Sports Concussion and Chronic Traumatic Encephalopathy: Finding a Path Forward.

Sports concussion has recently assumed special importance because of the widely publicized entity of chronic traumatic encephalopathy (CTE). Identified primarily in former contact sports athletes with repeated mild traumatic brain injury (mTBI), CTE is a distinct tauopathy that can only be diagnosed postmortem and for which no specific treatment is available. Although the hazards of repeated mTBI are generally acknowledged, a spirited controversy has developed because a firm link between sports concussion and CTE has been questioned. We briefly review the history of CTE, discuss areas of uncertainty, and offer suggestions to assist neurologists confronting these issues and advance understanding of this vexing problem. ANN NEUROL 2023;93:222-225.

Psychiatric Screening Measures in Behavioral Variant Frontotemporal Dementia.

OBJECTIVE: Behavioral variant frontotemporal dementia (bvFTD) is sometimes misdiagnosed as a primary psychiatric disorder, such as major depressive disorder, bipolar disorder, an anxiety disorder, autism spectrum disorder (ASD), or attention-deficit hyperactivity disorder (ADHD). Nonspecialists often use screening measures for primary psychiatric disorders in early assessments of persons with bvFTD. The investigators aimed to evaluate the manifestations of bvFTD in surveys intended to screen for primary psychiatric disorders. METHODS: Patients with bvFTD (N=27) presenting to an academic neurobehavior specialty clinic and their caregivers were provided questionnaire packets including the Mood Disorder Questionnaire (MDQ), the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 scale (GAD-7), the Adult ADHD Self-Report Scale, version 1.1, the Ritvo Autism and Asperger Diagnostic Scale, and the Neuropsychiatric Inventory Questionnaire. Established cutoff scores suggesting the presence of a primary psychiatric disorder were used to define a "positive" response. Individual questions from each screening questionnaire were examined for a more granular characterization of bvFTD. RESULTS: Overall, 15% of bvFTD patients screened positive for bipolar disorder, 54% screened positive for ADHD, and 89% screened positive for ASD. Hyperactivity or hypersensitivity symptoms were infrequently endorsed. In addition, 57% of respondents screened positive for depressive symptoms on the PHQ-9, and 43% screened positive for anxiety symptoms on the GAD-7. CONCLUSIONS: The use of cutoff scores on screening measures for primary psychiatric disorders resulted in potentially problematic positive screens of primary psychiatric disorders among persons with bvFTD. Identifying specific questions that distinguish between bvFTD and primary psychiatric disorders requires further study.

Astrogliosis, neuritic microstructure, and sex effects: GFAP is an indicator of neuritic orientation in women.

BACKGROUND: Data from human studies suggest that immune dysregulation is associated with Alzheimer's disease (AD) pathology and cognitive decline and that neurites may be affected early in the disease trajectory. Data from animal studies further indicate that dysfunction in astrocytes and inflammation may have a pivotal role in facilitating dendritic damage, which has been linked with negative cognitive outcomes. To elucidate these relationships further, we have examined the relationship between astrocyte and immune dysregulation, AD-related pathology, and neuritic microstructure in AD-vulnerable regions in late life. METHODS: We evaluated panels of immune, vascular, and AD-related protein markers in blood and conducted in vivo multi-shell neuroimaging using Neurite Orientation Dispersion and Density Imaging (NODDI) to assess indices of neuritic density (NDI) and dispersion (ODI) in brain regions vulnerable to AD in a cohort of older adults (n = 109). RESULTS: When examining all markers in tandem, higher plasma GFAP levels were strongly related to lower neurite dispersion (ODI) in grey matter. No biomarker associations were found with higher neuritic density. Associations between GFAP and neuritic microstructure were not significantly impacted by symptom status, APOE status, or plasma Aß42/40 ratio; however, there was a large sex effect observed for neurite dispersion, wherein negative associations between GFAP and ODI were only observed in females. DISCUSSION: This study provides a comprehensive, concurrent appraisal of immune, vascular, and AD-related biomarkers in the context of advanced grey matter neurite orientation and dispersion methodology. Sex may be an important modifier of the complex associations between astrogliosis, immune dysregulation, and brain microstructure in older adults.

Incongruences Between Facial Expression and Self-Reported Emotional Reactivity in Frontotemporal Dementia and Related Disorders.

OBJECTIVE: Emotional reactivity normally involves a synchronized coordination of subjective experience and facial expression. These aspects of emotional reactivity can be uncoupled by neurological illness and produce adverse consequences for patient and caregiver quality of life because of misunderstandings regarding the patient's presumed internal state. Frontotemporal dementia (FTD) is often associated with altered social and emotional functioning. FTD is a heterogeneous disease, and socioemotional changes in patients could result from altered internal experience, altered facial expressive ability, altered language skills, or other factors. The authors investigated how individuals with FTD subtypes differ from a healthy control group regarding the extent to which their facial expressivity aligns with their self-reported emotional experience. METHODS: Using a compound measure of emotional reactivity to assess reactions to three emotionally provocative videos, the authors explored potential explanations for differences in alignment of facial expressivity with emotional experience, including parkinsonism, physiological reactivity, and nontarget verbal responses. RESULTS: Participants with the three main subtypes of FTD all tended to express less emotion on their faces than they did through self-report. CONCLUSIONS: Exploratory analyses suggest that reasons for this incongruence likely differ not only between but also within diagnostic subgroups.

New Frontier: The First Year of an Adult Neurodevelopmental Disabilities Clinic.

BACKGROUND: As patients with neurodevelopmental disorders (NDDs) transition from pediatric to adult health care systems, they often have difficulty finding physicians to address their NDD-related needs. In response to this care gap, we established a new consultation clinic within a behavioral neurology clinic in an adult neurology department to address the neurodevelopmental concerns of these adult patients. OBJECTIVE: To characterize the population of adult patients with NDDs seen in the adult NDD clinic in its first year. METHOD: Data were obtained by a retrospective chart review of all patients with NDDs seen in the adult NDD clinic from September 2020 through December 2021. RESULTS: Of the 86 patients who were seen in the adult NDD clinic, the average age was 34 years (SD = 15, range = 18-74 years). Developmental diagnoses included intellectual disability (63%), autism spectrum disorder (47%), Down syndrome (15%), cerebral palsy (9%), and other genetic disorders (26%). Comorbidities addressed included behavioral concerns (34%), anxiety (29%), seizure disorders (22%), and depression (15%). Behavioral and/or mental health concerns prompted 65% of the initial clinic visits. The most common recommendation made was to begin or increase exercise (59%), followed by facilitating connection to community, social, and employment resources. CONCLUSION: Adults with NDDs have diagnoses, comorbidities, and concerns that are similar to, but also distinct from, those addressed in other adult neurology clinics. This study addresses the need for, and feasibility of, caring for the diverse population of adults with NDDs in an adult neurology setting.

White Matter, Behavioral Neurology, and the Influence of Corticocentrism.

White matter in the human brain occupies roughly the same volume as gray matter but has received far less attention in behavioral neurology and related disciplines. In particular, the cerebral cortex has long dominated thinking about the organization of brain-behavior relationships. As a result, subcortical structures, including deep gray matter and, most notably, white matter, have been accorded relatively little neuroscientific study compared with the extensive work devoted to the cerebral cortex. The influence of corticocentrism can be explained by several factors, including historical precedent in neurology strongly emphasizing the importance of the cortex, a preponderance of investigative methods that selectively target this structure, and a misinterpretation of comparative neuroanatomic data gathered from normal brains. This paper will describe the background of the corticocentric bias and emphasize that white matter merits its own place within the study of the higher functions. Although corticocentrism continues to exert a powerful impact on behavioral neurology, considerable progress is being made in the study of white matter-a development that promises to expand our knowledge of the normal brain and lead to an improved understanding of how it mediates behavior. In turn, a range of vexing neurologic and psychiatric disorders may become better illuminated by considering pathology within, or dysfunction of, white matter tracts. A complete appreciation of brain-behavior relationships requires an understanding not only of the outermost layer of the cerebral hemispheres, but also of white matter connectivity that links gray matter regions into distributed neural networks that subserve cognition and emotion.

Cognitive Dysfunction in White Matter Disorders: New Perspectives in Treatment and Recovery.

White matter disorders are increasingly appreciated as capable of disrupting cognitive function, and this impairment may be sufficiently severe to produce the syndrome of white matter dementia. Although recognizing this problem is important for diagnostic accuracy, the treatment of cognitive dysfunction and dementia in the white matter disorders has received relatively little attention. Similarly, few data are available regarding the potential for cognitive recovery in these disorders. Recent clinical and laboratory advances, however, indicate that effective treatment and meaningful recovery may be achievable goals for many patients with macrostructural or microstructural white matter pathology. One recent observation is that leukoaraiosis has been observed to regress with treatment of hypertension, often with concomitant improvement in cognition. Equally novel is emerging evidence that white matter exhibits substantial plasticity related to activity-dependent myelination and that this phenomenon may produce clinical benefit. These insights suggest that noninvasive and inexpensive interventions targeting white matter are warranted for a wide range of cognitively impaired patients. Moreover, given the well-established risk that vascular white matter pathology portends for developing dementia-including both vascular dementia and Alzheimer's disease-the application of these principles before dementia onset may also be efficacious for prevention. In view of the increasingly compelling case for early white matter involvement in the etiopathogenesis of late-life dementia and the continuing lack of disease-modifying therapy, progress in treating cognitive disturbances arising from white matter disorders offers the prospect that this approach may enhance the prevention of dementia as well as the treatment of cognitive dysfunction.

The Marcus Institute for Brain Health: an integrated practice unit for the care of traumatic brain injury in military veterans.

PRIMARY OBJECTIVE: Traumatic brain injury (TBI) is a signature wound of recent Unites States military conflicts. The National Intrepid Center of Excellence (NICoE) has demonstrated that interdisciplinary care is effective for active-duty military personnel with TBI and related psychological health conditions. This paper details how the Marcus Institute for Brain Health (MIBH), established in 2017 as an Integrated Practice Unit (IPU), is founded on the NICoE model and is dedicated to interdisciplinary care for Veterans with persistent symptoms due to TBI and psychological comorbidities. RESEARCH DESIGN: A highly integrated group of clinicians from diverse disciplines combine their expertise to offer comprehensive evaluation, intensive outpatient treatment, and program outcomes evaluation. METHODS AND PROCEDURES: The role of each discipline in the provision of care, and the regular interaction of all clinicians, are delineated. A strong connection to academic medicine is maintained so that clinical research and education complement patient care. MAIN OUTCOMES AND RESULTS: Over three hundred veterans and family members have received treatment at the MIBH. Program evaluation is underway. CONCLUSIONS: As the understanding of TBI and related psychological conditions continues its rapid evolution, the expert interdisciplinary care at the MIBH has great promise as a Veteran counterpart of the NICoE.

Social Cognition and White Matter: Connectivity and Cooperation.

Humans are highly social animals whose survival and well-being depend on their capacity to cooperate in complex social settings. Advances in anthropology and psychology have demonstrated the importance of cooperation for enhancing social cohesion and minimizing conflict. The understanding of social behavior is informed by the notion of social cognition, a set of mental operations including emotion perception, mentalizing, and empathy. The social brain hypothesis posits that the mammalian brain has enlarged over evolution to meet the challenges of social life, culminating in a large human brain well adapted for social cognition. The structures subserving social cognition are mainly located in the frontal and temporal lobes, and although gray matter is critical, social cognition also requires white matter. Whereas the social brain hypothesis assumes that brain enlargement has been driven by neocortical expansion, cerebral white matter has expanded even more robustly than the neocortex, coinciding with the emergence of social cognition. White matter expansion is most evident in the frontal and temporal lobes, where it enhances connectivity between regions critical for social cognition. Myelination has, in turn, conferred adaptive social advantages by enabling prompt empathic concern for offspring and by strengthening networks that support cooperation and the related capacities of altruism and morality. Social cognition deficits related to myelinated tract involvement occur in many disorders, including stroke, Binswanger disease, traumatic brain injury, multiple sclerosis, glioma, and behavioral variant frontotemporal dementia. The contribution of white matter to social cognition can be conceptualized as the enhancement of cooperation through brain connectivity.

Morality and the Brain: The Right Hemisphere and Doing Right.

Morality, the set of shared attitudes and practices that regulate individual behavior to facilitate cohesion and well-being, is a function of the brain, yet its localization is uncertain. Neuroscientific study of morality has been conducted by examining departures from moral conduct after neurologic insult and by functional neuroimaging of moral decision-making in cognitively intact individuals. These investigations have yielded conflicting results: Acquired sociopathy, a syndromic surrogate for acquired immorality, has been reported predominantly after right frontotemporal lesions, whereas functional neuroimaging during moral decision-making has demonstrated bilateral activation. Although morality is bilaterally represented, the right hemisphere is clinically more critical in light of focal lesion data suggesting that moral behavior is subserved by a network of right frontotemporal structures and their subcortical connections. Evolution may have endowed the brain with bilaterally represented but unilaterally right-dominant morality. The unilateral dominance of morality permits concentration of an essential social cognitive function to support the perceptual and executive operations of moral behavior within a single hemisphere; the bilateral representation of morality allows activation of reserve tissue in the contralateral hemisphere in the event of an acquired hemispheric injury. The observed preponderance of right hemisphere lesions in individuals with acquired immorality offers a plausible hypothesis that can be tested in clinical settings. Advances in the neuroscience of morality promise to yield potentially transformative clinical and societal benefits. A deeper understanding of morality would help clinicians address disordered conduct after acquired neurologic insults and guide society in bolstering public health efforts to prevent brain disease.

Aprosodia and prosoplegia with right frontal neurodegeneration.

Affective prosody and facial expression are essential components of human communication. Aprosodic syndromes are associated with focal right cerebral lesions that impair the affective-prosodic aspects of language, but are rarely identified because affective prosody is not routinely assessed by clinicians. Inability to produce emotional faces (affective prosoplegia) is a related and important aspect of affective communication has overlapping neuroanatomic substrates with affective prosody. We describe a patient with progressive aprosodia and prosoplegia who had right greater than left perisylvian and temporal atrophy with an anterior predominance. We discuss the importance of assessing affective prosody and facial expression to arrive at an accurate clinical diagnosis.

The Expanding Prominence of Toxic Leukoencephalopathy.

Toxic leukoencephalopathy (TL) is a disorder of brain white matter caused by exposure to leukotoxic agents. Magnetic resonance imaging (MRI) can readily identify this syndrome, and, together with diffusion tensor imaging, MRI continues to offer important insights into its nature. Since the first formal description of TL in 2001, many new leukotoxic disorders have been recognized, and the range of leukotoxins has expanded to include more therapeutic drugs, drugs of abuse, and environmental insults. While the understanding of pathophysiology remains incomplete, TL is increasingly common in clinical practice, and the potential long-term cognitive sequelae of toxic white matter injury merit attention.

White matter and cognition: making the connection.

Whereas the cerebral cortex has long been regarded by neuroscientists as the major locus of cognitive function, the white matter of the brain is increasingly recognized as equally critical for cognition. White matter comprises half of the brain, has expanded more than gray matter in evolution, and forms an indispensable component of distributed neural networks that subserve neurobehavioral operations. White matter tracts mediate the essential connectivity by which human behavior is organized, working in concert with gray matter to enable the extraordinary repertoire of human cognitive capacities. In this review, we present evidence from behavioral neurology that white matter lesions regularly disturb cognition, consider the role of white matter in the physiology of distributed neural networks, develop the hypothesis that white matter dysfunction is relevant to neurodegenerative disorders, including Alzheimer's disease and the newly described entity chronic traumatic encephalopathy, and discuss emerging concepts regarding the prevention and treatment of cognitive dysfunction associated with white matter disorders. Investigation of the role of white matter in cognition has yielded many valuable insights and promises to expand understanding of normal brain structure and function, improve the treatment of many neurobehavioral disorders, and disclose new opportunities for research on many challenging problems facing medicine and society.

Clinical Phenotype of Adult Fragile X Gray Zone Allele Carriers: a Case Series.

Considerable research has focused on patients with trinucleotide (CGG) repeat expansions in the fragile X mental retardation 1 (FMR1) gene that fall within either the full mutation (>200 repeats) or premutation range (55-200 repeats). Recent interest in individuals with gray zone expansions (41-54 CGG repeats) has grown due to reported phenotypes that are similar to those observed in premutation carriers, including neurological, molecular, and cognitive signs. The purpose of this manuscript is to describe a series of adults with FMR1 alleles in the gray zone presenting with movement disorders or memory loss. Gray zone carriers ascertained in large FMR1 screening studies were identified and their clinical phenotypes studied. Thirty-one gray zone allele carriers were included, with mean age of symptom onset of 53 years in patients with movement disorders and 57 years in those with memory loss. Four patients were chosen for illustrative case reports and had the following diagnoses: early-onset Parkinson disease (PD), atypical parkinsonism, dementia, and atypical essential tremor. Some gray zone carriers presenting with parkinsonism had typical features, including bradykinesia, rigidity, and a positive response to dopaminergic medication. These patients had a higher prevalence of peripheral neuropathy and psychiatric complaints than would be expected. The patients seen in memory clinics had standard presentations of cognitive impairment with no apparent differences. Further studies are necessary to determine the associations between FMR1 expansions in the gray zone and various phenotypes of neurological dysfunction.

White Matter Dementia: Origin, Development, Progress, and Prospects.

The term white matter dementia (WMD) was introduced in 1988 to highlight the role of white matter in the development of dementia. As the concept has been refined with new insights into the structure and function of normal and abnormal white matter, research has expanded to consider normal cognition, network connectivity, novel treatment ideas, and the etiopathogenesis of neurodegenerative dementia. Emerging data are also identifying new opportunities for dementia prevention by avoidance of acquired vascular and traumatic white matter insults. The idea of WMD promises to continue as a useful construct informing the study of dementia and the understanding of brain-behavior relationships.

The nature of verbal memory impairment in multiple sclerosis: a list-learning and meta-analytic study.

The primary purpose of this study was to test the hypothesis that multiple sclerosis (MS) patients have impaired acquisition rather than a retrieval deficit. Verbal memory impairment in MS was examined in 53 relapsing-remitting MS patients and 31 healthy controls (HC), and in a meta-analysis of studies that examined memory functioning in MS with list-learning tasks. The MS group demonstrated significantly lower acquisition and delayed recall performance than the HC group, and the meta-analysis revealed that the largest effect sizes were obtained for acquisition measures relative to delayed recall and recognition. Our data argue against a retrieval deficit as the sole explanation for verbal memory impairment in MS, and make a consistent case for the position that deficient acquisition contributes to the memory dysfunction of MS patients. Deficient acquisition may result from demyelination in relevant white matter tracts that reduces encoding efficiency as a result of impaired speed of information processing.