Traumatic Brain Injuries: Manifestations, Evaluation, Management, and Outcomes.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.Prim Care Companion CNS Disord 2024;26(3):23f03667. Author affiliations are listed at the end of this article.

Plasma neurofilament light chain is increased in Niemann-Pick Type C but glial fibrillary acidic protein remains normal.

OBJECTIVE: Niemann-Pick Type C (NPC) is a genetic neurodegenerative lysosomal storage disorder commonly associated with psychiatric symptoms and delays to accurate diagnosis and treatment. This study investigated biomarker levels and diagnostic utility of plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in NPC compared to healthy controls. METHODS: Patients with NPC were recruited from a specialist assessment and management service. Data was available from an age and sex-matched healthy control group. NfL and GFAP were measured on Quanterix Simoa HD-X analysers and groups compared using generalised linear models. NfL levels were compared to, and percentiles derived from, recently developed NfL reference ranges. RESULTS: Plasma NfL was significantly elevated in 11 patients with NPC compared to 25 controls (mean 17.1 vs. 7.4 pg/ml, p < 0.001), and reference ranges (all >98th percentile). NfL distinguished NPC from controls with high accuracy. GFAP levels were not elevated in NPC (66.6 vs. 75.1 pg/ml). DISCUSSION: The study adds important evidence on the potential diagnostic utility of plasma NfL in NPC, extends the literature of NfL as a diagnostic tool to differentiate neurodegenerative from primary psychiatric disorders, and adds support to the pathology in NPC primarily involving neuronal, particularly axonal, degeneration.

Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were initially addressed by a systematic literature review, resulting in different evidence levels of strength according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The highest level of evidence (level A), based on randomized controlled trials, was unavailable for any of the statements. Based on cohort studies, Level B evidence was available for 12 (40%) of the statements. Thereupon, through a process following the Delphi Method and directed by the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria, expert opinion was sought, and members of an SSADHD Consensus Group evaluated all the statements. The group consisted of neurologists, epileptologists, neuropsychologists, neurophysiologists, metabolic disease specialists, clinical and biochemical geneticists, and laboratory scientists affiliated with 19 institutions from 11 countries who have clinical experience with SSADHD patients and have studied the disorder. Representatives from parent groups were also included in the Consensus Group. An analysis of the survey's results yielded 25 (83%) strong and 5 (17%) weak agreement strengths. These first-of-their-kind consensus guidelines intend to consolidate and unify the optimal care that can be provided to individuals with SSADHD.

Investigating Equivalence of In-Person and Telehealth-Based Neuropsychological Assessment Performance for Individuals Being Investigated for Younger Onset Dementia.

OBJECTIVE: Given the rapid shift to in-home teleneuropsychology models, more research is needed to investigate the equivalence of non-facilitator models of teleneuropsychology delivery for people with younger onset dementia (YOD). This study aimed to determine whether equivalent performances were observed on neuropsychological measures administered in-person and via teleneuropsychology in a sample of people being investigated for YOD. METHOD: Using a randomized counterbalanced cross-over design, 43 participants (Mage = 60.26, SDage = 7.19) with a possible or probable YOD diagnosis completed 14 neuropsychological tests in-person and via teleneuropsychology, with a 2-week interval. Repeated measures t-tests, intraclass correlation coefficients (ICC), and Bland Altman analyses were used to investigate equivalence across the administration conditions. RESULTS: No statistical differences were found between in-person and teleneuropsychology conditions, except for the Hospital Anxiety and Depression Scale Anxiety subtest. Small to negligible effect sizes were observed (ranging from .01 to .20). ICC estimates ranged from .71 to .97 across the neuropsychological measures. Bland Altman analyses revealed that the Wechsler Adult Intelligence Scale-Fourth Edition Block Design subtest had slightly better overall performance in the in-person condition and participants reported higher levels of anxiety symptoms during the teleneuropsychology condition; however, average anxiety symptoms remained within the clinically normal range. Participants reported a high level of acceptability for teleneuropsychology assessments. CONCLUSIONS: These results suggest that performances are comparable between in-person and teleneuropsychology assessment modalities. Our findings support teleneuropsychology as a feasible alternative to in-person neuropsychological services for people under investigation of YOD, who face significant barriers in accessing timely diagnoses and treatment options.

Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.

BACKGROUND: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C. METHODS: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo. RESULTS: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred. CONCLUSIONS: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).

Cerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders.

OBJECTIVE: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. METHODS: We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. RESULTS: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CONCLUSIONS: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.

Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders.

OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.

The shape of things to come. Mapping spatiotemporal progression of striatal morphology in Huntington disease: The IMAGE-HD study.

Mapping the spatiotemporal progression of neuroanatomical change in Huntington's Disease (HD) is fundamental to the development of bio-measures for prognostication. Statistical shape analysis to measure the striatum has been performed in HD, however there have been a limited number of longitudinal studies. To address these limitations, we utilised the Spherical Harmonic Point Distribution Method (SPHARM-PDM) to generate point distribution models of the striatum in individuals, and used linear mixed models to test for localised shape change over time in pre-manifest HD (pre-HD), symp-HD (symp-HD) and control individuals. Longitudinal MRI scans from the IMAGE-HD study were used (baseline, 18 and 30 months). We found significant differences in the shape of the striatum between groups. Significant group-by-time interaction was observed for the putamen bilaterally, but not for caudate. A differential rate of shape change between groups over time was observed, with more significant deflation in the symp-HD group in comparison with the pre-HD and control groups. CAG repeats were correlated with bilateral striatal shape in pre-HD and symp-HD. Robust statistical analysis of the correlates of striatal shape change in HD has confirmed the suitability of striatal morphology as a potential biomarker correlated with CAG-repeat length, and potentially, an endophenotype.

Midline brain structures in adult Niemann-Pick type C disease: a cross-sectional study.

OBJECTIVE: A range of neuropathological changes occur in the brains of individuals with adult Niemann-Pick type C disease (NPC), a recessive disorder of cholesterol trafficking that results in accumulation of cholesterol and gangliosides in lysosomes, particularly in neurons. One of the most significant regions of grey matter loss occurs in the thalami, which abut the midline. What is not known is whether these are neurodevelopmental in origin well prior to symptomatic onset. We aimed to examine other markers of midline developmental anomalies in adults with NPC. METHOD: We examined the size of adhesio interthalamica (AI) and cavum septum pellucidum (CSP) (if present) in nine individuals diagnosed with NPC and nine healthy comparison subjects, matched for age and gender, using a 3T magnetic resonance volumetric sequence and measured the length of the AI and CSP in mm. RESULTS: We found that 5/9 NPC patients and 0/9 controls had a missing AI. AI length was significantly shorter in the patient group. No subject in other group had a large CSP, and CSP length did not differ. Duration of illness showed a trend to a negative correlation with AI length in patients. CONCLUSIONS: Our findings suggest that adult NPC patients show some markers of early neurodevelopmental disturbance, matching findings seen in psychotic disorders. The differences in AI, but not CSP, suggest neurodevelopmental change may occur early in gestation rather than post-partum. The relationship with duration of illness suggests that there may be atrophy over time in these structures, consistent with prior analyses of grey matter regions in NPC.

Hippocampal morphology in Huntington's disease, implications for plasticity and pathogenesis: The IMAGE-HD study.

While striatal changes in Huntington's Disease (HD) are well established, few studies have investigated changes in the hippocampus, a key neuronal hub. Using MRI scans obtained from the IMAGE-HD study, hippocampi were manually traced and then analysed with the Spherical Harmonic Point Distribution Method (SPHARM-PDM) in 36 individuals with presymptomatic-HD, 37 with early symptomatic-HD, and 36 healthy matched controls. There were no significant differences in overall hippocampal volume between groups. Interestingly we found decreased bilateral hippocampal volume in people with symptomatic-HD who took selective serotonin reuptake inhibitors compared to those who did not, despite no significant differences in anxiety, depressive symptoms, or motor incapacity between the two groups. In symptomatic-HD, there was also significant shape deflation in the right hippocampal head, showing the utility of using manual tracing and SPHARM-PDM to characterise subtle shape changes which may be missed by other methods. This study confirms previous findings of the lack of hippocampal volumetric differentiation in presymptomatic-HD and symptomatic-HD compared to controls. We also find novel shape and volume findings in those with symptomatic-HD, especially in relation to decreased hippocampal volume in those treated with SSRIs.

First-Onset Psychosis After COVID-19 Infection: A Systematic Review of the Literature.

BACKGROUND: The COVID-19 pandemic has been an inciting factor for a wide variety of neuropsychiatric symptoms, including first-episode psychosis (FEP). OBJECTIVE: The aim of this systematic review was to summarize the current literature on COVID-19 associated postviral FEP. METHODS: A systematic review was completed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and identified 81 articles that met inclusion criteria. RESULTS: Articles included case reports, case series, and cohort studies with postviral FEP occurring outside the setting of delirium, demonstrating a broad range of symptoms. CONCLUSIONS: This systematic review shows that postviral FEP associated with COVID-19 follows a pattern similar to psychosis associated with other viral infections and is an important consideration when building a differential for FEP when delirium has been ruled out. Better understanding of postviral FEP associated with COVID-19 and other viral illnesses may help clarify aspects of underlying pathophysiology of psychotic symptoms broadly.

Structural and microstructural thalamocortical network disruption in sporadic behavioural variant frontotemporal dementia.

BACKGROUND: Using multi-block methods we combined multimodal neuroimaging metrics of thalamic morphology, thalamic white matter tract diffusion metrics, and cortical thickness to examine changes in behavioural variant frontotemporal dementia. (bvFTD). METHOD: Twenty-three patients with sporadic bvFTD and 24 healthy controls underwent structural and diffusion MRI scans. Clinical severity was assessed using the Clinical Dementia Rating scale and behavioural severity using the Frontal Behaviour Inventory by patient caregivers. Thalamic volumes were manually segmented. Anterior and posterior thalamic radiation fractional anisotropy and mean diffusivity were extracted using Tract-Based Spatial Statistics. Finally, cortical thickness was assessed using Freesurfer. We used shape analyses, diffusion measures, and cortical thickness as features in sparse multi-block partial least squares (PLS) discriminatory analyses to classify participants within bvFTD or healthy control groups. Sparsity was tuned with five-fold cross-validation repeated 10 times. Final model fit was assessed using permutation testing. Additionally, sparse multi-block PLS was used to examine associations between imaging features and measures of dementia severity. RESULTS: Bilateral anterior-dorsal thalamic atrophy, reduction in mean diffusivity of thalamic projections, and frontotemporal cortical thinning, were the main features predicting bvFTD group membership. The model had a sensitivity of 96%, specificity of 68%, and was statistically significant using permutation testing (p = 0.012). For measures of dementia severity, we found similar involvement of regional thalamic and cortical areas as in discrimination analyses, although more extensive thalamo-cortical white matter metric changes. CONCLUSIONS: Using multimodal neuroimaging, we demonstrate combined structural network dysfunction of anterior cortical regions, cortical-thalamic projections, and anterior thalamic regions in sporadic bvFTD.

Selective perforant-pathway atrophy in Huntington disease: MRI analysis of hippocampal subfields.

INTRODUCTION: While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions. METHODS: We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months. RESULTS: Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group. CONCLUSIONS: Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.

Survival in Huntington's disease and other young-onset dementias.

OBJECTIVES: To compare survival and risk factors associated with mortality in common young-onset dementias (YOD) including Huntington's disease. METHODS: This retrospective cohort study included inpatients from an Australian specialist neuropsychiatry service, over 20 years. Dementia diagnoses were based on consensus criteria and Huntington's disease (HD) was confirmed genetically. Mortality and cause of death were determined using linkage to the Australian Institute of Health and Welfare National Death Index. RESULTS: There were 386 individuals with YOD included. The dementia types included frontotemporal dementia (FTD) (24.5%), HD (21.2%) and Alzheimer's disease (AD) (20.5%). 63% (n = 243) individuals had died. The longest median survival was for those who had HD, 18.8 years from symptom onset and with a reduced mortality risk compared to AD and FTD (hazard ratio 0.5). Overall, people with YOD had significantly increased mortality, of 5-8 times, compared to the general population. Females with a YOD had higher standardised mortality ratio compared to males (9.3 vs. 4.9) overall. The most frequent cause of death in those with HD was reported as HD, with other causes of death in the other YOD-subtypes related to dementia and mental/behavioural disorders. DISCUSSION: This is the first Australian study to investigate survival and risk factors of mortality in people with YOD. YOD has a significant risk of death compared to the general population. Our findings provide useful clinical information for people affected by YOD as well as future planning and service provision.

Comparing survival and mortality in patients with late-onset and young-onset vascular dementia.

OBJECTIVES: Vascular dementia (VD) is one of the more common types of dementia. Much is known about VD in older adults in terms of survival and associated risk factors, but comparatively less is known about VD in a younger population. This study aimed to investigate survival in people with young-onset VD (YO-VD) compared to those with late-onset VD (LO-VD) and to investigate predictors of mortality. DESIGN: Retrospective file review from 1992 to 2014. SETTING: The inpatient unit of a tertiary neuropsychiatry service in Victoria, Australia. PARTICIPANTS: Inpatients with a diagnosis of VD. MEASUREMENTS AND METHODS: Mortality information was obtained from the Australian Institute of Health and Welfare. Clinical variables included age of onset, sex, vascular risk factors, structural neuroimaging, and Hachinksi scores. Statistical analyses used were Kaplan-Meier curves for median survival and Cox regression for predictors of mortality. RESULTS: Eighty-four participants were included with few clinical differences between the LO-VD and YO-VD groups. Sixty-eight (81%) had died. Median survival was 9.9 years (95% confidence interval 7.9, 11.7), with those with LO-VD having significantly shorter survival compared to those with YO-VD (6.1 years and 12.8 years, respectively) and proportionally more with LO-VD had died (94.6%) compared to those with YO-VD (67.5%), χ2(1) = 9.16, p = 0.002. The only significant predictor of mortality was increasing age (p = 0.001). CONCLUSION: While there were few clinical differences, and older age was the only factor associated with survival, further research into the effects of managing cardiovascular risk factors and their impact on survival are recommended.

Mania Following Traumatic Brain Injury: A Systematic Review.

OBJECTIVE: Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. Mania is an uncommon, but debilitating, psychiatric occurrence following TBI. The literature on mania following TBI is largely limited to case reports and case series. In the present review, the investigators describe the clinical, diagnostic, and treatment characteristics of mania following TBI. METHODS: A systematic search of MEDLINE, EMBASE, and PsycINFO was conducted for English-language studies published from 1980 to July 15, 2021. The included studies provided the required individual primary data and sufficient information on clinical presentation or treatment of manic symptoms. Studies with patients who reported a history of mania or bipolar disorder prior to TBI and studies with patients who sustained TBI before adulthood were excluded. RESULTS: Forty-one studies were included, which reported information for 50 patients (the mean±SD age at mania onset was 39.1±14.3 years). Patients were more frequently male, aged <50 years, and without a personal or family history of psychiatric disorders. Although 74% of patients reported mania developing within 1 year following TBI, latencies of up to 31 years were observed. Illness trajectory varied from a single manic episode to recurrent mood episodes. Rapid cycling was reported in six patients. Mood stabilizers and antipsychotics were most frequently used to improve symptoms. CONCLUSIONS: Heterogeneity of lesion locations and coexisting vulnerabilities make causality difficult to establish. Valproate or a second-generation antipsychotic, such as olanzapine or quetiapine, may be considered first-line therapy in the absence of high-level evidence for a more preferred treatment. Early escalation to combined therapy (mood stabilizer and second-generation antipsychotic) is recommended to control symptoms and prevent recurrence. Larger prospective studies and randomized controlled trials are needed to refine diagnostic criteria and provide definitive treatment recommendations.

Carer burden and behavioral disturbance is similar between younger-onset Alzheimer's disease and behavioral variant frontotemporal dementia.

OBJECTIVES: Carer burden is common in younger-onset dementia (YOD), often due to the difficulty of navigating services often designed for older people with dementia. Compared to Alzheimer's disease (AD), the burden is reported to be higher in behavioral variant frontotemporal dementia (bvFTD). However, there is little literature comparing carer burden specifically in YOD. This study hypothesized that carer burden in bvFTD would be higher than in AD. DESIGN: Retrospective cross-sectional study. SETTING: Tertiary neuropsychiatry service in Victoria, Australia. PARTICIPANTS: Patient-carer dyads with YOD. MEASUREMENTS: We collected patient data, including behaviors using the Cambridge Behavioral Inventory-Revised (CBI-R). Carer burden was rated using the Zarit Burden Inventory-short version (ZBI-12). Descriptive statistics and Mann-Whitney U tests were used to analyze the data. RESULTS: Carers reported high burden (ZBI-12 mean score = 17.2, SD = 10.5), with no significant difference in burden between younger-onset AD and bvFTD. CBI-R stereotypic and motor behaviors, CBI-R everyday skills, and total NUCOG scores differed between the two groups. There was no significant difference in the rest of the CBI-R subcategories, including the behavior-related domains. CONCLUSION: Carers of YOD face high burden and are managing significant challenging behaviors. We found no difference in carer burden between younger-onset AD and bvFTD. This could be due to similarities in the two subtypes in terms of abnormal behavior, motivation, and self-care as measured on CBI-R, contrary to previous literature. Clinicians should screen for carer burden and associated factors including behavioral symptoms in YOD syndromes, as they may contribute to carer burden regardless of the type.

Cerebrospinal fluid neurofilament light and cerebral atrophy in younger-onset dementia and primary psychiatric disorders.

BACKGROUND AND AIMS: Neurodegeneration underpins the pathological processes of younger-onset dementia (YOD) and has been implicated in primary psychiatric disorders (PSYs). Cerebrospinal fluid (CSF) neurofilament light (NfL) has been used to investigate neurodegeneration severity through correlation with structural brain changes in various conditions, but has seldom been evaluated in YOD and PSYs. METHODS: This retrospective study included patients with YOD or PSYs with magnetic resonance imaging (MRI) of the brain and CSF NfL analysis. Findings from brain MRI were analysed using automated volumetry (volBrain) to measure white matter (WM), grey matter (GM) and whole brain (WB) volumes expressed as percentages of total intracranial volume. Correlations between NfL and brain volume measurements were computed whilst adjusting for age. RESULTS: Seventy patients (47 with YOD and 23 with PSY) were identified. YOD types included Alzheimer disease and behavioural variant frontotemporal dementia. PSY included schizophrenia and major depressive disorder. MRI brain sequences were either fast spoiler gradient-echo (FSPGR) or magnetization-prepared rapid acquisition gradient-echo (MPRAGE). In the total cohort, higher NfL was associated with reduced WB in the FSPGR and MPRAGE sequences (r = -0.402 [95% confidence interval (CI), -0.593 to -0.147], P = 0.008 and r = -0.625 [95% CI, -0.828 to -0.395], P < 0.001, respectively). Higher NfL was related to reduced GM in FSPGR (r = 0.385 [95% CI, -0.649 to -0.014], P = 0.017) and reduced WM in MPRAGE (r = -0.650 [95% CI, -0.777 to -0.307], P < 0.001). Similar relationships were seen in YOD, but not in PSY. CONCLUSION: Higher CSF NfL is related to brain atrophy in YOD, further supporting its use as a nonspecific marker of neurodegeneration severity.

Use of Olanzapine to Treat Agitation in Traumatic Brain Injury: A Series of N-of-One Trials.

Agitation is common during post-traumatic amnesia (PTA) following traumatic brain injury (TBI) and is associated with risk of harm to patients and caregivers. Antipsychotics are frequently used to manage agitation in early TBI recovery despite limited evidence to support their efficacy, safety, and impact upon patient outcomes. The sedating and cognitive side effects of these agents are theorized to exacerbate confusion during PTA, leading to prolonged PTA duration and increased agitation. This study, conducted in a subacute inpatient rehabilitation setting, describes the results of a double-blind, randomized, placebo-controlled trial investigating the efficacy of olanzapine for agitation management during PTA, analyzed as an n-of-1 series. Group comparisons were additionally conducted, examining level of agitation; number of agitated days; agitation at discharge, duration, and depth of PTA; length of hospitalization; cognitive outcome; adverse events; and rescue medication use. Eleven agitated participants in PTA (mean [M] age = 39.82 years, standard deviation [SD] = 20.06; mean time post-injury = 46.09 days, SD = 32.75) received oral olanzapine (n = 5) or placebo (n = 6) for the duration of PTA, beginning at a dose of 5 mg/day and titrated every 3 to 4 days to a maximum dose of 20 mg/day. All participants received recommended environmental management for agitation. A significant decrease in agitation with moderate to very large effect (Tau-U effect size = 0.37-0.86) was observed for three of five participants receiving olanzapine, while no significant reduction in agitation over the PTA period was observed for any participant receiving placebo. Effective olanzapine dose ranged from 5-20 mg. Response to treatment was characterized by lower level of agitation and response to treatment within 3 days. In group analyses, participants receiving olanzapine demonstrated poorer orientation and memory during PTA with large effect size (olanzapine, mean = 9.32, SD = 0.69; placebo, M = 10.68, SD = 0.30; p = .009, d = -2.16), and a trend toward longer PTA duration with large effect size (olanzapine, M = 71.96 days, SD = 20.31; placebo, M = 47.50 days, SD = 11.27; p = 0.072, d = 1.26). No further group comparisons were statistically significant. These results suggest that olanzapine can be effective in reducing agitation during PTA, but not universally so. Importantly, administration of olanzapine during PTA may lead to increased patient confusion, possibly prolonging PTA. When utilizing olanzapine, physicians must therefore balance the possible advantages of agitation management with the possibility that the patient may never respond to the medication and may experience increased confusion, longer PTA and potentially poorer outcomes. Further high-quality research is required to support these findings and the efficacy and outcomes associated with the use of any pharmacological agent for the management of agitation during the PTA period.

Neuroimaging in the Acute Psychiatric Setting: Associations With Neuropsychiatric Risk Factors.

OBJECTIVE: The appropriateness and clinical utility of neuroimaging in psychiatric populations has been long debated, and the ambiguity of guideline recommendations is well established. Most of the literature is focused on first-episode psychosis. The investigators aimed to review ordering practices and identify risk factors associated with neuroradiological MRI abnormalities and their clinical utility in a general psychiatric population. METHODS: A retrospective file review was undertaken for 100 consecutive brain MRI scans for adult psychiatric inpatients who received scanning as part of their clinical care in an Australian hospital. RESULTS: Brain MRI was abnormal in 79.0% of scans; in these cases, 72.2% of patients required further investigation or follow-up, with 17.7% requiring urgent referral within days to weeks, despite only 3.7% of admitted patients undergoing MRI during the study period. Psychiatrically relevant abnormalities were found in 32.0% of scans. Abnormalities were more likely to be found in the presence of cognitive impairment, older age, and longer duration of psychiatric disorder. Psychiatrically relevant abnormalities had further associations with older age at onset of the psychiatric disorder and a weak association with abnormal neurological examination. Multiple indications for imaging were present in 57.0% of patients; the most common indications were physical, neurological, and cognitive abnormalities. CONCLUSIONS: Brain MRI is a useful part of psychiatric management in the presence of certain neuropsychiatric risk factors. The present findings suggest that treating teams can judiciously tailor radiological investigations while limiting excessive imaging. Future research in larger cohorts across multiple centers may contribute to shaping more consistent neuroimaging guidelines in psychiatry.