DHTs are safe, effective, accessible, and equitable.
PMCID:11014948
PMID: 38609447
ISSN: 2398-6352
CID: 5646182

Clinical Outcomes and Tau Pathology in Retired Football Players: Associations With Diagnosed and Witnessed Sleep Apnea

Banks, Sarah J; Yhang, Eukyung; Tripodis, Yorghos; Su, Yi; Protas, Hillary; Adler, Charles H; Balcer, Laura J; Bernick, Charles; Mez, Jesse B; Palmisano, Joseph; Barr, William B; Wethe, Jennifer V; Dodick, David W; Mcclean, Michael D; Martin, Brett; Hartlage, Kaitlin; Turner, Arlener; Turner, Robert W; Malhotra, Atul; Colman, Michael; Pasternak, Ofer; Lin, Alexander P; Koerte, Inga K; Bouix, Sylvain; Cummings, Jeffrey L; Shenton, Martha E; Reiman, Eric M; Stern, Robert A; Alosco, Michael L
BACKGROUND AND OBJECTIVES/UNASSIGNED:Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. METHODS/UNASSIGNED:The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. RESULTS/UNASSIGNED:gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. DISCUSSION/UNASSIGNED:Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.
PMCID:10900387
PMID: 38425491
ISSN: 2163-0402
CID: 5722802

Subacute Vision Loss in a Patient With HIV

Park, George T; Gold, Doria M; Modi, Yasha; Rucker, Janet C
PMID: 37995149
ISSN: 1536-5166
CID: 5608722

Treatment of Periodic Alternating Nystagmus as a Consequence of Ataxia-Telangiectasia

Jauregui, Ruben; Bhagat, Dhristie; Garcia, Mekka R; Miller, Claire; Grossman, Scott N
PMID: 36730924
ISSN: 1536-5166
CID: 5420452

Flortaucipir tau PET findings from former professional and college American football players in the DIAGNOSE CTE research project

Su, Yi; Protas, Hillary; Luo, Ji; Chen, Kewei; Alosco, Michael L; Adler, Charles H; Balcer, Laura J; Bernick, Charles; Au, Rhoda; Banks, Sarah J; Barr, William B; Coleman, Michael J; Dodick, David W; Katz, Douglas I; Marek, Kenneth L; McClean, Michael D; McKee, Ann C; Mez, Jesse; Daneshvar, Daniel H; Palmisano, Joseph N; Peskind, Elaine R; Turner, Robert W; Wethe, Jennifer V; Rabinovici, Gil; Johnson, Keith; Tripodis, Yorghos; Cummings, Jeffrey L; Shenton, Martha E; Stern, Robert A; Reiman, Eric M; ,
INTRODUCTION/BACKGROUND:Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD/METHODS:We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS:Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups. DISCUSSION/CONCLUSIONS:Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.
PMID: 38134231
ISSN: 1552-5279
CID: 5611852