Synergistic effects of GFAP and Aß42: Implications for white matter integrity and verbal memory across the cognitive spectrum.

Background: Plasma glial fibrillary acidic protein (GFAP), an astrocytic biomarker, has previously been linked with Alzheimer's disease (AD) status, amyloid levels, and memory performance in older adults. The neuroanatomical pathways by which astrogliosis/astrocyte reactivity might impact cognitive outcomes remains unclear. We evaluated whether plasma GFAP and amyloid levels had a synergistic effect on fornix structure, which is critically involved in AD-associated cholinergic pathways. We also examined whether fornix structure mediates associations between GFAP and verbal memory. Methods: In a cohort of both asymptomatic and symptomatic older adults (total n = 99), we assessed plasma GFAP, amyloid-ß42 (Aß42), other AD-related proteins, and vascular markers, and we conducted comprehensive memory testing. Tractography-based methods were used to assess fornix structure with whole brain diffusion metrics to control for diffuse alterations in brain white matter. Results: In individuals in the low plasma amyloid-ß42 (Aß42) group, higher plasma GFAP was associated with lower fractional anisotropy (FA; p = 0.007), higher mean diffusivity (MD; p < 0.001), higher radial diffusivity (RD; p < 0.001), and higher axial diffusivity (DA; p = 0.001) in the left fornix. These associations were independent of APOE gene status, plasma levels of total tau and neurofilament light, plasma vascular biomarkers, and whole brain diffusion metrics. In a sub-analysis of participants in the low plasma Aß42 group (n = 33), fornix structure mediated the association between higher plasma GFAP levels and lower verbal memory performance. Discussion: Higher plasma GFAP was associated with altered fornix microstructure in the setting of greater amyloid deposition. We also expanded on our prior GFAP-verbal memory findings by demonstrating that in the low plasma Aß42 group, left fornix integrity may be a primary white matter conduit for the negative associations between GFAP and verbal memory performance. Overall, these findings suggest that astrogliosis/astrocyte reactivity may play an early, pivotal role in AD pathogenesis, and further demonstrate that high GFAP and low Aß42 in plasma may reflect a particularly detrimental synergistic role in forniceal-memory pathways.

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.

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.

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.

Posterior white matter integrity and self-reported posterior cortical symptoms using the Colorado Posterior Cortical Questionnaire.

Background: The Colorado Posterior Cortical Questionnaire (CPC-Q) is a self-report, 15-item screening questionnaire for posterior cortical symptoms, including visuospatial and visuoperceptual difficulties. Changes in white matter connectivity may precede obvious gray matter atrophy in neurodegenerative conditions, especially posterior cortical atrophy. Integration of CPC-Q scores and measures of white matter integrity could contribute to earlier detection of posterior cortical syndromes. Methods: We investigated the relationships between posterior cortical symptoms as captured by the CPC-Q and diffusion tensor imaging fractional anisotropy (DTI FA) of white matter regions of interest localized to posterior brain regions (posterior thalamic radiations, splenium of corpus callosum, tapetum). Comparisons were also made by diagnostic group [healthy older adult (n = 31), amnestic Alzheimer's disease (AD, n = 18), and posterior cortical atrophy (PCA, n = 9)] and by SENAS battery visuospatial composite score quartile. Exploratory comparisons of all available individual white matter region DTI FA to CPC-Q, as well as comparisons of DTI FA between diagnostic groups and visuospatial quartiles, were also made. Results: CPC-Q score was correlated with the average DTI FA for the averaged posterior white matter regions of interest (r = -0.31, p = 0.02). Posterior thalamic radiation DTI FA was most strongly associated with CPC-Q (r = -0.34, p = 0.01) and visuospatial composite (r = 0.58, p < 0.01) scores and differed between the PCA and AD groups and the lower and higher visuospatial quartiles. The DTI FA of body and splenium of the corpus callosum also demonstrated this pattern but not the DTI FA of the tapetum. Conclusion: The integrity of posterior white matter tracts is associated with scores on the CPC-Q, adding to the validation evidence for this new questionnaire. White matter regions that may be related to posterior cortical symptoms detected by the CPC-Q, and distinct from those affected in amnestic syndromes, include the posterior thalamic radiations and body and splenium of the corpus callosum. These findings are in line with previous neuroimaging studies of PCA and support continued research on white matter in posterior cortical dysfunction.

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.

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.

White matter dementia then and now.

White matter dementia (WMD) is a concept introduced in 1988 to highlight the importance of white matter pathology in producing cognitive dysfunction and dementia. Whereas gray matter, particularly the cerebral cortex, has been primarily investigated in the dementias, subcortical pathology has long been correlated with cognitive loss, and a corticocentric perspective cannot account for the full range of neurobehavioral disorders. Within the subcortical regions, white matter is prominent, accounting for about half the volume of the adult brain, and many white matter diseases, injuries, and intoxications can produce cognitive dysfunction so severe as to justify the term dementia. Recognition of this novel syndrome relied heavily on the introduction of magnetic resonance imaging (MRI) that permitted in vivo visualization of white matter lesions. Neuropsychological studies clarified the clinical presentation of WMD by identifying a profile dominated by cognitive slowing and executive dysfunction, and a precursor syndrome of mild cognitive dysfunction was proposed to identify early cognitive impairment that may later evolve to WMD. As knowledge advanced, the role of white matter in structural connectivity within distributed neural networks was elucidated. In addition, highlighting the frequent commingling of gray and white matter involvement, white matter pathology was associated with neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy, with potentially transformative clinical implications. In particular, preventive measures and treatments exploiting white matter restoration and plasticity are gaining much attention. Today, WMD has matured into a concept that not only integrates knowledge from across the spectrum of clinical neuroscience, but also informs new investigations into many perplexing disorders and enables a more complete understanding of brain-behavior relationships.

Multisensory integration and white matter pathology: Contributions to cognitive dysfunction.

The ability to simultaneously process and integrate multiple sensory stimuli is paramount to effective daily function and essential for normal cognition. Multisensory management depends critically on the interplay between bottom-up and top-down processing of sensory information, with white matter (WM) tracts acting as the conduit between cortical and subcortical gray matter (GM) regions. White matter tracts and GM structures operate in concert to manage both multisensory signals and cognition. Altered sensory processing leads to difficulties in reweighting and modulating multisensory input during various routine environmental challenges, and thus contributes to cognitive dysfunction. To examine the specific role of WM in altered sensory processing and cognitive dysfunction, this review focuses on two neurologic disorders with diffuse WM pathology, multiple sclerosis and mild traumatic brain injury, in which persistently altered sensory processing and cognitive impairment are common. In these disorders, cognitive dysfunction in association with altered sensory processing may develop initially from slowed signaling in WM tracts and, in some cases, GM pathology secondary to WM disruption, but also because of interference with cognitive function by the added burden of managing concurrent multimodal primary sensory signals. These insights promise to inform research in the neuroimaging, clinical assessment, and treatment of WM disorders, and the investigation of WM-behavior relationships.

Prognosis in substance abuse-related acute toxic leukoencephalopathy: A scoping review.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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, 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.

Cannabis Use in a Cohort of Healthcare-Seeking United States Military Veterans With Persisting Symptoms After Mild Traumatic Brain Injury: Preliminary Observations.

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 < .00001). Among the 72 MIBH patients reporting cannabis use, 62 (86.1%) reported THC or combination product use, and 10 (13.9%) reported CBD product use. Concurrent medication use, including psychotropic medications use, did not differ significantly between cannabis users and nonusers. 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.

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.

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.

Use of coffee grounds to test olfaction for predicting cognitive dysfunction and decline.

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.