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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. While 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. This article is protected by copyright. All rights reserved.

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.A highly integrated group of clinicians from diverse disciplines combine their expertise to offer comprehensive evaluation, intensive outpatient treatment, and program outcomes evaluation.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.Over three hundred veterans and family members have received treatment at the MIBH. Program evaluation is underway.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.

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.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.Participants with the three main subtypes of FTD all tended to express less emotion on their faces than they did through self-report.Exploratory analyses suggest that reasons for this incongruence likely differ not only between but also within diagnostic subgroups.

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.

Introduction Cannabis products, including cannabidiol (CBD) and tetrahydrocannabinol (THC), are increasingly easy to procure and use across the United States. The 2018 National Survey on Drug Use and Health (NSDUH) reported a past-month cannabis use rate of 8.6% among adults 26 years of age or older in the U.S. general population. Cannabis use is commonly reported by U.S. Military Veterans with histories of mild traumatic brain injury (mTBI) receiving services at the Marcus Institute for Brain Health (MIBH), a specialty interdisciplinary clinic serving this population. The aims of this study are to describe the frequency and characteristics of cannabis product use among Veterans evaluated at MIBH and to compare the rate of cannabis use in this group to that in the general and Veteran populations reported in the 2018 NSDUH. Materials and Methods Study data were collected as part of MIBH clinical assessments between January 2018 and December 2019, which included the evaluation of the current use of cannabis products. Affirmative cannabis use responses were clarified with inquiries about the frequency of use, method of administration, product ingredients (i.e., THC and/or CBD), and reason(s) for use. Results Among 163 MIBH patients (92.6% male), 72 (44.2%) endorsed cannabis product use during the month preceding the clinical assessment. Cannabis users were significantly younger than nonusers. The frequency of past-month cannabis use was significantly greater than that reported in the comparably aged NSDUH survey general and Veteran populations (44.2% vs. 8.6% and 44.2% vs. 7.7%, respectively, both P Conclusions Self-reported cannabis use is significantly higher in the MIBH population than in similarly aged individuals in the general population and significantly more frequent among younger than older members of this cohort. Self-reported reasons for cannabis use in this cohort included mTBI-associated neuropsychiatric symptoms, sleep disturbances, and pain for which standard treatments (both pharmacologic and nonpharmacologic) provided insufficient relief and/or produced treatment-limiting adverse events. However, cannabis use did not provide sufficient improvement in those symptoms to obviate the need for further evaluation and treatment of those problems at MIBH or to replace, in part or in whole, standard medications and other treatments for those problems. Further study of cannabis use, including standardized individual cannabinoid (i.e., THC and CBD) and whole-plant cannabis preparations, in this and similar cohorts is needed to more fully understand the drivers, benefits, risks, and safety of cannabis use in this and in similar Veteran populations, as well as the potential pharmacological and/or nonpharmacological therapeutic alternatives to cannabis use.

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.

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.

Abuse of opiates, cocaine, and lipophilic inhalants (e.g., toluene) can damage brain myelin and cause acute toxic leukoencephalopathy (TL), but little is known about recovery or prognosis in this condition. In light of the ongoing opiate epidemic in the United States, it is important to understand the natural history of patients who have acute neurological complications from illicit drug exposure. Our aim was to conduct a scoping review of the literature regarding prognosis in described cases of substance abuse-related TL.A strategic search of PubMed, Ovid, Cumulative Index to Nursing, and Allied Health Literature (CINAHL) databases yielded adult cases of acute TL from opiates, cocaine, or inhalants. Cases and case series were eligible for inclusion if they described acute leukoencephalopathy with a clear temporal association with opiate, cocaine, or inhalant abuse. Inclusion was contingent on availability of clinical descriptions until death or ≥ 4 weeks follow-up with neuroimaging consistent with TL.Among 52 cases from 14 articles, 21 (40.4%) individuals died with mean time to death of 28.2 days; with mean follow-up of 12.8 months, 10 (19.2%) survived with no recovery, 17 (32.7%) had partial recovery, and 4 (7.7%) individuals had full recovery.Substance abuse-related acute TL often has a poor prognosis, but partial or even full recovery is possible in a subgroup of individuals over months to years.

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.

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.

Genetic variants influence structural connectivity with intriguing clinical implications

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.

OBJECTIVE: To determine whether serum neurofilament light (NfL) correlates with CSF NfL, traumatic brain injury (TBI) diagnosis, injury severity, brain volume, and diffusion tensor imaging (DTI) estimates of traumatic axonal injury (TAI). METHODS: Participants were prospectively enrolled in Sweden and the United States between 2011 and 2019. The Swedish cohort included 45 hockey players with acute concussion sampled at 6 days, 31 with repetitive concussion with persistent postconcussive symptoms (PCS) assessed with paired CSF and serum (median 1.3 years after concussion), 28 preseason controls, and 14 nonathletic controls. Our second cohort included 230 clinic-based participants (162 with TBI and 68 controls). Patients with TBI also underwent serum, functional outcome, and imaging assessments at 30 (n = 30), 90 (n = 48), and 180 (n = 59) days and 1 (n = 84), 2 (n = 57), 3 (n = 46), 4 (n = 38), and 5 (n = 29) years after injury. RESULTS: In athletes with paired specimens, CSF NfL and serum NfL were correlated (r = 0.71, p < 0.0001). CSF and serum NfL distinguished players with PCS >1 year from PCS ≤1 year (area under the receiver operating characteristic curve [AUROC] 0.81 and 0.80). The AUROC for PCS >1 year vs preseason controls was 0.97. In the clinic-based cohort, NfL at enrollment distinguished patients with mild from those with moderate and severe TBI (p < 0.001 and p = 0.048). Serum NfL decreased over the course of 5 years (ß = −0.09 log pg/mL, p < 0.0001) but remained significantly elevated compared to controls. Serum NfL correlated with measures of functional outcome, MRI brain atrophy, and DTI estimates of TAI. CONCLUSIONS: Serum NfL shows promise as a biomarker for acute and repetitive sports-related concussion and patients with subacute and chronic TBI. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that increased concentrations of NfL distinguish patients with TBI from controls.

Individuals with a history of concussion report a notable rate of psychiatric symptoms. Some of these are best described as postconcussive and remit within days to weeks. However, other symptoms are more persistent and may require intervention. Within this chapter we will discuss psychiatric symptoms frequently noted among those with mild traumatic brain injury and strategies for assessment and treatment.

Introduction: Aging is associated with heterogeneous cognitive trajectories. There is considerable interest in identifying risk factors for pathological aging, with recent studies demonstrating a link between surgical procedures and proximal cognitive decline; however, the role of lifetime exposure to surgical procedures and cognitive function has been relatively unexplored. This pilot study aimed to evaluate the association between total lifetime surgical procedures and memory function in older adults. Methods: A cohort of 62 older adults underwent a neuropsychological evaluation and health history assessment. Self-reported lifetime surgical history was categorized as "cardiac" or "non-cardiac." General linear models were fit with demographics as nuisance covariates, and the total number of non-cardiac surgeries as our predictor of interest. Total scores on measures of episodic memory, language, working memory, fluency, and visuospatial function were separate outcome variables. In a secondary analysis, vascular risk factors were included as covariates. Diffusion tensor imaging was obtained for exploratory analyses of selected regions of interest. Results: The mean age of participants was 70, and 0-13 lifetime non-cardiac surgical procedures were reported. Higher numbers of lifetime non-cardiac surgical procedures were associated with worse verbal learning and memory (p = .04). The negative association between lifetime non-cardiac procedures and cognition was specific to memory. Exploratory analyses showed that higher number of lifetime non-cardiac procedures was related to lower FA in the fornix body (p = .02). Conclusions: These results of this pilot study suggest that greater lifetime exposure to surgery may be associated with worse verbal learning and memory in healthy older adults. These findings add to a growing body of literature suggesting that cumulative medical events may be risk factors for negative cognitive outcomes.

Introduction Our objective was to determine whether non-standardized testing of olfaction may provide useful information for predicting cognitive dysfunction and decline in patients with neurobehavioral disorders. Methods We conducted cross-sectional and longitudinal analyses of 82 patients who presented to a Memory Clinic with a chief complaint of cognitive deficits using non-standardized odor identification testing (nSOIT). Each patient was classified as having intact or impaired olfaction based on the ability to identify and name the odor of coffee grounds. The cross-sectional study used Student's t-test to examine whether nSOIT results were related to cognitive dysfunction as approximated by Montreal Cognitive Assessment (MoCA) scores. The longitudinal study used mixed effects multiple regression with an interaction term to investigate whether nSOIT results were predictive of cognitive decline over a period of follow-up testing (0.4 to 4.0 years [mean 1.4, SD 0.8]) to compare patients who exhibited cognitive decline over the evaluation period (decliners) and those who did not (non-decliners). Results Analysis of the initial use of nSOIT in the cross-sectional study demonstrated no association between nSOIT performance and objective cognitive dysfunction. In the longitudinal study, impairment in follow-up nSOIT testing was found to be a sensitive but nonspecific predictor of cognitive decline. Conclusion These results suggest that routine olfactory testing may serve as a convenient and readily available method that can be used by clinicians to better predict cognitive dysfunction and decline in patients with a variety of neurobehavioral disorders.

Objective Standardized cognitive tests and functional magnetic resonance imaging (fMRI) studies of systemic lupus erythematosus (SLE) patients demonstrate deficits in working memory and executive function. These neurobehavioral abnormalities are not well studied in antiphospholipid syndrome, which may occur independently of or together with SLE. This study compares an fMRI paradigm involving motor skills, working memory, and executive function in SLE patients without antiphospholipid antibody (aPL) (the SLE group), aPL-positive non-SLE patients (the aPL-positive group), and controls. Methods Brain MRI, fMRI, and standardized cognitive assessment results were obtained from 20 SLE, 20 aPL-positive, and 10 healthy female subjects with no history of neuropsychiatric abnormality. Results Analysis of fMRI data showed no differences in performance across groups on bilateral motor tasks. When analysis of variance was used, significant group differences were found in 2 executive function tasks (word generation and word rhyming) and in a working memory task (N-Back). Patients positive for aPL demonstrated higher activation in bilateral frontal, temporal, and parietal cortices compared to controls during working memory and executive function tasks. SLE patients also demonstrated bilateral frontal and temporal activation during working memory and executive function tasks. Conclusion Compared to controls, both aPL-positive and SLE patients had elevated cortical activation, primarily in the frontal lobes, during tasks involving working memory and executive function. These findings are consistent with cortical overactivation as a compensatory mechanism for early white matter neuropathology in these disorders.

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 representation of cognitive function in the cerebral cortex has a long and cherished history, but much evidence also supports a critical role of subcortical structures in the operations of cognition. The idea of subcortical dementia, first proposed in 1932 and substantially expanded in the 1970s, is the most prominent formulation intended to capture the phenomenology of cognitive impairment attributable to subcortical involvement. Despite criticism highlighting its imprecision, subcortical dementia has endured as a useful general concept assisting the classification of dementia syndromes based on the primary site(s) of neuropathology. As neuroscientific knowledge expanded with the advent of modern structural and functional neuroimaging, a more detailed understanding of the contributions of specific subcortical regions emerged, such that the cognitive affiliations of the basal ganglia, thalamus, cerebellum, brainstem, and white matter are all better defined. Important advances have been made by the study of both neurodegenerative diseases and focal lesions. Today, the complex admixture of cortical and subcortical foundations of cognition is increasingly well appreciated, and has been conceptually organized within the broadly inclusive notion of distributed neural networks. These networks are thought to integrate cortical and subcortical gray and white matter structures throughout the brain into functional neuronal ensembles subserving various domains of cognition. In this light, specific disorders of subcortical regions produce cognitive sequelae that can be usefully analyzed within the context of networks that involve key cortical regions as well. The study of subcortical contributions to cognition has been highly informative in expanding neurobehavioral thinking to include regions beyond the cerebral cortex, adding nuance and sophistication to the conceptualization of brain-behavior relationships.

Objective This pilot study aimed to examine longitudinal changes in brain structure and function in patients with systemic lupus erythematosus (SLE) using diffusion tensor imaging (DTI) and neuropsychological testing. Methods Fifteen female SLE patients with no history of major neuropsychiatric (NP) manifestations had brain magnetic resonance imaging (MRI) with DTI at baseline and approximately 1.5 years later. At the same time points, a standardized battery of cognitive tests yielding a global cognitive impairment index (CII) was administered. At baseline, the SLE patients had mean age of 34.0 years (SD = 11.4), mean education of 14.9 years (SD = 2.1), and mean disease duration of 121.5 months (SD = 106.5). The MRI images were acquired with a 3T GE MRI scanner. A DTI sequence with 33 diffusion directions and b-value of 800 s/mm2 was used. Image acquisition time was about 10 minutes. Results No significant change in cognitive dysfunction (from the CII) was detected. Clinically evaluated MRI scans remained essentially unchanged, with 62% considered normal at both times, and the remainder showing white matter (WM) hyperintensities that remained stable or resolved. DTI showed decreased fractional anisotropy (FA) and increased mean diffusivity (MD) in bilateral cerebral WM and gray matter (GM) with no major change in NP status, medical symptoms, or medications over time. Lower FA was found in the following regions: left and right cerebral WM, and in GM areas including the parahippocampal gyrus, thalamus, precentral gyrus, postcentral gyrus, angular gyrus, parietal lobe, and cerebellum. Greater MD was found in the following regions: left and right cerebral WM, frontal cortex, left cerebral cortex, and the putamen. Conclusions This is the first longitudinal study of DTI and cognition in SLE, and results disclosed changes in both WM and GM without cognitive decline over an 18-month period. DTI abnormalities in our participants were not associated with emergent NP activity, medical decline, or medication changes, and the microstructural changes developed in the absence of macrostructural abnormalities on standard MRI. Microstructural changes may relate to ongoing inflammation, and the stability of cognitive function may be explained by medical treatment, the variability of NP progression in SLE, or the impact of cognitive reserve.

Traumatic brain injury (TBI) is a leading cause of disability and produces a wide range of cognitive, emotional, and physical consequences. The impact of TBI on cognition is among the most important questions in this field but remains incompletely understood. The immediate cognitive effects of concussion, while usually short-lived, may be profound and lasting in some individuals, and long-term sequelae of TBI may include dementia of several varieties including post-traumatic leukoencephalopathy, chronic traumatic encephalopathy, and Alzheimer's disease. Whereas the etiopathogenesis of cognitive dysfunction after TBI remains uncertain, a reasonable point to begin is a focus on the white matter of the brain, where the neuropathological lesion known as diffuse axonal injury (DAI) is routinely identified. White matter is not typically accorded the significance granted to cortical gray matter in discussions of cognitive dysfunction and dementia, but increasing evidence is accumulating to suggest that cognitive decline after TBI is a direct result of white matter injury, and that lesions in this brain component are crucial in the sequence of events leading ultimately to dementia of several types. In this review, we consider the topic of white matter and cognition in TBI, beginning with DAI and proceeding to the role of inflammation in the pathogenesis of cognitive dysfunction and dementia that can follow. A brief review of possible therapeutic options will also be offered, including the use of anti-inflammatory agents and the exploitation of white matter plasticity, to treat acute and post-acute injuries, and lower the incidence of dementia resulting from TBI.

Objective: This cross-sectional, observational study examined the role of white matter involvement in the cognitive impairment of individuals with the fragile X mental retardation 1 ( FMR1 ) premutation. Methods: Eight asymptomatic premutation carriers, 5 participants with fragile X tremor/ataxia syndrome (FXTAS), and 7 noncarrier controls were studied. The mean age of the asymptomatic premutation carriers, participants with FXTAS, and noncarrier controls was 60, 71, and 67 years, respectively. Magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) were used to examine the middle cerebellar peduncles (MCP) and the genu and splenium of the corpus callosum in relation to executive function and processing speed. MRS measures were N -acetyl aspartate/creatine (NAA/Cr) and choline/creatine, and fractional anisotropy (FA) was used for DTI. Executive function was assessed with the Behavioral Dyscontrol Scale and the Controlled Oral Word Association Test (COWAT), and processing speed with the Symbol Digit Modalities Test. Results: Among all 13 FMR1 premutation carriers, significant correlations were found between N -acetyl aspartate/creatine and choline/creatine in the MCP and COWAT scores, and between FA in the genu and performance on the Behavioral Dyscontrol Scale, COWAT, and Symbol Digit Modalities Test; a correlation was also found between FA in the splenium and COWAT performance. In all regions studied, participants with FXTAS had the lowest mean FA. Conclusion: Microstructural white matter disease as determined by MRS and DTI correlated with executive dysfunction and slowed processing speed in these FMR1 premutation carriers. Neuroimaging abnormalities in the genu and MCP suggest that disruption of white matter within frontocerebellar networks has an important role in the cognitive impairment associated with the FMR1 premutation.

Alzheimer disease (AD) poses a major threat to medicine and society, but recent epidemiologic data indicate declining incidence of the disease. This development may be due to prevention of many cases by attention to modifiable risk factors. Meanwhile, all treatment efforts using drugs targeting amyloid have failed. In contrast to the assumption of recent decades that sporadic AD is primarily a genetic disease in which neuritic plaques and neurofibrillary tangles are mainly responsible for clinical features, it is now time for a more nuanced approach that considers the role of environmental factors preceding dementia onset and the appearance of aggregated proteins. This view of AD has important implications for medical care and health policy, and for counseling individuals to adopt lifestyle strategies that can be effective for prevention.

The details of human neuroanatomy are vast, intricate, and continually expanding. A working knowledge of neuroanatomy is fundamental for neuropsychologists. This chapter presents an overview of human neuroanatomy while emphasizing the most relevant aspects for those engaged in the neuropsychological study of higher functions. It provides a discussion on various MR imaging techniques to highlight neuroanatomy. The chapter also provides an overview on computed tomography (CT) and magnetic resonance imaging (MRI) methods for neuroanatomic identification. Since the introduction of CT in the early 1970s, the fidelity of brain imaging to visualize gross brain anatomy has improved at a rapid pace hastened by the development of MRI. The neuropsychologist plays a crucial role in characterizing the nature and severity of the syndrome, defining the likely localization of the problem, helping to guide further diagnostic testing, assisting with providing the best possible medical care, and contributing to neuroscientific research on cerebral localization.

The representation of cognitive function in the cerebral cortex has a long and cherished history, but much evidence also supports a critical role of subcortical structures in the operations of cognition. The idea of subcortical dementia, first proposed in 1932 and substantially expanded in the 1970s, is the most prominent formulation intended to capture the phenomenology of cognitive impairment attributable to subcortical involvement. Despite criticism highlighting its imprecision, subcortical dementia has endured as a useful general concept assisting the classification of dementia syndromes based on the primary site(s) of neuropathology. As neuroscientific knowledge expanded with the advent of modern structural and functional neuroimaging, a more detailed understanding of the contributions of specific subcortical regions emerged, such that the cognitive affiliations of the basal ganglia, thalamus, cerebellum, brainstem, and white matter are all better defined. Important advances have been made by the study of both neurodegenerative diseases and focal lesions. Today, the complex admixture of cortical and subcortical foundations of cognition is increasingly well appreciated, and has been conceptually organized within the broadly inclusive notion of distributed neural networks. These networks are thought to integrate cortical and subcortical gray and white matter structures throughout the brain into functional neuronal ensembles subserving various domains of cognition. In this light, specific disorders of subcortical regions produce cognitive sequelae that can be usefully analyzed within the context of networks that involve key cortical regions as well. The study of subcortical contributions to cognition has been highly informative in expanding neurobehavioral thinking to include regions beyond the cerebral cortex, adding nuance and sophistication to the conceptualization of brain-behavior relationships.

Background: There is growing interest in the application of palliative care principles to improve care for patients and families affected by neurologic diseases. We developed an interdisciplinary outpatient clinic for patients and families affected by neurologic disorders to better address the problems faced by our highest need patients. We have developed and improved this program over the past three years and share several of our most important lessons as well as ongoing challenges and areas where we see our clinic evolving in the future. Methods: We provide a description of our clinic logistics, including key steps in the initiation of the clinic, and provide descriptions from similar clinics at other institutions to demonstrate some of the variability in this growing field. We also provide results from a formal one-year quality improvement project and a one-year retrospective study of patients attending this clinic. Results: Our clinic has grown steadily since its inception and maintains high satisfaction ratings from patients, caregivers, and referring providers. To maintain standardized and efficient care we have developed materials for patients and referring physicians as well as checklists and other processes used by our interdisciplinary team. Feedback from our quality improvement project helped define optimal visit duration and refine communication among team members and with patients and families. Results from our chart review suggest our clinic influences advance care planning and place of death. Common referral reasons include psychosocial support, complex symptom management, and advance care planning. Current challenges for our clinic include developing a strategy for continued growth, creating a sustainable financial model for interdisciplinary care, integrating our services with disease-specific sections, improving primary palliative care knowledge and skills within our referral base, and building effective alliances with community neurologists, geriatrics, primary care, nursing homes, and hospices. Conclusions: Specialized outpatient palliative care for neurologic disorders fills several important gaps in care for this patient population, provides important educational opportunities for trainees, and creates opportunities for patient and caregiver-centered research. Educational initiatives are needed to train general neurologists in primary palliative care, to train neurologists in specialist palliative care, and to train palliative medicine specialists in neurology. Research is needed to build an evidence base to identify patient and caregiver needs, support specific interventions, and to build more efficient models of care in both academic and community settings.

Alzheimer disease (AD) poses a major threat to medicine and society, but recent epidemiologic data indicate declining incidence of the disease. This development may be due to prevention of many cases by attention to modifiable risk factors. Meanwhile, all treatment efforts using drugs targeting amyloid have failed. In contrast to the assumption of recent decades that sporadic AD is primarily a genetic disease in which neuritic plaques and neurofibrillary tangles are mainly responsible for clinical features, it is now time for a more nuanced approach that considers the role of environmental factors preceding dementia onset and the appearance of aggregated proteins. This view of AD has important implications for medical care and health policy, and for counseling individuals to adopt lifestyle strategies that can be effective for prevention.

The brain is the primary target of toluene (methylbenzene), the major solvent in spray paint and a constituent of many other easily obtained commercial and industrial products. The effects of acute intoxication can be dramatic and the lasting adverse effects of inhalants may be highly injurious. Mental status alterations range from acute confusional state to coma. Toluene abuse effects on white matter are demonstrable neuroradiologically and neuropathologically, and have important neurobehavioral consequences.

Many patients with systemic lupus erythematosus (SLE) have working memory deficits. Few studies have evaluated working memory performance and neurometabolite profile using magnetic resonance spectroscopy in SLE.We gave the Paced Auditory Serial Addition Test (PASAT), a measure of working memory, to 73 patients with SLE. We calculated total score, dyads, chunking, and cognitive fatigue. Using magnetic resonance spectroscopy, we determined the ratio of choline to creatine (Ch/Cr) in normal-looking right and left frontal lobe white matter.Twenty-nine percent of patients showed impaired working memory on the PASAT. Total PASAT score inversely correlated with right and left frontal white matter Ch/Cr. Left frontal white matter Ch/Cr correlated with percent chunking and inversely correlated with total and percent dyads. Right frontal white matter Ch/Cr correlated with percent chunking and inversely correlated with total and percent dyads. There was no relationship between cognitive fatigue and either left or right frontal white matter Ch/Cr. Longer disease duration was associated with higher left frontal white matter Ch/Cr. Correlations remained significant when we considered disease duration and left frontal white matter Ch/Cr against total PASAT score and total dyads.Patients with SLE were impaired on the PASAT. Lower total PASAT score and fewer dyads correlated with higher left frontal microstructural white matter damage, while cognitive fatigue did not. This pattern suggests that early white matter damage interferes with working memory in SLE and provides further insight into the neurobiological basis of mild cognitive dysfunction related to microstructural white matter injury.