Selective Inhibitory Circuit Dysfunction after Chronic Frontal Lobe Contusion.

Traumatic brain injury (TBI) is a leading cause of neurologic disability; the most common deficits affect prefrontal cortex-dependent functions such as attention, working memory, social behavior, and mental flexibility. Despite this prevalence, little is known about the pathophysiology that develops in frontal cortical microcircuits after TBI. We investigated whether alterations in subtype-specific inhibitory circuits are associated with cognitive inflexibility in a mouse model of frontal lobe contusion in both male and female mice that recapitulates aberrant mental flexibility as measured by deficits in rule reversal learning. Using patch-clamp recordings and optogenetic stimulation, we identified selective vulnerability in the non-fast-spiking and somatostatin-expressing (SOM+) subtypes of inhibitory neurons in layer V of the orbitofrontal cortex 2 months after injury. These subtypes exhibited reduced intrinsic excitability and a decrease in their synaptic output onto pyramidal neurons, respectively. By contrast, the fast-spiking and parvalbumin-expressing interneurons did not show changes in intrinsic excitability or synaptic output, respectively. Impairments in non-fast-spiking/SOM+ inhibitory circuit function were also associated with network hyperexcitability. These findings provide evidence for selective disruptions within specific inhibitory microcircuits that may guide the development of novel therapeutics for TBI.SIGNIFICANCE STATEMENT TBI frequently leads to chronic deficits in cognitive and behavioral functions that involve the prefrontal cortex, yet the maladaptive changes that occur in these cortical microcircuits are unknown. Our data indicate that alterations in subtype-specific inhibitory circuits, specifically vulnerability in the non-fast-spiking/somatostatin-expressing interneurons, occurs in the orbitofrontal cortex in the context of chronic deficits in reversal learning. These neurons exhibit reduced excitability and synaptic output, whereas the other prominent inhibitory population in layer V, the fast-spiking/parvalbumin-expressing interneurons as well as pyramidal neurons are not affected. Our work offers mechanistic insight into the subtype-specific function of neurons that may contribute to mental inflexibility after TBI.

The neuropathology of intimate partner violence.

Lifelong brain health consequences of traumatic brain injury (TBI) include the risk of neurodegenerative disease. Up to one-third of women experience intimate partner violence (IPV) in their lifetime, often with TBI, yet remarkably little is known about the range of autopsy neuropathologies encountered in IPV. We report a prospectively accrued case series from a single institution, the New York City Office of Chief Medical Examiner, evaluated in partnership with the Brain Injury Research Center of Mount Sinai, using a multimodal protocol comprising clinical history review, ex vivo imaging in a small subset, and comprehensive neuropathological assessment by established consensus protocols. Fourteen brains were obtained over 2 years from women with documented IPV (aged 3rd-8th decade; median, 4th) and complex histories including prior TBI in 6, nonfatal strangulation in 4, cerebrovascular, neurological, and/or psychiatric conditions in 13, and epilepsy in 7. At autopsy, all had TBI stigmata (old and/or recent). In addition, white matter regions vulnerable to diffuse axonal injury showed perivascular and parenchymal iron deposition and microgliosis in some subjects. Six cases had evidence of cerebrovascular disease (lacunes and/or chronic infarcts). Regarding neurodegenerative disease pathologies, Alzheimer disease neuropathologic change was present in a single case (8th decade), with no chronic traumatic encephalopathy neuropathologic change (CTE-NC) identified in any. Findings from this initial series then prompted similar exploration in an expanded case series of 70 archival IPV cases (aged 2nd-9th decade; median, 4th) accrued from multiple international institutions. In this secondary case series, we again found evidence of vascular and white matter pathologies. However, only limited neurodegenerative proteinopathies were encountered in the oldest subjects, none meeting consensus criteria for CTE-NC. These observations from this descriptive exploratory study reinforce a need to consider broad co-morbid and neuropathological substrates contributing to brain health outcomes in the context of IPV, some of which may be potentially modifiable.

Comorbid neuropathological diagnoses in early versus late-onset Alzheimer's disease.

Co-pathologies play an important role in the expression of the Alzheimer's disease clinical phenotype and may influence treatment efficacy. Early-onset Alzheimer's disease, defined as manifesting before age 65, is viewed as a relatively pure form of Alzheimer's disease with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with early-onset Alzheimer's disease (median age of onset = 55 years, 44 females) and 48 with late-onset Alzheimer's disease (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of Alzheimer's disease. Prevalence and stage of Lewy body disease, limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease, hippocampal sclerosis, cerebral amyloid angiopathy, and vascular brain injury were compared between the two cohorts. We found at least one non-Alzheimer's disease pathological diagnosis in 98% of patients with early-onset Alzheimer's disease (versus 100% of late onset), and the number of comorbid diagnoses per patient was lower in early-onset than in late-onset Alzheimer's disease (median = 2 versus 3, Mann-Whitney Z = 3.00, P = 0.002). Lewy body disease and cerebral amyloid angiopathy were common in both early and late onset Alzheimer's disease (cerebral amyloid angiopathy: 86% versus 79%, Fisher exact P = 0.33; Lewy body disease: 49% versus 42%, P = 0.48, respectively), although amygdala-predominant Lewy body disease was more common in early than late onset Alzheimer's disease (22% versus 6%, P = 0.02). In contrast, LATE (35% versus 8%, P < 0.001), hippocampal sclerosis (15% versus 3%, P = 0.02), argyrophilic grain disease (58% versus 41%, P = 0.052), and vascular brain injury (65% versus 39%, P = 0.004) were more common in late than in early onset Alzheimer's disease, respectively. The number of co-pathologies predicted worse cognitive performance at the time of death on Mini-Mental State Examination [1.4 points/pathology (95% confidence interval, CI -2.5 to -0.2) and Clinical Dementia Rating-Sum of Boxes (1.15 point/pathology, 95% CI 0.45 to 1.84)], across early and late onset cohorts. The effect of sex on the number of co-pathologies was not significant (P = 0.17). Prevalence of at least one APOE ε4 allele was similar across the two cohorts (52% and 54%) and was associated with a greater number of co-pathologies (+0.40, 95% CI 0.01 to 0.79, P = 0.047), independent of age of symptom onset, sex, and disease duration. Females showed higher density of neurofibrillary tangles compared to males, controlling for age of onset, APOE ε4, and disease duration. Our findings suggest that non-Alzheimer's disease pathological diagnoses play an important role in the clinical phenotype of early onset Alzheimer's disease with potentially significant implications for clinical practice and clinical trials design.

Alzheimer's disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation.

The clinical spectrum of Alzheimer's disease (AD) extends well beyond the classic amnestic-predominant syndrome. The previous studies have suggested differential neurofibrillary tangle (NFT) burden between amnestic and logopenic primary progressive aphasia presentations of AD. In this study, we explored the regional distribution of NFT pathology and its relationship to AD presentation across five different clinical syndromes. We assessed NFT density throughout six selected neocortical and hippocampal regions using thioflavin-S fluorescent microscopy in a well-characterized clinicopathological cohort of pure AD cases enriched for atypical clinical presentations. Subjects underwent apolipoprotein E genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established composite z score. Our results showed that NFT regional burden aligns with the clinical presentation and region-specific cognitive scores. Cortical, but not hippocampal, NFT burden was higher among atypical clinical variants relative to the amnestic syndrome. In analyses of specific clinical variants, logopenic primary progressive aphasia showed higher NFT density in the superior temporal gyrus (p = 0.0091), and corticobasal syndrome showed higher NFT density in the primary motor cortex (p = 0.0205) relative to the amnestic syndrome. Higher NFT burden in the angular gyrus and CA1 sector of the hippocampus were independently associated with worsening visuospatial dysfunction. In addition, unbiased hierarchical clustering based on regional NFT densities identified three groups characterized by a low overall NFT burden, high overall burden, and cortical-predominant burden, respectively, which were found to differ in sex ratio, age, disease duration, and clinical presentation. In comparison, the typical, hippocampal sparing, and limbic-predominant subtypes derived from a previously proposed algorithm did not reproduce the same degree of clinical relevance in this sample. Overall, our results suggest domain-specific functional consequences of regional NFT accumulation. Mapping these consequences presents an opportunity to increase understanding of the neuropathological framework underlying atypical clinical manifestations.

Resiliency to Alzheimer's disease neuropathology can be distinguished from dementia using cortical astrogliosis imaging.

Despite the presence of significant Alzheimer's disease (AD) pathology, characterized by amyloid ß (Aß) plaques and phosphorylated tau (pTau) tangles, some cognitively normal elderly individuals do not inevitably develop dementia. These findings give rise to the notion of cognitive 'resilience', suggesting maintained cognitive function despite the presence of AD neuropathology, highlighting the influence of factors beyond classical pathology. Cortical astroglial inflammation, a ubiquitous feature of symptomatic AD, shows a strong correlation with cognitive impairment severity, potentially contributing to the diversity of clinical presentations. However, noninvasively imaging neuroinflammation, particularly astrogliosis, using MRI remains a significant challenge. Here we sought to address this challenge and to leverage multidimensional (MD) MRI, a powerful approach that combines relaxation with diffusion MR contrasts, to map cortical astrogliosis in the human brain by accessing sub-voxel information. Our goal was to test whether MD-MRI can map astroglial pathology in the cerebral cortex, and if so, whether it can distinguish cognitive resiliency from dementia in the presence of hallmark AD neuropathological changes. We adopted a multimodal approach by integrating histological and MRI analyses using human postmortem brain samples. Ex vivo cerebral cortical tissue specimens derived from three groups comprised of non-demented individuals with significant AD pathology postmortem, individuals with both AD pathology and dementia, and non-demented individuals with minimal AD pathology postmortem as controls, underwent MRI at 7 T. We acquired and processed MD-MRI, diffusion tensor, and quantitative T 1 and T 2 MRI data, followed by histopathological processing on slices from the same tissue. By carefully co-registering MRI and microscopy data, we performed quantitative multimodal analyses, leveraging targeted immunostaining to assess MD-MRI sensitivity and specificity towards Aß, pTau, and glial fibrillary acidic protein (GFAP), a marker for astrogliosis. Our findings reveal a distinct MD-MRI signature of cortical astrogliosis, enabling the creation of predictive maps for cognitive resilience amid AD neuropathological changes. Multiple linear regression linked histological values to MRI changes, revealing that the MD-MRI cortical astrogliosis biomarker was significantly associated with GFAP burden (standardized ß=0.658, pFDR<0.0001), but not with Aß (standardized ß=0.009, p FDR =0.913) or pTau (standardized ß=-0.196, p FDR =0.051). Conversely, none of the conventional MRI parameters showed significant associations with GFAP burden in the cortex. While the extent to which pathological glial activation contributes to neuronal damage and cognitive impairment in AD is uncertain, developing a noninvasive imaging method to see its affects holds promise from a mechanistic perspective and as a potential predictor of cognitive outcomes.

Mapping the individual human cortex using multidimensional MRI and unsupervised learning.

Human evolution has seen the development of higher-order cognitive and social capabilities in conjunction with the unique laminar cytoarchitecture of the human cortex. Moreover, early-life cortical maldevelopment has been associated with various neurodevelopmental diseases. Despite these connections, there is currently no noninvasive technique available for imaging the detailed cortical laminar structure. This study aims to address this scientific and clinical gap by introducing an approach for imaging human cortical lamina. This method combines diffusion-relaxation multidimensional MRI with a tailored unsupervised machine learning approach that introduces enhanced microstructural sensitivity. This new imaging method simultaneously encodes the microstructure, the local chemical composition and importantly their correlation within complex and heterogenous tissue. To validate our approach, we compared the intra-cortical layers obtained using our ex vivo MRI-based method with those derived from Nissl staining of postmortem human brain specimens. The integration of unsupervised learning with diffusion-relaxation correlation MRI generated maps that demonstrate sensitivity to areal differences in cytoarchitectonic features observed in histology. Significantly, our observations revealed layer-specific diffusion-relaxation signatures, showing reductions in both relaxation times and diffusivities at the deeper cortical levels. These findings suggest a radial decrease in myelin content and changes in cell size and anisotropy, reflecting variations in both cytoarchitecture and myeloarchitecture. Additionally, we demonstrated that 1D relaxation and high-order diffusion MRI scalar indices, even when aggregated and used jointly in a multimodal fashion, cannot disentangle the cortical layers. Looking ahead, our technique holds the potential to open new avenues of research in human neurodevelopment and the vast array of disorders caused by disruptions in neurodevelopment.

Performance of a condensed protocol to assess limbic-predominant age-related TDP-43 encephalopathy neuropathologic change.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a dementia-related proteinopathy common in the elderly population. LATE-NC stages 2 or 3 are consistently associated with cognitive impairment. A condensed protocol (CP) for the assessment of Alzheimer disease neuropathologic change and other disorders associated with cognitive impairment, recommended sampling of small brain portions from specific neuroanatomic regions that were consolidated, resulting in significant cost reduction. Formal evaluation of the CP for LATE-NC staging was not previously performed. Here, we determined the ability of the CP to identify LATE-NC stages 2 or 3. Forty brains donated to the University of Washington BioRepository and Integrated Neuropathology laboratory with known LATE-NC status were resampled. Slides containing brain regions required for LATE-NC staging were immunostained for phospho-TDP-43 and reviewed by 6 neuropathologists blinded to original LATE-NC diagnosis. Overall group performance distinguishing between LATE-NC stages 0-1 and 2-3 was 85% (confidence interval [CI]: 75%-92%). We also used the CP to evaluate LATE-NC in a hospital autopsy cohort, in which LATE-NC was more common in individuals with a history of cognitive impairment, older age, and/or comorbid hippocampal sclerosis. This study shows that the CP can effectively discriminate higher stages of LATE-NC from low or no LATE-NC and that it can be successfully applied in clinical practice using a single tissue block and immunostain.

Association of Traumatic Brain Injury with Late Life Neuropathological Outcomes in a Community-Based Cohort.

BACKGROUND: Prior studies into the association of head trauma with neuropathology have been limited by incomplete lifetime neurotrauma exposure characterization. OBJECTIVE: To investigate the neuropathological sequelae of traumatic brain injury (TBI) in an autopsy sample using three sources of TBI ascertainment, weighting findings to reflect associations in the larger, community-based cohort. METHODS: Self-reported head trauma with loss of consciousness (LOC) exposure was collected in biennial clinic visits from 780 older adults from the Adult Changes in Thought study who later died and donated their brain for research. Self-report data were supplemented with medical record abstraction, and, for 244 people, structured interviews on lifetime head trauma. Neuropathology outcomes included Braak stage, CERAD neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral/cortical atrophy. Exposures were TBI with or without LOC. Modified Poisson regressions adjusting for age, sex, education, and APOE ɛ4 genotype were weighted back to the full cohort of 5,546 participants. RESULTS: TBI with LOC was associated with the presence of cerebral cortical atrophy (Relative Risk 1.22, 95% CI 1.02, 1.42). None of the other outcomes was associated with TBI with or without LOC. CONCLUSION: TBI with LOC was associated with increased risk of cerebral cortical atrophy. Despite our enhanced TBI ascertainment, we found no association with the Alzheimer's disease-related neuropathologic outcomes among people who survived to at least age 65 without dementia. This suggests the pathophysiological processes underlying post-traumatic neurodegeneration are distinct from the hallmark pathologies of Alzheimer's disease.

Protocol for the Systematic Fixation, Circuit-Based Sampling, and Qualitative and Quantitative Neuropathological Analysis of Human Brain Tissue.

Human brain tissue has long been a critical resource for neuroanatomy and neuropathology, but with the advent of advanced imaging and molecular sequencing techniques, it has become possible to use human brain tissue to study, in great detail, the structural, molecular, and even functional underpinnings of human brain disease. In the century following the first description of Alzheimer's disease (AD), numerous technological advances applied to human tissue have enabled novel diagnostic approaches using diverse physical and molecular biomarkers, and many drug therapies have been tested in clinical trials (Schachter and Davis, Dialogues Clin Neurosci 2:91-100, 2000). The methods for brain procurement and tissue stabilization have remained somewhat consistently focused on formalin fixation and freezing. Although these methods have enabled research protocols of multiple modalities, new, more advanced technologies demand improved methodologies for the procurement, characterization, stabilization, and preparation of both normal and diseased human brain tissues. Here, we describe our current protocols for the procurement and characterization of fixed brain tissue, to enable systematic and precisely targeted diagnoses, and describe the novel, quantitative molecular, and neuroanatomical studies that broadly expand the use of formalin-fixed, paraffin-embedded (FFPE) tissue that will further our understanding of the mechanisms underlying human neuropathologies.

Tractography-Pathology Correlations in Traumatic Brain Injury: A TRACK-TBI Study.

Diffusion tractography magnetic resonance imaging (MRI) can infer changes in network connectivity in patients with traumatic brain injury (TBI), but the pathological substrates of disconnected tracts have not been well defined because of a lack of high-resolution imaging with histopathological validation. We developed an ex vivo MRI protocol to analyze tract terminations at 750-µm isotropic resolution, followed by histopathological evaluation of white matter pathology, and applied these methods to a 60-year-old man who died 26 days after TBI. Analysis of 74 cerebral hemispheric white matter regions revealed a heterogeneous distribution of tract disruptions. Associated histopathology identified variable white matter injury with patchy deposition of amyloid precursor protein (APP), loss of neurofilament-positive axonal processes, myelin dissolution, astrogliosis, microgliosis, and perivascular hemosiderin-laden macrophages. Multiple linear regression revealed that tract disruption strongly correlated with the density of APP-positive axonal swellings and neurofilament loss. Ex vivo diffusion MRI can detect tract disruptions in the human brain that reflect axonal injury.

The Delayed Neuropathological Consequences of Traumatic Brain Injury in a Community-Based Sample.

The late neuropathological effects of traumatic brain injury have yet to be fully elucidated, particularly with respect to community-based cohorts. To contribute to this critical gap in knowledge, we designed a multimodal neuropathological study, integrating traditional and quantitative approaches to detect pathologic changes in 532 consecutive brain autopsies from participants in the Adult Changes in Thought (ACT) study. Diagnostic evaluation including assessment for chronic traumatic encephalopathy (CTE) and quantitative immunoassay-based methods were deployed to examine levels of pathological (hyperphosphorylated) tau (pTau) and amyloid (A) ß in brains from ACT participants with (n = 107) and without (n = 425) history of remote TBI with loss of consciousness (w/LOC). Further neuropathological assessments included immunohistochemistry for α-synuclein and phospho-TDP-43 pathology and astro- (GFAP) and micro- (Iba1) gliosis, mass spectrometry analysis of free radical injury, and gene expression evaluation (RNA sequencing) in a smaller sub-cohort of matched samples (49 cases with TBI and 49 non-exposed matched controls). Out of 532 cases, only 3 (0.6%-none with TBI w/LOC history) showed evidence of the neuropathologic signature of chronic traumatic encephalopathy (CTE). Across the entire cohort, the levels of pTau and Aß showed expected differences for brain region (higher levels in temporal cortex), neuropathological diagnosis (higher in participants with Alzheimer's disease), and APOE genotype (higher in participants with one or more APOE ε4 allele). However, no differences in PHF-tau or Aß1-42 were identified by Histelide with respect to the history of TBI w/LOC. In a subset of TBI cases with more carefully matched control samples and more extensive analysis, those with TBI w/LOC history had higher levels of hippocampal pTau but no significant differences in Aß, α-synuclein, pTDP-43, GFAP, Iba1, or free radical injury. RNA-sequencing also did not reveal significant gene expression associated with any measure of TBI exposure. Combined, these findings suggest long term neuropathological changes associated with TBI w/LOC may be subtle, involve non-traditional pathways of neurotoxicity and neurodegeneration, and/or differ from those in autopsy cohorts specifically selected for neurotrauma exposure.

Language and spatial dysfunction in Alzheimer disease with white matter thorn-shaped astrocytes.

OBJECTIVES: Alzheimer disease (AD) shows a broad array of clinical presentations, but the mechanisms underlying these phenotypic variants remain elusive. Aging-related astrogliopathy (ARTAG) is a relatively recent term encompassing a broad array of tau deposition in astroglia outside the range of traditional tauopathies. White matter thorn-shaped astrocyte (WM-TSA) clusters, a specific ARTAG subtype, has been associated with atypical language presentation of AD in a small study lacking replication. To interrogate the impact of WM-TSA in modifying clinical phenotype in AD, we investigated a clinicopathologic sample of 83 persons with pure cortical AD pathology and heterogeneous clinical presentations. METHODS: We mapped WM-TSA presence and density throughout cortical areas and interrogated whether WM-TSA correlated with atypical AD presentation or worse performance in neuropsychological testing. RESULTS: WM-TSA was present in nearly half of the cases and equally distributed in typical and atypical AD presentations. Worsening language and visuospatial functions were correlated with higher WM-TSA density in language-related and visuospatial-related regions, respectively. These findings were unrelated to regional neurofibrillary tangle burden. Next, unsupervised clustering divided the participants into 2 groups: a high-WM-TSA (n = 9) and low-WM-TSA (n = 74) pathology signature. The high-WM-TSA group scored significantly worse in language but not in other cognitive domains. CONCLUSIONS: The negative impact of WM-TSA pathology to language and possibly visuospatial networks suggests that WM-TSA is not as benign as other ARTAG types and may be explored as a framework to understand the mechanisms and impact of astrocytic tau deposition in AD in humans.

Antimalarial myopathy in a systemic lupus erythematosus patient with quadriparesis and seizures: a case-based review.

Weakness, seizures, and encephalopathy have a broad differential diagnosis in patients with systemic lupus erythematosus (SLE). We present a case of a 26-year-old female with a recent diagnosis of SLE who experienced a clinical deterioration with quadriparesis, seizures, and encephalopathy. Her quadriparesis was found to be secondary to biopsy-proven hydroxychloroquine-induced myopathy with concomitant inflammatory myopathy. Her seizures and encephalopathy were suspected to be multifactorial in the setting of sepsis and critical illness with possible contributions from neuropsychiatric manifestations of SLE and macrophage activation syndrome. She experienced a dramatic clinical recovery with discontinuation of hydroxychloroquine, treatment of lupus disease activity with mycophenolate mofetil and prednisone, and antibiotic treatment for methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. This case-based review provides a systematic approach to quadriparesis, seizures, and encephalopathy in patients with SLE and an evidence-based discussion of antimalarial myopathy, which is of critical importance given the widespread use of antimalarial medications for rheumatologic diseases.

Pathologic manifestations of levamisole-adulterated cocaine exposure.

Rheumatic manifestations of cocaine have been well described, but more recently, a dramatic increase in the levamisole-adulterated cocaine supply in the United States has disclosed unique pathologic consequences that are distinct from pure cocaine use. Most notably, patients show skin lesions and renal dysfunction in the setting of extremely high perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA). Unexpectedly, antibodies to myeloperoxidase, the typical target of p-ANCA, are relatively low if at all present. This discrepancy is due to the fact that p-ANCA seen in association with levamisole-adulterated cocaine exposure is often directed against atypical p-ANCA-associated antigens within the neutrophil granules such as human neutrophil elastase, lactoferrin, and cathepsin G. Biopsies of the skin lesions reveal leukocytoclastic vasculitis often involving both superficial and deep dermal vessels. Renal injury most typically manifests as crescentic and necrotizing pauci-immune glomerulonephritis. In this review, the manifestations of levamisole-adulterated cocaine-induced vasculitis are discussed with an emphasis on the typical histomorphologic findings seen on biopsy. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1764738711370019 .

Evaluating and treating neurobehavioral symptoms in professional American football players: Lessons from a case series.

In the aftermath of multiple high-profile cases of chronic traumatic encephalopathy (CTE) in professional American football players, physicians in clinical practice are likely to face an increasing number of retired football players seeking evaluation for chronic neurobehavioral symptoms. Guidelines for the evaluation and treatment of these patients are sparse. Clinical criteria for a diagnosis of CTE are under development. The contribution of CTE vs other neuropathologies to neurobehavioral symptoms in these players remains unclear. Here we describe the experience of our academic memory clinic in evaluating and treating a series of 14 self-referred symptomatic players. Our aim is to raise awareness in the neurology community regarding the different clinical phenotypes, idiosyncratic but potentially treatable symptoms, and the spectrum of underlying neuropathologies in these players.