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.

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.

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.

Childhood trauma in patients with epileptic vs nonepileptic seizures.

OBJECTIVE: Childhood trauma has been implicated as a risk factor for the etiology of psychogenic nonepileptic seizures (PNES). Relatively little attention has been paid to whether profiles of specific trauma types differ between patients with epilepsy and PNES. Investigating childhood trauma profiles in these patient groups may identify psychological vulnerabilities that predispose to developing PNES, and aid early diagnoses, prevention, and treatment. METHODS: Data were collected from two cohorts (nRetrospective  = 203; nProspective  = 209) admitted to video-electroencephalography (EEG) monitoring units in Melbourne Australia. The differences in Childhood Trauma Questionnaire domain score between patient groups were investigated using standardized effect sizes and general linear mixed-effects models (GLMMs). Receiver-operating characteristic curves were used to investigate classification accuracy. RESULTS: In the retrospective cohort, patients diagnosed with PNES reported greater childhood emotional abuse, emotional neglect, physical abuse, sexual abuse, and physical neglect relative to patients with epilepsy. These differences were replicated in the prospective cohort, except for physical abuse. GLMMs revealed significant main effects for group in both cohorts, but no evidence for any group by domain interactions. Reported sexual abuse showed the best screening performance of PNES, although no psychometric scores were adequate as isolated measures. SIGNIFICANCE: Patients with PNES report a greater frequency of childhood trauma than patients with epilepsy. This effect appears to hold across all trauma types, with no strong evidence emerging for a particular trauma type that is more prevalent in PNES. From a practical perspective, inquiry regarding a history of sexual abuse shows the most promise as a screening measure.

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.

Do normative data specific to Greek Australian older adults improve validity of neuropsychological assessment results?

OBJECTIVE: This study aimed to compare Greek Australian and English language normative data with regard to impairment rates yielded within a healthy Greek Australian older adult sample. We also examined whether optimal cut scores could be identified and capable of sensitively and specifically distinguishing between healthy Greek Australians from those with a diagnosis of Alzheimer's disease (AD). METHOD: Ninety healthy Greek Australian older adults and 20 demographically matched individuals with a diagnosis of AD completed a range of neuropsychological measures, including the Wechsler Adult Intelligence Scale-Fourth Edition, Greek Adaptation (WAIS-IV GR), verbal and visual memory, language and naming, and executive functions. Impairment rates derived from the use of either Greek Australian or English language normative data were calculated and compared, using a 1.5 standard deviation criterion to denote impairment. Receiver operating characteristics curve analysis was used to investigate the sensitivity and specificity of alternate cut scores. RESULTS: Impairment rates derived from the Greek Australian normative data showed that rates of impairment generally fell within the expected 7% range. In contrast, impairment rates for all tests derived using English language normative data were significantly higher and ranged from 11%-66%. Comparisons between healthy and AD participants with moderate dementia showed significant differences across all measures. Area under the curve results ranged from .721 to .999 across all measures, with most tests displaying excellent sensitivity and specificity. CONCLUSIONS: English language normative data were found to be inappropriate for use with Greek Australian elders, potentially leading to erroneous diagnostic outcomes. The use of minority group specific normative data and associated cut points appear to partially ameliorate this issue. Clinical implications are discussed alongside future research directions.

Understanding Clinician's Experiences with Implementation of a Younger Onset Dementia Telehealth Service.

The successful implementation of telehealth services depends largely on clinician acceptance of telehealth as a viable healthcare option and their adoption of telehealth methods into their clinical practice. While growing research supports the feasibility of telehealth services, no research has evaluated clinicians' experiences during the implementation of a younger onset dementia telehealth service. Semi-structured group interviews were conducted with 7 metropolitan (hub) clinicians and 16 rural (spoke) clinicians during the pre-and post-implementation phases of a novel Younger onset dementia (YOD) telehealth service. Reflexive thematic analysis identified five themes at pre-implementation: clinical need, previous experiences and views, potential telehealth barriers, solutions to potential telehealth barriers, and potential clinical outcomes. At post-implementation, nine themes were identified: clinical need, clinical relationships, concerns about the future of rural healthcare, clinical practice and resourcing factors, patient suitability, difficulties with technology, service quality, the way forward, and the impact of COVID-19. Most clinicians held positive views regarding the service, particularly the ability to provide more options to rural-dwelling patients. However, some concerns about threats to rural healthcare and the validity of telehealth assessments remained. Overall, this study has identified service implementation barriers and facilitators and contributes to the long-term sustainability of current and future telehealth YOD services.

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.

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.

Young-onset dementia diagnosis, management and care: a narrative review.

Young-onset dementia comprises a heterogeneous range of dementias, with onset at less than 65 years of age. These include primary dementias such as Alzheimer disease, frontotemporal and vascular dementias; genetic/familial dementias; metabolic disorders; and secondary dementias such as those that result from alcohol use disorder, traumatic brain injury, and infections. The presentation of young-onset dementia is varied and may include cognitive, psychiatric and neurological symptoms. Diagnostic delay is common, with a frequent diagnostic conundrum being, "Is this young-onset dementia or is this psychiatric?". For assessment and accurate diagnosis, a thorough screen is recommended, such as collateral history and investigations such as neuroimaging, lumbar puncture, neuropsychology, and genetic testing. The management of young-onset dementia needs to be age-appropriate and multidisciplinary, with timely access to services and consideration of the family (including children).

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.

A thematic analysis of psychotic symptoms in young-onset dementia.

OBJECTIVES: Exploration of the themes and content of psychotic symptoms in young-onset dementia (YOD) is limited to case analysis. The primary objective of this study was to determine the themes of psychotic symptoms in individuals diagnosed with YOD. DESIGN: Comprehensive retrospective file review of discharge summaries. SETTING: Neuropsychiatry, a specialist mental health service located at the Royal Melbourne Hospital, Australia. PARTICIPANTS: Inpatients at Neuropsychiatry admitted between 2018 and 2020 (inclusive). MEASUREMENTS: Data extracted included descriptions and prevalence of psychotic symptoms as well as general demographic and clinical data. Data analysis was conducted using a thematic approach. RESULTS: Twenty-three inpatients had a diagnosis of YOD with psychotic symptoms. Themes were identified in the domains of delusions (six themes), auditory hallucinations (five themes), and visual hallucinations (two themes). Strong recurring themes across the modalities of hallucinations and delusions were beliefs and experiences relating to paranoia, suspicion, harm, and abuse. Themes did not clearly intersect across the modalities of hallucinations and delusions. A degree of thematic heterogeneity existed within individuals, and individuals experienced delusions or hallucinations of multiple themes. The themes of the psychotic symptoms did not clearly relate to diagnostic category, nor to time from diagnosis. CONCLUSION: This study is the first thematic analysis of psychotic symptoms in YOD and provides further understanding of patient phenomenology and experiences of psychosis in YOD.

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.

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.

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.

Principles for delivering improved care of people with functional seizures: Closing the treatment gap.

Patients diagnosed with functional (psychogenic nonepileptic) seizures have similar or greater levels of disability, morbidity and mortality than people with epilepsy, but there are far fewer treatment services. In contrast to epilepsy, the current understanding of pathophysiological mechanisms and the development of evidence-based treatments for functional seizures is rudimentary. This leads to high direct healthcare costs and high indirect costs to the patient, family and wider society. There are many patient, clinician and system-level barriers to improving outcomes for functional seizures. At a patient level, these include the heterogeneity of symptoms, diagnostic uncertainty, family factors and difficulty in perceiving psychological aspects of illness and potential benefits of treatment. Clinician-level barriers include sub-specialism, poor knowledge, skills and attitudes and stigma. System-level barriers include the siloed nature of healthcare, the high prevalence of functional seizures and funding models relying on individual medical practitioners. Through the examination of international examples and expert recommendations, several themes emerge that may address some of these barriers. These include (1) stepped care with low-level, brief generalised interventions, proceeding to higher level, extended and individualised treatments; (2) active triage of complexity, acuity and treatment readiness; (3) integrated interdisciplinary teams that individualise formulation, triage, and treatment planning and (4) shared care with primary, emergency and community providers and secondary consultation. Consideration of the application of these principles to the Australian and New Zealand context is proposed as a significant opportunity to meet an urgent need.

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.

Clinical impact of whole-genome sequencing in patients with early-onset dementia.

BACKGROUND: In the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation. METHODS: WGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer's disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD. RESULTS: Clinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk. DISCUSSION: WGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.

The Diagnostic Challenge of Young-Onset Dementia Syndromes and Primary Psychiatric Diseases: Results From a Retrospective 20-Year Cross-Sectional Study.

OBJECTIVE: Distinguishing a dementia syndrome from a primary psychiatric disease in younger patients can be challenging and may lead to diagnostic change over time. The investigators aimed to examine diagnostic stability in a cohort of patients with younger-onset neurocognitive disorders. METHODS: A retrospective review of records was conducted for patients who were admitted to an inpatient neuropsychiatry service unit between 2000 and 2019, who were followed up for at least 12 months, and who received a diagnosis of young-onset dementia at any time point. Initial diagnosis included Alzheimer's disease-type dementia (N=30), frontotemporal dementia (FTD) syndromes (N=44), vascular dementia (N=7), mild cognitive impairment (N=10), primary psychiatric diseases (N=6), and other conditions, such as Lewy body dementia (N=30). RESULTS: Among 127 patients, 49 (39%) had a change in their initial diagnoses during the follow-up period. Behavioral variant FTD (bvFTD) was the least stable diagnosis, followed by dementia not otherwise specified and mild cognitive impairment. Compared with patients with a stable diagnosis, those who changed exhibited a higher cognitive score at baseline, a longer follow-up period, greater delay to final diagnosis, and no family history of dementia. Patients whose diagnosis changed from a neurodegenerative to a psychiatric diagnosis were more likely to have a long psychiatric history, while those whose diagnosis changed from a psychiatric to a neurodegenerative one had a recent manifestation of psychiatric symptoms. CONCLUSIONS: Misdiagnosis of younger patients with neurocognitive disorders is not uncommon, especially in cases of bvFTD. Late-onset psychiatric symptoms may be the harbinger to a neurodegenerative disease. Close follow-up and monitoring of these patients are necessary.

Multidimensional psychopathological profile differences between patients with psychogenic nonepileptic seizures and epileptic seizure disorders.

OBJECTIVE: Early differential diagnosis of psychogenic nonepileptic seizures (PNES) and epileptic seizures (ES) remains difficult. Self-reported psychopathology is often elevated in patients with PNES, although relatively few studies have examined multiple measures of psychopathology simultaneously. This study aimed to identify differences in multidimensional psychopathology profiles between PNES and ES patient groups. METHOD: This was a retrospective case-control study involving patients admitted for video-EEG monitoring (VEM) over a two-year period. Clinicodemographic variables and psychometric measures of depression, anxiety, dissociation, childhood trauma, maladaptive personality traits, and cognition were recorded. Diagnosis of PNES or ES was determined by multidisciplinary assessment and consensus opinion. General linear mixed models (GLMMs) were used to investigate profile differences between diagnostic groups across psychometric measures. A general psychopathology factor was then computed using principal components analysis (PCA) and differences between groups in this 'p' factor were investigated. RESULTS: 261 patients (77 % with ES and 23 % with PNES) were included in the study. The PNES group endorsed greater symptomatology with GLMM demonstrating a significant main effect of group (η2p = 0.05) and group by measure interaction (η2p = 0.03). Simple effects analysis indicated that the PNES group had particularly elevated scores for childhood trauma (ß = 0.78), dissociation (ß = 0.70), and depression (ß = 0.60). There was a high correlation between psychopathology measures, with a single p factor generated to explain 60 % variance in the psychometric scores. The p factor was elevated in the PNES group (ß = 0.61). ROC curve analysis indicated that these psychometric measures had limited usefulness when considered individually (AUC range = 0.63-0.69). CONCLUSION: Multidimensional psychopathological profile differences exist between patients with PNES and ES. Patients with PNES report more psychopathology overall, with particular elevations in childhood trauma, dissociation, and depression. Although not suitable to be used as a standalone screening tool to differentiate PNES and ES, understanding of these profiles at a construct level might help triage patients and guide further psychiatric examination and enquiry.