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Creutzfeldt-Jakob disease (CJD) is a rare, uniformly fatal prion disease. Although CJD commonly presents with rapidly progressive dementia, ataxia, and myoclonus, substantial clinicopathological heterogeneity is observed in clinical practice. Unusual and predominantly cognitive clinical manifestations of CJD mimicking common dementia syndromes are known to pose as an obstacle to early diagnosis and prognosis. We report a series of three patients with probable or definite CJD (one male and two females, ages 52, 58 and 68) who presented to our tertiary behavioral neurology clinic at Mayo Clinic Rochester that met criteria for a newly defined progressive dysexecutive syndrome. Glucose hypometabolism patterns assessed by 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) strongly resembled those of dysexecutive variant of Alzheimer's disease (dAD). However, magnetic resonance imaging (MRI) demonstrated restricted diffusion in neocortical areas and deep nuclei, while cerebrospinal fluid biomarkers indicated abnormal levels of 14-3-3, total-tau, and prion seeding activity (RT-QuIC), establishing the diagnosis of CJD. Electroencephalogram (EEG) additionally revealed features previously documented in atypical cases of CJD. This series of clinical cases demonstrates that CJD can present with a predominantly dysexecutive syndrome and FDG-PET hypometabolism typically seen in dAD. This prompts for the need to integrate information on clinical course with multimodal imaging and fluid biomarkers to provide a precise etiology for dementia syndromes. This has important clinical implications for the diagnosis and prognosis of CJD in the context of emerging clinical characterization of progressive dysexecutive syndromes in neurodegenerative diseases like dAD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Abstract: Dementia with Lewy bodies (DLB) is the third most frequent type of dementia. The range of symptoms it causes is quite broad and includes parkinsonism, autonomic dysfunction, cognitive deficits, visual and auditory hallucinations, dream disturbances, and other unusual manifestations such as "sense of presence," Capgras syndrome, and fluctuations in neurologic status. The author, an experienced behavioral neurologist and previous Continuum author, has been diagnosed with DLB and assumes the dual role of physician and patient. Each role provides a unique perspective. He discusses the importance of hope and fear in coping with the illness., (Copyright © 2021 American Academy of Neurology.)

Posterior cortical atrophy is a neurodegenerative syndrome with a heterogeneous clinical presentation due to variable involvement of the left, right, dorsal and ventral parts of the visual system, as well as inconsistent involvement of other cognitive domains and systems. 18 F-fluorodeoxyglucose (FDG)-PET is a sensitive marker for regional brain damage or dysfunction, capable of capturing the pattern of neurodegeneration at the single-participant level. We aimed to leverage these inter-individual differences on FDG-PET imaging to better understand the associations of heterogeneity of posterior cortical atrophy. We identified 91 posterior cortical atrophy participants with FDG-PET data and abstracted demographic, neurologic, neuropsychological and Alzheimer's disease biomarker data. The mean age at reported symptom onset was 59.3 (range: 45-72 years old), with an average disease duration of 4.2 years prior to FDG-PET scan, and a mean education of 15.0 years. Females were more common than males at 1.6:1. After standard preprocessing steps, the FDG-PET scans for the cohort were entered into an unsupervised machine learning algorithm which first creates a high-dimensional space of inter-individual covariance before performing an eigen-decomposition to arrive at a low-dimensional representation. Participant values ('eigenbrains' or latent vectors which represent principle axes of inter-individual variation) were then compared to the clinical and biomarker data. Eight eigenbrains explained over 50% of the inter-individual differences in FDG-PET uptake with left (eigenbrain 1) and right (eigenbrain 2) hemispheric lateralization representing 24% of the variance. Furthermore, eigenbrain-loads mapped onto clinical and neuropsychological data (i.e. aphasia, apraxia and global cognition were associated with the left hemispheric eigenbrain 1 and environmental agnosia and apperceptive prosopagnosia were associated with the right hemispheric eigenbrain 2), suggesting that they captured important axes of normal and abnormal brain function. We used NeuroSynth to characterize the eigenbrains through topic-based decoding, which supported the idea that the eigenbrains map onto a diverse set of cognitive functions. These eigenbrains captured important biological and pathophysiologic data (i.e. limbic predominant eigenbrain 4 patterns being associated with older age of onset compared to frontoparietal eigenbrain 7 patterns being associated with younger age of onset), suggesting that approaches that focus on inter-individual differences may be important to better understand the variability observed within a neurodegenerative syndrome like posterior cortical atrophy., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

We report a group of patients presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions, relatively young age of onset and positive biomarkers for Alzheimer's pathophysiology. Atypical frontal, dysexecutive/behavioural variants and early-onset variants of Alzheimer's disease have been previously reported, but no diagnostic criteria exist for a progressive dysexecutive syndrome. In this retrospective review, we report on 55 participants diagnosed with a clinically defined progressive dysexecutive syndrome with 18 F-fluorodeoxyglucose-positron emission tomography and Alzheimer's disease biomarkers available. Sixty-two per cent of participants were female with a mean of 15.2 years of education. The mean age of reported symptom onset was 53.8 years while the mean age at diagnosis was 57.2 years. Participants and informants commonly referred to initial cognitive symptoms as 'memory problems' but upon further inquiry described problems with core executive functions of working memory, cognitive flexibility and cognitive inhibitory control. Multi-domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently affected. The frontal and parietal regions which overlap with working memory networks consistently demonstrated hypometabolism on positron emission tomography. Genetic testing for autosomal dominant genes was negative in all eight participants tested and at least one APOE ε 4 allele was present in 14/26 participants tested. EEG was abnormal in 14/17 cases with 13 described as diffuse slowing. Furthermore, CSF or neuroimaging biomarkers were consistent with Alzheimer's disease pathophysiology, although CSF p-tau was normal in 24% of cases. Fifteen of the executive predominate participants enrolled in research neuroimaging protocols and were compared to amnestic ( n  = 110), visual ( n  = 18) and language ( n  = 7) predominate clinical phenotypes of Alzheimer's disease. This revealed a consistent pattern of hypometabolism in parieto-frontal brain regions supporting executive functions with relative sparing of the medial temporal lobe (versus amnestic phenotype), occipital (versus visual phenotype) and left temporal (versus language phenotype). We propose that this progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype disambiguated from behavioural presentations and not linked specifically to the frontal lobe or a particular anatomic substrate without further study. This clinical presentation can be due to Alzheimer's disease but is likely not specific for any single aetiology. Diagnostic criteria are proposed to facilitate additional research into this understudied clinical presentation., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Little is known about the role of age on neurodegeneration and protein deposition in atypical variants of Alzheimer's disease (AD)., Methods: Regional tau and β-amyloid positron emission tomography standard uptake value ratios and gray matter volumes were calculated in a cohort of 42 participants with atypical AD. The relationship between regional metrics and age was modeled using a Bayesian hierarchical linear model., Results: Age was strongly associated with tau uptake across all cortical regions, particularly parietal, with greater uptake in younger participants. Younger age was associated with smaller parietal and lateral temporal volumes. Regional β-amyloid differed little by age. Age showed a stronger association with tau than volume and β-amyloid in all cortical regions. Age was not associated with cognitive performance., Discussion: Age is an important determinant of severity of cortical tau uptake in atypical AD, with young participants more likely to show widespread and severe cortical tau uptake., (Copyright © 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) can present with atypical clinical forms where the prominent domain of deficit is not memory, that is, atypical AD. Atypical AD patients show cortical atrophy on MRI, hypometabolism on [ 18 F]fluorodeoxyglucose (FDG) PET, tau uptake on [ 18 F]AV-1451 PET, and white matter tract degeneration on diffusion tensor imaging (DTI). How these disease processes relate to each other locally and distantly remains unclear. We aimed to examine multimodal neuroimaging relationships in individuals with atypical AD, using univariate and multivariate techniques at region- and voxel-level. Forty atypical AD patients underwent MRI, FDG-PET, tau-PET, beta-amyloid PET, and DTI. Patients were all beta-amyloid positive. Partial Pearson's correlations were performed between tau and FDG standardized uptake value ratios, gray matter MRI-volumes and white matter tract fractional anisotropy. Sparse canonical correlation analysis was applied to identify multivariate relationships between the same quantities. Voxel-level associations across modalities were also assessed. Tau showed strong local negative correlations with FDG metabolism in the occipital and frontal lobes. Tau in frontal and parietal regions was negatively associated with temporoparietal gray matter MRI-volume. Fractional anisotropy in a set of posterior white matter tracts, including the splenium of the corpus callosum, cingulum, and posterior thalamic radiation, was negatively correlated with parietal and occipital tau, atrophy and, predominantly, with hypometabolism. These results support the view that tau is the driving force behind neurodegeneration in atypical AD, and that a breakdown in structural connectivity is related to cortical neurodegeneration, particularly hypometabolism., (© 2018 Wiley Periodicals, Inc.)

Background: Posterior cortical atrophy and dementia with Lewy bodies are 2 distinct clinical syndromes, yet they can overlap in symptoms and occipital hypometabolism. Patients with dementia with Lewy bodies often have overlapping Alzheimer's disease pathology. Similarly, Lewy bodies can be found in patients with posterior cortical atrophy. We investigated differences in the distribution and magnitude of F18-AV-1451 uptake in patients with these 2 syndromes., Methods: Consecutive patients with probable dementia with Lewy bodies (n = 33), posterior cortical atrophy (n = 18), and cognitively unimpaired controls (n = 100) underwent 18 F-AV-1451 positron emission tomography. Regional differences in AV-1451 uptake were assessed using voxel-wise and an atlas-based approach. The greatest differences in AV-1451 uptake between patient groups were identified using area under receiver operating curve statistics, and a composite region was derived., Results: AV-1451 uptake in both patient groups was predominantly localized to the lateral occipital regions, but the magnitude of uptake was markedly greater in posterior cortical atrophy compared with dementia with Lewy bodies. The posterior cortical atrophy group showed the greatest AV-1451 uptake throughout all the gray matter compared with that in other groups. The occipital composite region, consisting of superior, middle, and inferior occipital cortices, distinguished posterior cortical atrophy from dementia with Lewy bodies (area under the curve >0.97; P < 0.001, Bonferroni-corrected) with excellent sensitivity (88%) and specificity (100%)., Conclusions: Posterior cortical atrophy and dementia with Lewy bodies can share clinical features, and although the pattern of AV-1451 uptake in occipital cortices overlaps between these 2 syndromes, its magnitude is significantly higher in posterior cortical atrophy. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

The aims of this study were: to examine regional rates of change in tau-PET uptake and grey matter volume in atypical Alzheimer's disease (AD); to investigate the role of age in such changes; to describe multimodal regional relationships between tau accumulation and atrophy. Thirty atypical AD patients underwent baseline and one-year follow-up MRI, [ 18 F]AV-1451 PET and PiB PET. Region- and voxel-level rates of tau accumulation and grey matter atrophy relative to cognitively unimpaired individuals, and the influence of age on such rates, were assessed. Univariate and multivariate analyses were performed between baseline measurements and rates of change, between baseline tau and atrophy, and between the two rates of change. Regional patterns of change in tau and volume differed, with highest rates of tau accumulation in frontal lobe and highest rates of atrophy in temporoparietal regions. Age had a negative effect on disease progression, predominantly on tau, with younger patients having a more rapid accumulation. Baseline tau uptake and regions of tau accumulation were disconnected, with high baseline tau uptake across the cortex correlated with high rates of tau accumulation in frontal and sensorimotor regions. In contrast, baseline volume and atrophy were locally related in the occipitoparietal regions. Higher tau uptake at baseline was locally related to higher rates of atrophy in frontal and occipital lobes. Tau accumulation rates positively correlated with rates of atrophy. In summary, our study showed that tau accumulation and atrophy presented different regional patterns in atypical AD, with tau spreading into the frontal lobes while atrophy remains in temporoparietal and occipital cortex, suggesting a temporal disconnect between protein deposition and neurodegeneration., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

In this prospective evaluation of serum and CSF samples, all but two CSF GFAPα-IgG positive patients had autoimmune meningoencephalomyelitis while serum GFAPα-IgG positivity alone was less specific. Phenotypes were diverse among patients that were serum positive only. Adult and pediatric clinical presentations were similar. Most patients were immunotherapy responsive. Co-existing NMDA-R-IgG and cancer were associated with lack of response to first-line immunotherapy. Among patients with follow-up information, 18% had relapses. This study demonstrates CSF GFAPα-IgG is a specific autoimmune meningoencephalomyelitis biomarker, with favorable corticosteroid response. Lack of response should prompt evaluation for co-existing NMDA-R-IgG or malignancy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Neuroimaging modalities can measure different aspects of the disease process in Alzheimer's disease, although the relationship between these modalities is unclear., Methods: We assessed subject-level regional correlations between tau on [ 18 F]AV-1451 positron emission tomography (PET), β amyloid on Pittsburgh compound B PET, hypometabolism on [ 18 F] fluorodeoxyglucose PET, and cortical thickness on magnetic resonance imaging in 96 participants with typical and atypical Alzheimer's disease presentations. We also assessed how correlations between modalities varied according to age, presenting syndrome, tau-PET severity, and asymmetry., Results: [ 18 F]AV-1451 uptake showed the strongest regional correlation with hypometabolism. Correlations between [ 18 F]AV-1451 uptake and both hypometabolism and cortical thickness were stronger in participants with greater cortical tau severity. In addition, age, tau asymmetry, and clinical diagnosis influenced the strength of the correlation between [ 18 F]AV-1451 uptake and cortical thickness., Discussion: These findings support a close relationship between tau and hypometabolism in Alzheimer's disease but show that correlations between neuroimaging modalities vary across participants., (Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess [ 18 F]AV-1451 tau-PET (positron emission tomography) uptake patterns across the primary progressive aphasia (PPA) variants (logopenic, semantic, and agrammatic), examine regional uptake patterns of [ 18 F]AV-1451 independent of clinical diagnosis, and compare the diagnostic utility of [ 18 F]AV-1451, [ 18 F]-fluorodeoxygluclose (FDG)-PET and MRI (magnetic resonance imaging) to differentiate the PPA variants., Methods: We performed statistical parametric mapping of [ 18 F]AV-1451 across 40 PPA patients (logopenic-PPA = 14, semantic-PPA = 13, and agrammatic-PPA = 13) compared to 80 cognitively normal, Pittsburgh compound B-negative controls, age and gender matched 2:1. Principal component analysis of regional [ 18 F]AV-1451 tau-PET standard uptake value ratio was performed to understand underlying patterns of [ 18 F]AV-1451 uptake independent of clinical diagnosis. Penalized multinomial regression analyses were utilized to assess diagnostic utility., Results: Logopenic-PPA showed striking uptake throughout neocortex, particularly temporoparietal, compared to controls, semantic-PPA, and agrammatic-PPA. Semantic-PPA and agrammatic-PPA showed milder patterns of focal [ 18 F]AV-1451 uptake. Semantic-PPA showed elevated uptake (left>right) in anteromedial temporal lobes, compared to controls and agrammatic-PPA. Agrammatic-PPA showed elevated uptake (left>right) throughout prefrontal white matter and in subcortical gray matter structures, compared to controls and semantic-PPA. The principal component analysis of regional [ 18 F]AV-1451 indicated two primary dimensions, a severity dimension that distinguished logopenic-PPA from agrammatic-PPA and semantic-PPA, and a frontal versus temporal contrast that distinguishes agrammatic-PPA and semantic-PPA cases. Diagnostic utility of [ 18 F]AV-1451was superior to MRI and at least equal to FDG-PET., Interpretation: [ 18 F]AV-1451binding characteristics differ across the PPA variants and were excellent at distinguishing between the variants. [ 18 F]AV-1451binding characteristics were as good or better than other brain imaging modalities utilized in clinical practice, suggesting that [ 18 F]AV-1451 may have clinical diagnostic utility in PPA. Ann Neurol 2018 Ann Neurol 2018;83:599-611., (© 2018 American Neurological Association.)

Objective: To use a cluster analysis of [ 18 F]AV-1451 tau-PET data to determine how subjects with Alzheimer's disease (AD) vary in the relative involvement of the entorhinal cortex and neocortex, and determine whether relative involvement of these two regions can help explain variability in age and clinical phenotype in AD., Methods: We calculated [ 18 F]AV-1451 uptake in entorhinal cortex and neocortex in 62 amyloid-positive AD patients (39 typical and 23 atypical presentation). tau-PET (positron emission tomography) values were normalized to the cerebellum to create standard uptake value ratios (SUVRs). tau-PET SUVRs were log-transformed and clustered blinded to clinical information into three groups using K-median cluster analysis. Demographics, clinical phenotype, cognitive performance, and apolipoprotein e4 frequency were compared across clusters., Results: The cluster analysis identified a cluster with low entorhinal and cortical uptake (E Lo /C Lo ), one with low entorhinal but high cortical uptake (E Lo /C Hi ), and one with high cortical and entorhinal uptake (E Hi /C Hi ). Clinical phenotype differed across clusters, with typical AD most commonly observed in the E Lo /C Lo and E Hi /C Hi clusters, and atypical AD most commonly observed in the E Lo /C Hi cluster. The E Lo /C Lo cluster had an older age at PET and onset than the other clusters. Apolipoprotein e4 frequency was lower in the E Lo /C Hi cluster. The E Hi /C Hi cluster had the worst memory impairment, whereas the E Lo /C Hi cluster had the worst impairment in nonmemory domains., Interpretation: This study demonstrates considerable variability in [ 18 F]AV-1451 tau-PET uptake in AD, but shows that a straightforward clustering based on entorhinal and cortical uptake maps well onto age and clinical presentation in AD. Ann Neurol 2018 Ann Neurol 2018;83:248-257., (© 2018 American Neurological Association.)

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapid and fatal neurodegenerative disease defined by misfolded prion proteins accumulating in the brain. A minority of cases initially present with posterior cortical atrophy (PCA) phenotype, also known as Heidenhain variant or visual variant CJD. This case provides further evidence of sCJD presenting as PCA. The case also provides evidence for early DWI changes and cortical atrophy over 30 months before neurologic decline and subsequent death. The prolonged disease course correlates with prion protein codon 129 heterozygosity and coexistence of multiple prion strains.

The relationship between clinicopathologic diagnosis and 123 I-FP-CIT SPECT in 18 patients with dementia (12 with Lewy body disease) from one center in the United States was assessed. The sensitivity and specificity of abnormal 123 I-FP-CIT SPECT with reduced striatal uptake on visual inspection for predicting Lewy body disease were 91.7% and 83.3%, respectively. The mean calculated putamen to occipital ratio (mPOR) based on regions of interest was significantly reduced in Lewy body disease compared to non-Lewy body disease cases ( P = 0.002). In this study, abnormal 123 I-FP-CIT SPECT was strongly associated with underlying Lewy body disease pathology, supporting the utility of 123 I-FP-CIT SPECT in the clinical diagnosis of dementia with Lewy bodies.

Background: Despite common pathology, Alzheimer's disease (AD) can have multiple clinical presentations which pathological studies suggest result from differences in the regional distribution of tau pathology. Positron emission tomography (PET) ligands are now available that can detect tau proteins in vivo and hence can be used to investigate the biological mechanisms underlying atypical AD., Objective: To assess regional patterns of tau uptake on PET imaging in two atypical AD variants, posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA)., Methods: Eighteen PCA and 19 lvPPA subjects that showed amyloid-β deposition on PET underwent tau-PET imaging with [18F]AV-1451. Group comparisons of tau uptake in PCA and lvPPA were performed using voxel-level and regional-level analyses. We also assessed the degree of lobar tau asymmetry and correlated regional tau uptake to age and performance on clinical evaluations., Results: Both syndromes showed diffuse tau uptake throughout all cortical regions, although PCA showed greater uptake in occipital regions compared to lvPPA, and lvPPA showed greater uptake in left frontal and temporal regions compared to PCA. While lvPPA showed predominant left-asymmetric tau deposition, PCA was more bilateral. Younger subjects showed greater tau uptake bilaterally in frontal and parietal lobes than older subjects, and sentence repetition, Boston naming test, simultanagnosia, and visuoperceptual function showed specific regional tau correlates., Conclusion: Tau deposition is closely related to clinical presentation in atypical AD with age playing a role in determining the degree of cortical tau deposition.

Posterior cortical atrophy (PCA) and dementia with Lewy bodies (DLB) have both been associated with occipital lobe hypometabolism on 18 F-FDG PET, whereas relative sparing of posterior cingulate metabolism compared with precuneus/cuneus (i.e., cingulate island sign) is a feature of DLB. We aimed to determine whether patterns of hypometabolism or the cingulate island sign differed between PCA and DLB. Methods: Sixteen clinically diagnosed PCA and 13 probable DLB subjects underwent 18 F-FDG PET. All PCA subjects showed β-amyloid deposition on PET scanning. Regional hypometabolism was assessed compared with a control cohort ( n = 29) using voxel- and region-level analyses in statistical parametric mapping. A ratio of metabolism in the posterior cingulate to precuneus plus cuneus was calculated to assess the cingulate island sign. In addition, the 18 F-FDG PET scans were visually assessed to determine whether the cingulate island sign was present in each subject. Results: PCA and DLB showed overlapping patterns of hypometabolism involving the lateral occipital lobe, lingual gyrus, cuneus, precuneus, posterior cingulate, inferior parietal lobe, supramarginal gyrus, striatum, and thalamus. However, DLB showed greater hypometabolism in the medial occipital lobe, orbitofrontal cortex, anterior temporal lobe, and caudate nucleus than PCA, and PCA showed more asymmetric patterns of hypometabolism than DLB. The cingulate island sign was present in both DLB and PCA, although it was more asymmetric in PCA. Conclusion: Regional hypometabolism overlaps to a large degree between PCA and DLB, although the degree of involvement of the frontal and anterior temporal lobes and the presence of asymmetry could be useful in differential diagnosis., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Background/aims: Hypersomnia is common in dementia with Lewy bodies (DLB). We assessed the efficacy, safety, and tolerability of armodafinil for hypersomnia associated with DLB., Methods: We performed a 12-week pilot trial of armodafinil therapy (125-250 mg orally daily) in DLB outpatients with hypersomnia. The patients underwent neurologic examinations, a neuropsychological battery, laboratory testing, electrocardiography, and polysomnography. Efficacy was assessed at 2, 4, 8, and 12 weeks. Safety assessment included laboratory examinations, QTc interval, and heart rate. Tolerability was assessed by analysis of adverse events. Data were analyzed using the last-observation-carried-forward method., Results: Of 20 participants, 17 completed the protocol. The median age was 72 years, most of the participants were men (80%), and most had spouses as caregivers. The Epworth Sleepiness Scale (p < 0.001), Maintenance of Wakefulness Test (p = 0.003), and Clinical Global Impression of Change (p < 0.001) scores improved at week 12. The Neuropsychiatric Inventory total score (p = 0.003), visual hallucinations (p = 0.003), and agitation (p = 0.02) improved at week 4. Caregiver overall quality of life improved at week 12 (p = 0.004). No adverse events occurred., Conclusion: These pilot data suggest improvements in hypersomnia and wakefulness and reasonable safety and tolerability of armodafinil therapy in hypersomnolent patients with DLB. Our findings inform the use of pharmacologic strategies for managing hypersomnolence in these patients., (© 2017 S. Karger AG, Basel.)

Background: Different clinical syndromes can arise from Alzheimer's disease (AD) neuropathology, including dementia of the Alzheimer's type (DAT), logopenic primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA)., Objective: To assess similarities and differences in patterns of white matter tract degeneration across these syndromic variants of AD., Methods: Sixty-four subjects (22 DAT, 24 lvPPA, and 18 PCA) that had diffusion tensor imaging and showed amyloid-β deposition on PET were assessed in this case-control study. A whole-brain voxel-based analysis was performed to assess differences in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity across groups., Results: All three groups showed overlapping diffusion abnormalities in a network of tracts, including fornix, corpus callosum, posterior thalamic radiations, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate fasciculus. Subtle regional differences were also observed across groups, with DAT particularly associated with degeneration of fornix and cingulum, lvPPA with left inferior fronto-occipital fasciculus and uncinate fasciculus, and PCA with posterior thalamic radiations, superior longitudinal fasciculus, posterior cingulate, and splenium of the corpus callosum., Conclusion: These findings show that while each AD phenotype is associated with degeneration of a specific structural network of white matter tracts, striking spatial overlap exists among the three network patterns that may be related to AD pathology.

Autoimmune dementia and encephalopathies (ADE) are complex disorders that can cause immune-mediated cognitive deficits and have confusing nomenclature. Presentation varies from acute limbic encephalitis to subacute or chronic disorders of cognition mimicking neurodegenerative dementia. It may occur as a paraneoplastic phenomenon or an idiopathic autoimmune phenomenon. The presence of a personal/family history of autoimmunity, inflammatory spinal fluid, serologic evidence of autoimmunity (neural or nonorgan-specific), or mesial temporal magnetic resonance imaging abnormalities are clues to diagnosis. Bedside cognitive assessment and/or detailed neuropsychologic testing are useful. Neural-specific autoantibodies, mostly discovered in the past two decades, may bind antigens on the cell surface (e.g., N-methyl-d-aspartate receptor autoantibodies) and are likely to be pathogenic, with treatment aimed at antibody-depleting agents often with success, while antibodies binding intracellular antigens (e.g., antineuronal nuclear autoantibody type 1 (ANNA1 or anti-Hu)) are a marker of a T-cell-mediated process and treated with T-cell-depleting immunotherapies, with variable responses. Detection and treatment of cancer (when present) are essential. High-dose corticosteroids are the initial treatment in most patients and may serve as a diagnostic test when the diagnosis is uncertain. Repeat cognitive testing after immunotherapy helps document objective improvements. Maintenance immunotherapy is recommended in those at risk for relapse. Prognosis is variable, but paraneoplastic ADE with antibodies to intracellular antigens have a worse prognosis. The field is still developing and future studies should provide guidelines for diagnosis and treatments., (© 2016 Elsevier B.V. All rights reserved.)

Purpose of Review: This article discusses the neurobiology, clinical features, and treatment of obsessive-compulsive disorder (OCD), as well as its association with psychiatric and neurologic disease., Recent Findings: OCD can be associated with various neurologic disorders. Recent studies have better elucidated the neurobiology of OCD, and this new knowledge promises to have a significant impact on future treatments., Summary: OCD is a syndrome characterized by obsessions and compulsions, as well as other neuropsychiatric features, and is often associated with primary psychiatric disorders and various neurologic conditions. If severe, OCD can seriously interfere with the patient's quality of life. The mainstay of treatment is psychotherapy, especially cognitive-behavioral therapy, and pharmacologic interventions, especially with selective serotonin reuptake inhibitors (SSRIs). Unfortunately, a significant proportion of patients are refractory to these treatment modalities. New understanding about the neurobiology of OCD has led to novel investigational treatments, especially neuromodulation techniques.

The purpose of this study was to identify the clinical, [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and amyloid-PET findings in a large cohort of posterior cortical atrophy (PCA) patients, to examine the neural correlates of the classic features of PCA, and to better understand the features associated with early PCA. We prospectively recruited 25 patients who presented to the Mayo Clinic between March 2013 and August 2014 and met diagnostic criteria for PCA. All patients underwent a standardized set of tests and amyloid imaging with [(11)C] Pittsburg compound B (PiB). Seventeen (68 %) underwent FDG-PET scanning. We divided the cohort at the median disease duration of 4 years in order to assess clinical and FDG-PET correlates of early PCA (n = 13). The most common clinical features were simultanagnosia (92 %), dysgraphia (68 %), poly-mini-myoclonus (64 %) and oculomotor apraxia (56.5 %). On FDG-PET, hypometabolism was observed bilaterally in the lateral and medial parietal and occipital lobes. Simultanagnosia was associated with hypometabolism in the right occipital lobe and posterior cingulum, optic ataxia with hypometabolism in left occipital lobe, and oculomotor apraxia with hypometabolism in the left parietal lobe and posterior cingulate gyrus. All 25 PCA patients were amyloid positive. Simultanagnosia was the only feature present in 85 % of early PCA patients. The syndrome of PCA is associated with posterior hemisphere hypometabolism and with amyloid deposition. Many of the classic features of PCA show associated focal, but not widespread, areas of involvement of these posterior hemispheric regions. Simultanagnosia appears to be the most common and hence sensitive feature of early PCA.

Background: Microbleeds in the brain have been shown to occur in Alzheimer's disease (AD), affecting approximately a third of subjects that present with typical dementia of the Alzheimer's type (DAT). However, little is known about the frequency or distribution of microbleeds in subjects with AD that present with atypical clinical presentations., Objective: To determine whether the frequency and regional distribution of microbleeds in atypical AD differs from that observed in subjects with DAT, and to determine whether microbleeds in atypical AD are associated with age, demographics, or cognitive impairment., Methods: Fifty-five subjects with amyloid-β deposition on Pittsburgh compound B (PiB) PET who presented with predominant language (n = 37) or visuospatial/perceptual (n = 18) deficits underwent T2*weighted MRI. These subjects were compared to 41 PiB-positive subjects with DAT. Microbleeds were identified and assigned a lobar location., Results: The proportion of subjects with microbleeds did not differ between atypical AD (42%) and DAT (32%). However, atypical AD had larger numbers of microbleeds than DAT. In addition, the topographic distribution of microbleeds differed between atypical AD and DAT, with atypical AD showing the highest density of microbleeds in the frontal lobes. Among atypical AD, number of microbleeds was associated with age, but not gender or cognition. Microbleeds were more common in subjects with language (51%) versus visuospatial/perceptual deficits (22%)., Conclusions: Microbleeds are relatively common in both DAT and atypical AD, although atypical AD subjects appear to be at particular risk for developing large numbers of microbleeds and for developing microbleeds in the frontal lobe.

We describe a 71-year-old patient with slowly progressive pure alexia in which analysis of her fluorodeoxyglucose FDG-PET scan revealed an area of focal hypometabolism in the visual word form area. She presented with difficulty reading. Examination revealed pure alexia with preservation of other cognitive domains. Brain MRI revealed only slight atrophy. A Fluorodeoxyglucose F18 positron emission tomography scan revealed hypometabolism in the occipital cortex bilaterally, left greater than right, with normal metabolism elsewhere in the brain. This case highlights the utility of FDG-PET scan in evaluating focal neurodegenerative conditions before clear atrophy can be seen on MRI.

Many patients with systemic lupus erythematosus have central nervous system involvement. Routine diagnostic studies may not yield evidence of neuropsychiatric dysfunction and are therefore not useful as objective measures to monitor treatment response. We present a case of a 64-year-old woman whom we diagnosed with systemic lupus erythematosus by the American College of Rheumatology criteria after she reported recent cognitive decline. Neuropsychological assessment showed prominent deficits, and an F-18 fluorodeoxyglucose positron emission tomography scan of the brain showed significant abnormalities. Both the neuropsychiatric and scan abnormalities improved dramatically with immunosuppressive treatment. F-18 fluorodeoxyglucose positron emission tomography shows promise in the diagnosis and treatment monitoring of patients who have lupus with neuropsychiatric involvement.

Background: Recently, we evaluated two patients with corticobasal syndrome (CBS) who reported symptom onset after limb immobilization. Our objective was to investigate the association between trauma, immobilization and CBS., Methods: The charts of forty-four consecutive CBS patients seen in the Mayo Clinic Alzheimer Disease Research Center were reviewed with attention to trauma and limb immobilization., Results: 10 CBS patients (23%) had immobilization or trauma on the most affected limb preceding the onset or acceleration of symptoms. The median age at onset was 61. Six patients manifested their first symptoms after immobilization from surgery or fracture with one after leg trauma. Four patients had pre-existing symptoms of limb dysfunction but significantly worsened after immobilization or surgery., Conclusions: 23 percent of patients had immobilization or trauma of the affected limb. This might have implications for management of CBS, for avoiding injury, limiting immobilization and increasing movement in the affected limb., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Steroid-responsive encephalopathies can be considered vasculitic or non-vasculitic. Clinicopathological studies of non-vasculitic steroid-responsive encephalopathy are unusual, but can explain the range of diagnoses consistent with a steroid-responsive presentation in life., Objective: To extend the range of clinical features and pathological findings consistent with steroid-responsive encephalopathy. Design, methods, and patients: A clinicopathological case series of four patients (two women, ages 54-71 years) with steroid-responsive encephalopathy followed at this institution until the time of death., Results: Clinical features were suggestive of Creutzfeld-Jakob disease (CJD), dementia with Lewy bodies (DLB), and parkinsonism, but pathological examination revealed only Alzheimer's disease-related findings without evidence of Lewy bodies or prion disease in all cases. All patients demonstrated marked, sustained improvement following steroid treatment, based on clinical, magnetic resonance imaging, and/or electroencephalogram studies. Alzheimer's disease was not diagnosed in life due to the atypical clinical features, lack of hippocampal atrophy on brain imaging, and a dramatic symptomatic response to steroids., Conclusions: Steroid-responsive encephalopathy is the clinical presentation of some patients with Alzheimer's disease-related pathology at autopsy, and can be consistent with the clinical diagnoses of parkinsonism, DLB, or CJD disease in life.

The authors describe the neuropsychiatric spectrum of voltage-gated potassium-channel complex (VGKC) autoimmunity among 67 seropositive patients; 2 had initially been assigned a primary psychiatric diagnosis. Diverse manifestations were recorded, often affective-predominant. Symptoms for 24 patients with florid presentations included confusion, 92%; memory impairment, 75%; personality change, 58%; depression, 33%; and anxiety, 29%. Of 15 who received immunotherapy, 67% improved. Forty-three patients with milder presentations or low positive VGKC complex Ab values are also described. Neuropsychiatric presentations were significantly associated with higher autoantibody values. Improvements were most evident in patients treated early, which emphasizes the need for early diagnosis and immunotherapy initiation.

Background: Behavioral variant frontotemporal dementia (bvFTD) is a relatively well-defined clinical syndrome. It is associated with frontal and temporal lobe structural/metabolic changes and pathologic findings of a neurodegenerative disease. We have been evaluating patients with clinical and imaging features partially consistent with bvFTD but with evidence also suggestive of brain sagging, which we refer to as frontotemporal brain sagging syndrome (FBSS)., Methods: Retrospective medical chart review to identify all patients seen at our institution between 1996 and 2010, who had a clinical diagnosis of FTD and imaging evidence of brain sag., Results: Eight patients, 7 male and 1 female, were diagnosed with FBSS. The median age at symptom onset was 53 years. All patients had insidious onset and slow progression of behavioral and cognitive dysfunction accompanied by daytime somnolence and headache. Of the 5 patients with functional imaging, all showed evidence of hypometabolism of the frontotemporal regions. On brain MRI, all patients had evidence of brain sagging with distortion of the brainstem; 3 patients had diffuse pachymeningeal enhancement. CSF opening pressure was varied and CSF protein was mildly elevated. A definite site of CSF leak was not identified by myelogram or cisternography, except in one patient with a site highly suggestive of leak who subsequently underwent surgery confirming a CSF leak. In 2 patients with a neuropathologic examination, there was no evidence of a neurodegenerative disease., Conclusions: This case series demonstrates that FBSS may mimic typical bvFTD but should be recognized as an unusual presentation that is potentially treatable.

The question whether human beings have free will has been debated by philosophers and theologians for thousands of years. More recently, neuroscientists have applied novel concepts and tools in neuroscience to address this question. We submit that human beings do have free will and the physiological substrate for its exercise is contained within neural networks. We discuss the potential neurobiology of free will by exploring volitionally initiated motor activity and the behavioural-response to a stimulus-response paradigm. We also submit that the exercise of free will can be affected in patients with the certain neurological disorders such as the behavioural variant of frontotemporal dementia. Clinicopathological correlation in patients with this disorder provides an opportunity to further elucidate the neural substrate for this fundamental human attribute. We also discuss the clinical correlates of the loss of free will in this population, which is a source of significant distress to patients, significant others and care givers.

Objective: To define the diagnostic characteristics and predictors of treatment response in patients with suspected autoimmune dementia., Patients and Methods: Between January 1, 2002, and January 1, 2009, 72 consecutive patients received immunotherapy for suspected autoimmune dementia. Their baseline clinical, radiologic, and serologic characteristics were reviewed and compared between patients who were responsive to immunotherapy and those who were not. Patients were classified as responders if the treating physician had reported improvement after immunotherapy (documented in 80% by the Kokmen Short Test of Mental Status, neuropsychological testing, or both)., Results: Initial immunotherapeutic regimens included methylprednisolone in 56 patients (78%), prednisone in 12 patients (17%), dexamethasone in 2 patients (3%), intravenous immune globulin in 1 patient (1%), and plasma exchange in 1 patient (1%). Forty-six patients (64%) improved, most in the first week of treatment. Thirty-five percent of these immunotherapy responders were initially diagnosed as having a neurodegenerative or prion disorder. Pretreatment and posttreatment neuropsychological score comparisons revealed improvement in almost all cognitive domains, most notably learning and memory. Radiologic or electroencephalographic improvements were reported in 22 (56%) of 39 patients. Immunotherapy responsiveness was predicted by a subacute onset (P<.001), fluctuating course (P<.001), tremor (P=.007), shorter delay to treatment (P=.005), seropositivity for a cation channel complex autoantibody (P=.01; neuronal voltage-gated potassium channel more than calcium channel or neuronal acetylcholine receptor), and elevated cerebrospinal fluid protein (>100 mg/dL) or pleocytosis (P=.02). Of 26 immunotherapy-responsive patients followed up for more than 1 year, 20 (77%) relapsed after discontinuing immunotherapy., Conclusion: Identification of clinical and serologic clues to an autoimmune dementia allows early initiation of immunotherapy, and maintenance if needed, thus favoring an optimal outcome.

Objective: To evaluate the cancer detection rate of whole-body positron emission tomography-computed tomography (PET-CT) in a paraneoplastic neurologic context., Design: Retrospective medical record review., Setting: Mayo Clinic, Rochester, Minnesota., Patients: Fifty-six consecutive patients with clinically suspected paraneoplastic neurologic disorders who underwent PET-CT after negative standard evaluations, including CT., Main Outcome Measure: Rate of cancer detection., Results: Abnormalities suggestive of cancer were detected using PET-CT in 22 patients (39%); 10 patients (18%) had cancer confirmed histologically. Cancers detected (limited stage in 9 of 10 patients and extratruncal in 4) were as follows: 2 thyroid papillary cell carcinomas, 3 solitary lymph nodes with unknown primary (2 adenocarcinomas and 1 small cell carcinoma), 1 tonsil squamous cell carcinoma, 3 lung carcinomas (1 adenocarcinoma, 1 small cell, and 1 squamous cell), and 1 colon adenocarcinoma. Detection of a well-characterized neuronal nuclear or cytoplasmic paraneoplastic autoantibody was associated with a successful PET-CT-directed cancer search (P < .001). Detection of limited-stage cancer facilitated early initiation of oncologic treatments and immunotherapy; cancer remission was reported in 7 patients, and sustained improvements in neurologic symptoms were reported in 5 (median follow-up, 11 months; range, 2-48 months). Combined data from 2 previous studies using conventional PET alone (123 patients) revealed that 28% of patients had a PET abnormality suggestive of cancer and that 12% had a cancer diagnosis., Conclusion: In a paraneoplastic neurologic context, PET-CT improves the detection of cancers when other screening test results are negative, particularly in the setting of seropositivity for a neuronal nuclear or cytoplasmic autoantibody marker of cancer.

One of the most significant existential dilemmas for the religious person is the discrepancy between the assertion that God is everywhere and eternally present, and the inability to become aware of His presence. In this paper, we discuss how developments in our understanding of the brain's mechanisms for perception may resolve this apparent contradiction. We submit that if God is eternally present and unchangeable, then by the process of neuronal habituation, an individual can be "unaware" of the presence of God. We also discuss the limits of human perception and illustrate the biblical questions concerning the awareness of God.

Theory of Mind (ToM) refers to a cognitive process which allows an individual to "place him/herself" in the other person's "mind," so as to comprehend the latter's cognitive and emotional status, so as to predict his/her behavior and emotional response to a particular situation. ToM is necessary for everyday interaction among individuals and accounts for such human traits as empathy, compassion, and deceit. It is also particularly important in the relationship between a healer and his or her client, as well as in the God-human relationship. Recent research in the area of neurosciences has identified a specific brain "system" responsible for ToM, as well as described how these functions may be affected in certain neuropsychiatric conditions. In this article, we discuss the definition and neurobiological substrate of ToM. In addition, we discuss the cognitive steps important to achieve an "accurate" theory of mind, its relevance to "self-knowledge," and its limitations. We also review some of the data concerning abnormalities and "distortion" of ToM in neuropsychiatric disorders and aberrant human behavior.

Unlabelled: Traumatic brain injury (TBI) is a leading cause of disability in young people in the United States. Disorders of arousal and attention are common in closed head injury (CHI). Daytime drowsiness impairs participation in rehabilitation, whereas nighttime wakefulness leads to falls and behavioral disturbances. Sleep disturbances in TBI reported in the literature have included excessive daytime somnolence, sleep phase cycle disturbance, narcolepsy, and sleep apnea. Although well known to the clinician treating these patients, the extent and prevalence of disrupted sleep in patients in an acute inpatient rehabilitation unit has not been described., Objective: To determine the prevalence of sleep wake cycle disturbance (SWCD) in patients with CHI in a TBI rehabilitation unit., Design: Prospective observational., Setting: Inpatient specialized brain injury rehabilitation unit. Patients. Thirty-one consecutive admissions to a brain injury rehabilitation unit with the diagnosis of CHI., Results: Twenty-one patients (68%) had aberrations of nighttime sleep. There was no significant difference in Glasgow Coma Score on admission to trauma nor was there any significant difference in age between the affected and unaffected groups. Patients with SWCD had longer stays in both the trauma center (P < .003) and the rehabilitation center (P < .03)., Conclusions: There is a high prevalence of SWCD in CHI patients admitted to a brain injury rehabilitation unit. Patients with SWCD have longer stays in both acute and rehabilitation settings and may be a marker for more severe injury.

The aim of this study was to compare patterns of cerebral atrophy on MRI, and neurochemistry on magnetic resonance spectroscopy (MRS), in patients with posterior cortical atrophy (PCA) and typical Alzheimer's disease (AD). Voxel-based morphometry was used to assess grey matter atrophy in 38 patients with PCA, 38 patients with typical AD, and 38 controls. Clinical data was assessed in all PCA patients. Single voxel (1)H MRS located in the posterior cingulate was analyzed in a subset of patients with PCA, typical AD, and control subjects. PCA showed a pattern of atrophy affecting occipital, parietal and posterior temporal lobes, compared to controls. The pattern was bilateral, but more severe on the right. Patients with PCA showed greater atrophy in the right visual association cortex than patients with typical AD, whereas those with AD showed greater atrophy in the left hippocampus than those with PCA. (1)H MRS suggested loss of neuronal integrity and glial activation in subjects with PCA and typical AD. The differing patterns of atrophy on MRI suggest that PCA should be considered a distinct entity from typical AD.

Background: Visual hallucinations have been reported to occur in up to 25% of patients who meet the criteria for posterior cortical atrophy (PCA). It is not known, however, whether patients who meet the criteria for PCA and have hallucinations are different from those who meet the criteria and do not have hallucinations., Objective: To compare the clinical and imaging features of patients with PCA with and without well-formed visual hallucinations., Design: Case-control study., Setting: Tertiary care medical center., Patients: Fifty-nine patients fulfilling the criteria for PCA were retrospectively identified and divided into 2 groups based on the presence (n = 13) or absence (n = 46) of visual hallucinations., Main Outcome Measures: Statistically significant clinical differences and imaging differences using voxel-based morphometry between the 2 groups., Results: In patients with PCA and hallucinations, parkinsonism and rapid eye movement sleep behavior disorder occurred more frequently, as did myoclonic jerks (P<.001 for both). Voxel-based morphometry showed greater atrophy in a network of structures, including the primary visual cortex, lentiform nuclei, thalamus, basal forebrain, and midbrain, in patients with hallucinations., Conclusions: Hallucinations in patients with PCA are associated with parkinsonism, rapid eye movement sleep behavior disorder, and myoclonic jerks. The voxel-based morphometry results suggest that hallucinations in PCA cannot be exclusively attributed to atrophy of the posterior association cortices and may involve a circuit of thalamocortical connections.

The authors report a 50-year-old man with progressive left hemispheric atrophy, cognitive decline, infrequent seizures, and spells suggestive of complicated migraine. They discuss the association between migraine and cerebral hemiatrophy and suggest that the spectrum of acquired cerebral hemiatrophy may be broader than what has been commonly recognized.

Research in the neurosciences in recent decades has shown that the central nervous system is not a structurally static organ as was believed previously, but instead is a dynamic system that constantly undergoes structural and functional reorganization. The term brain plasticity refers to the constant cellular and intercellular modifications that occur during normal development and after neurologic injury and result in changes in neurologic function. The discovery that central nervous system plasticity after injury can be directed toward functional improvement with use of specific modalities has opened up a new dimension in the care of the neurologically impaired patient, termed restorative neurology.

The neuropsychological performance of 119 patients with severe closed traumatic brain injury (TBI) who had received toxicology screens at the time of trauma centre admission was examined. Three groups were created: normal screen, positive alcohol screen, or positive abused drugs screen (with or without the presence of alcohol). The admitting Glasgow Coma Scale (GCS) score was significantly lower in the positive alcohol screen group than the normal screen group, while the three groups did not differ in length of post-traumatic amnesia (PTA) or years of education. Neuropsychological assessment was conducted during inpatient rehabilitation, following resolution of PTA. Normal screen patients obtained significantly better scores than the abused-drugs patients on the Full Scale IQ (FIQ) and Verbal IQ (VIQ) indices of the Wechsler Adult Intelligence Scale-Revised and the Verbal Memory, General Memory, Attention-Concentration, and Delayed Recall indices of the Wechsler Memory Scale-Revised. Normal screen patients also scored significantly higher than positive alcohol screen patients on FIQ and VIQ indices and all five indices from the Wechsler Memory Scale-Revised. These data suggest the existence of an additive effect of substance abuse on neuropsychological outcome in TBI. Findings have potential implications for both acute management and rehabilitation of TBI.

We report on the clinical and radiological features in 16 adult patients who suffered a traumatic brain injury and subsequently developed pathological laughter and crying. Patients with pathological laughter and crying were identified from among 301 consecutive brain-injured admissions to a trauma centre and subsequently to a rehabilitation facility. Patients displaying pathological laughter and crying had a greater severity of injury than patients without the syndrome; they also had other associated neurological features compatible with pseudobulbar palsy. Pathological laughter alone, or combined with crying, was more frequent than crying alone. An attempt to correlate clinical features with focal lesions on neuroimaging studies yielded inconsistent results. The theoretical anatomical substrate for pathological laughter and crying in patients with traumatic brain injury is discussed.

Our work and multiple other lines of evidence suggest that patients suffering from neurologic and psychiatric disorders are over-represented in the population suffering traumatic injuries. In addition, a premorbid history of such disorders can impact on the severity of injury, as well as present particular problems in the acute management of this population. Constant vigilance, leading to prompt identification of concurrent neurologic and psychiatric illness in trauma victims, is critical for patient management. The interactions of these disorders and their treatments present complex clinical challenges to the traumatologist and the intensivist.

Background: Published reports on patients with cortical blindness describe bilateral brain hemispheric lesions visualized in radiological and functional imaging studies., Case Description: We present a case with a unilateral lesion on radiological studies and bilateral abnormalities on single-photon emission-computed tomographic (SPECT) scanning., Conclusions: SPECT images correlated much more closely than radiological studies with the patient's clinical status. We suggest that SPECT scanning can be a useful indicator of focal brain dysfunction in brain injury in spite of normal radiological studies. We also hypothesize that our patient's clinical and functional imaging findings could be attributed in part to the process of diaschisis.

The effects of substance abuse on the cause, severity, and recurrence of traumatic brain injury in 322 admissions to a large rehabilitation inpatient facility are explored. Study patients tended to be young and predominantly male. Few had completed high school and a significant minority had a history of cerebral dysfunction. Patients tended to have moderate to severe closed head injuries. Motor vehicle crashes were the most common cause of injury, but patients reporting drug or drug and alcohol abuse were more likely to sustain violent injuries (e.g., gunshot wounds).

The available data supporting a viral or immune mediated etiology of psychiatric disease is indirect and controversial, but there is a sufficient evidence to implicate such a process in a subgroup of the psychiatric population. Recent technological advances in neurovirology and neuroimmunology justify a re-assessment of this etiology in psychiatric disease. The author describes three patients with psychiatric symptomatolgy and cerebrospinal changes compatible with such a process. The evidence supporting a role for viral or immunological factors in the pathogenesis of psychiatric disease is reviewed, and guidelines for future research which could be of use in further clarifying this issue are proposed.