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Relapsing White Matter Disease and Subclinical Optic Neuropathy: From the National Multiple Sclerosis Society Case Conference Proceedings

O'Neill, Kimberly A; Dugue, Andrew; Abreu, Nicolas J; Balcer, Laura J; Branche, Marc; Galetta, Steven; Graves, Jennifer; Kister, Ilya; Magro, Cynthia; Miller, Claire; Newsome, Scott D; Pappas, John; Rucker, Janet; Steigerwald, Connolly; William, Christopher M; Zamvil, Scott S; Grossman, Scott N; Krupp, Lauren B
A 16-year-old adolescent boy presented with recurrent episodes of weakness and numbness. Brain MRI demonstrated subcortical, juxtacortical, and periventricular white matter T2 hyperintensities with gadolinium enhancement. CSF was positive for oligoclonal bands that were not present in serum. Despite treatment with steroids, IV immunoglobulins, plasmapheresis, and rituximab, he continued to have episodes of weakness and numbness and new areas of T2 hyperintensity on imaging. Neuro-ophthalmologic examination revealed a subclinical optic neuropathy with predominant involvement of the papillomacular bundle. Genetic evaluation and brain biopsy led to an unexpected diagnosis.
PMID: 38181317
ISSN: 2332-7812
CID: 5628442

Inflammatory biomarkers for neurobehavioral dysregulation in former American football players: findings from the DIAGNOSE CTE Research Project

van Amerongen, Suzan; Pulukuri, Surya V; Tuz-Zahra, Fatima; Tripodis, Yorghos; Cherry, Jonathan D; Bernick, Charles; Geda, Yonas E; Wethe, Jennifer V; Katz, Douglas I; Alosco, Michael L; Adler, Charles H; Balcer, Laura J; Ashton, Nicholas J; Blennow, Kaj; Zetterberg, Henrik; Daneshvar, Daniel H; Colasurdo, Elizabeth A; Iliff, Jeffrey J; Li, Gail; Peskind, Elaine R; Shenton, Martha E; Reiman, Eric M; Cummings, Jeffrey L; Stern, Robert A; ,
BACKGROUND:Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals. METHODS:Our cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES. RESULTS:CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations. CONCLUSION/CONCLUSIONS:Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.
PMCID:10854026
PMID: 38336728
ISSN: 1742-2094
CID: 5632112

Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players

Ly, Monica T; Tuz-Zahra, Fatima; Tripodis, Yorghos; Adler, Charles H; Balcer, Laura J; Bernick, Charles; Zetterberg, Henrik; Blennow, Kaj; Peskind, Elaine R; Au, Rhoda; Banks, Sarah J; Barr, William B; Wethe, Jennifer V; Bondi, Mark W; Delano-Wood, Lisa M; Cantu, Robert C; Coleman, Michael J; Dodick, David W; McClean, Michael D; Mez, Jesse B; Palmisano, Joseph; Martin, Brett; Hartlage, Kaitlin; Lin, Alexander P; Koerte, Inga K; Cummings, Jeffrey L; Reiman, Eric M; Shenton, Martha E; Stern, Robert A; Bouix, Sylvain; Alosco, Michael L; ,
BACKGROUND AND OBJECTIVES/OBJECTIVE:Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health. METHODS:ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI. RESULTS:(158%), and FA (287%) than the unexposed men. DISCUSSION/CONCLUSIONS:and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.
PMID: 38165330
ISSN: 1526-632x
CID: 5625972

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

Examination of parkinsonism in former elite American football players

Alosco, Michael L; Adler, Charles H; Dodick, David W; Tripodis, Yorghos; Balcer, Laura J; Bernick, Charles; Banks, Sarah J; Barr, William B; Wethe, Jennifer V; Palmisano, Joseph N; Martin, Brett; Hartlage, Kaitlin; Cantu, Robert C; Geda, Yonas E; Katz, Douglas I; Mez, Jesse; Cummings, Jeffery L; Shenton, Martha E; Reiman, Eric M; Stern, Robert A; ,
BACKGROUND:Former American football players are at risk for chronic traumatic encephalopathy (CTE) which may have parkinsonism as a clinical feature. OBJECTIVE:Former football players were prospectively assessed for parkinsonism. METHODS:120 former professional football players, 58 former college football players, and 60 same-age asymptomatic men without repetitive head impacts, 45-74 years, were studied using the MDS-UPDRS to assess for parkinsonism, and the Timed Up and Go (TUG). Traumatic encephalopathy syndrome (TES), the clinical syndrome of CTE, was adjudicated and includes parkinsonism diagnosis. Fisher's Exact Test compared groups on parkinsonism due to small cell sizes; analysis of covariance or linear regressions controlling for age and body mass index were used otherwise. RESULTS:Twenty-two (12.4%) football players (13.3% professional, 10.3% college) met parkinsonism criteria compared with two (3.3%) in the unexposed group. Parkinsonism was higher in professional (p = 0.037) but not college players (p = 0.16). There were no differences on the MDS-UPDRS Part III total scores. Scores on the individual MDS-UPDRS items were low. TUG times were longer in former professional but not college players compared with unexposed men (13.09 versus 11.35 s, p < 0.01). There were no associations between years of football, age of first exposure, position or level of play on motor outcomes. TES status was not associated with motor outcomes. CONCLUSIONS:Parkinsonism rates in this sample of football players was low and highest in the professional football players. The association between football and parkinsonism is inconclusive and depends on factors related to sample selection, comparison groups, and exposure characteristics.
PMID: 37981539
ISSN: 1873-5126
CID: 5608152

Amyloid PET across the cognitive spectrum in former professional and college American football players: findings from the DIAGNOSE CTE Research Project

Stern, Robert A; Trujillo-Rodriguez, Diana; Tripodis, Yorghos; Pulukuri, Surya V; Alosco, Michael L; Adler, Charles H; Balcer, Laura J; Bernick, Charles; Baucom, Zachary; Marek, Kenneth L; McClean, Michael D; Johnson, Keith A; McKee, Ann C; Stein, Thor D; Mez, Jesse; Palmisano, Joseph N; Cummings, Jeffrey L; Shenton, Martha E; Reiman, Eric M; ,
BACKGROUND:Exposure to repetitive head impacts (RHI) in American football players can lead to cognitive impairment and dementia due to neurodegenerative disease, particularly chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE consists of perivascular aggregates of hyper-phosphorylated tau in neurons at the depths of cortical sulci. However, it is unclear whether exposure to RHI accelerates amyloid-β (Aβ) plaque formation and increases the risk for Alzheimer's disease (AD). Although the Aβ neuritic plaques characteristic of AD are observed in a minority of later-stage CTE cases, diffuse plaques are more common. This study examined whether former professional and college American football players, including those with cognitive impairment and dementia, have elevated neuritic Aβ plaque density, as measured by florbetapir PET. Regardless of cognitive and functional status, elevated levels of florbetapir uptake were not expected. METHODS:We examined 237 men ages 45-74, including 119 former professional (PRO) and 60 former college (COL) football players, with and without cognitive impairment and dementia, and 58 same-age men without a history of contact sports or TBI (unexposed; UE) and who denied cognitive or behavioral symptoms at telephone screening. Former players were categorized into four diagnostic groups: normal cognition, subjective memory impairment, mild cognitive impairment, and dementia. Positive florbetapir PET was defined by cortical-cerebellar average SUVR of ≥ 1.10. Multivariable linear regression and analysis of covariance (ANCOVA) compared florbetapir average SUVR across diagnostic and exposure groups. Multivariable logistic regression compared florbetapir positivity. Race, education, age, and APOE4 were covariates. RESULTS:There were no diagnostic group differences either in florbetapir average SUVR or the proportion of elevated florbetapir uptake. Average SUVR means also did not differ between exposure groups: PRO-COL (p = 0.94, 95% C.I. = [- 0.033, 0.025]), PRO-UE (p = 0.40, 95% C.I. = [- 0.010, 0.029]), COL-UE (p = 0.36, 95% CI = [0.0004, 0.039]). Florbetapir was not significantly associated with years of football exposure, cognition, or daily functioning. CONCLUSIONS:Cognitive impairment in former American football players is not associated with PET imaging of neuritic Aβ plaque deposition. These findings are inconsistent with a neuropathological diagnosis of AD in individuals with substantial RHI exposure and have both clinical and medico-legal implications. TRIAL REGISTRATION:NCT02798185.
PMCID:10552261
PMID: 37798671
ISSN: 1758-9193
CID: 5610362

A Comparison of Patients' and Neurologists' Assessments of their Teleneurology Encounter: A Cross-Sectional Analysis

Thawani, Sujata P; Minen, Mia T; Grossman, Scott N; Friedman, Steven; Bhatt, Jaydeep M; Foo, Farng-Yang A; Torres, Daniel M; Weinberg, Harold J; Kim, Nina H; Levitan, Valeriya; Cardiel, Myrna I; Zakin, Elina; Conway, Jenna M; Kurzweil, Arielle M; Hasanaj, Lisena; Stainman, Rebecca S; Seixas, Azizi; Galetta, Steven L; Balcer, Laura J; Busis, Neil A
PMID: 37624656
ISSN: 1556-3669
CID: 5599032

Retinal hypoplasia and degeneration result in vision loss in Friedreich ataxia

Rodden, Layne N; McIntyre, Kellie; Keita, Medina; Wells, Mckenzie; Park, Courtney; Profeta, Victoria; Waldman, Amy; Rummey, Christian; Balcer, Laura J; Lynch, David R
OBJECTIVE:Friedreich ataxia (FRDA) is an inherited condition caused by a GAA triplet repeat (GAA-TR) expansion in the FXN gene. Clinical features of FRDA include ataxia, cardiomyopathy, and in some, vision loss. In this study, we characterize features of vision loss in a large cohort of adults and children with FRDA. METHODS:Using optical coherence tomography (OCT), we measured peripapillary retinal nerve fiber layer (RNFL) thickness in 198 people with FRDA, and 77 controls. Sloan letter charts were used to determine visual acuity. RNFL thickness and visual acuity were compared to measures of disease severity obtained from the Friedreich Ataxia Clinical Outcomes Measures Study (FACOMS). RESULTS:The majority of patients, including children, had pathologically thin RNFLs (mean = 73 ± 13 μm in FRDA; 98 ± 9 μm in controls) and low-contrast vision deficits early in the disease course. Variability in RNFL thickness in FRDA (range: 36 to 107 μm) was best predicted by disease burden (GAA-TR length X disease duration). Significant deficits in high-contrast visual acuity were apparent in patients with an RNFL thickness of ≤68 μm. RNFL thickness decreased at a rate of -1.2 ± 1.4 μm/year and reached 68 μm at a disease burden of approximately 12,000 GAA years, equivalent to disease duration of 17 years for participants with 700 GAAs. INTERPRETATION/CONCLUSIONS:These data suggest that both hypoplasia and subsequent degeneration of the RNFL may be responsible for the optic nerve dysfunction in FRDA and support the development of a vision-directed treatment for selected patients early in the disease to prevent RNFL loss from reaching the critical threshold.
PMID: 37334854
ISSN: 2328-9503
CID: 5542542

Vision as a piece of the head trauma puzzle [Comment]

Bell, Carter A; Grossman, Scott N; Balcer, Laura J; Galetta, Steven L
Approximately half of the brain's circuits are involved in vision and control of eye movements. Therefore, visual dysfunction is a common symptom of concussion, the mildest form of traumatic brain injury (TBI). Photosensitivity, vergence dysfunction, saccadic abnormalities, and distortions in visual perception have been reported as vision-related symptoms following concussion. Impaired visual function has also been reported in populations with a lifetime history of TBI. Consequently, vision-based tools have been developed to detect and diagnose concussion in the acute setting, and characterize visual and cognitive function in those with a lifetime history of TBI. Rapid automatized naming (RAN) tasks have provided widely accessible and quantitative measures of visual-cognitive function. Laboratory-based eye tracking approaches demonstrate promise in measuring visual function and validating results from RAN tasks in patients with concussion. Optical coherence tomography (OCT) has detected neurodegeneration in patients with Alzheimer's disease and multiple sclerosis and may provide critical insight into chronic conditions related to TBI, such as traumatic encephalopathy syndrome. Here, we review the literature and discuss the future directions of vision-based assessments of concussion and conditions related to TBI.
PMID: 36801966
ISSN: 1476-5454
CID: 5592092

Corrigendum to "Longitudinal stability of inter-eye differences in optical coherence tomography measures for identifying unilateral optic nerve lesions in multiple sclerosis" [Journal of the Neurological Sciences 449C (2023) Start page-End page/JOTNS D-23-00048R2]

Patil, Sachi A; Joseph, Binu; Tagliani, Paula; Sastre-Garriga, Jaume; Montalban, Xavier; Vidal-Jordana, Angela; Galetta, Steven L; Balcer, Laura J; Kenney, Rachel C
PMID: 37468371
ISSN: 1878-5883
CID: 5535862