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Supplemental material, sj-docx-1-anp-10.1177_00048674231187312 for Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders by Dhamidhu Eratne, Matthew Kang, Charles Malpas, Steve Simpson-Yap, Courtney Lewis, Christa Dang, Jasleen Grewal, Amy Coe, Hannah Dobson, Michael Keem, Wei-Hsuan Chiu, Tomas Kalincik, Suyi Ooi, David Darby, Amy Brodtmann, Oskar Hansson, Shorena Janelidze, Kaj Blennow, Henrik Zetterberg, Adam Walker, Olivia Dean, Michael Berk, Cassandra Wannan, Christos Pantelis, Samantha M Loi, Mark Walterfang, Samuel F Berkovic, Alexander F Santillo and Dennis Velakoulis in Australian & New Zealand Journal of Psychiatry

Funding Information: This work was supported by BioMarin Pharmaceutical Inc . Funding Information: The content of this manuscript was based on preparatory pre-meeting activities and presentations and discussions during two advisory board meetings that were coordinated and funded by BioMarin Pharmaceutical Inc. All authors or their institutions received funding from BioMarin to attend at least one or both meetings. Additional disclosures: BKB received consulting payments from BioMarin, Shire, Genzyme, Alexion, Horizon Therapeutics, Denali Therapeutics, JCR Pharma, Moderna, Aeglea BioTherapeutics, SIO Gene Therapies, Taysha Gene Therapy, Ultragenyx, and Inventiva Pharma, participated as clinical trial investigator for BioMarin, Shire, Denali Therapeutics, Homology Medicines, Ultragenyx, and Moderna as well as received speaker fees from BioMarin, Shire, Genzyme, and Horizon Therapeutics. AH received consulting payments from BioMarin, Chiesi, Shire, Genzyme, Amicus, and Ultragenyx, participated as clinical trial investigator for Ultragenyx as well as received speaker fees from Alexion, Amicus, BioMarin, Genzyme, Nutricia, Sobi, and Takeda. ABQ received consulting payments from BioMarin, speaker fees from BioMarin, Nutricia, Vitaflo, Sanofi, Takeda, Recordati, and travel support from Vitaflo . SEC received consulting payments and speaker fees from BioMarin as well as consulting payments from Synlogic Therapeutics. COH was clinical trial investigator for BioMarin and received consulting and speaker payments from BioMarin. SCJH received consulting payments and travel support from BioMarin and Homology Medicines. NL received consulting payments from Alnylam, Amicus, Astellas, BioMarin, BridgeBio, Chiesi, Genzyme/Sanofi, HemoShear, Horizon Therapeutics, Jaguar, Moderna, Nestle, PTC Therapeutics, Reneo, Shire, Synlogic, and Ultragenyx, participated as clinical trial investigator for Aeglea, Amicus, Astellas, BioMarin, Genzyme/Sanofi, Homology, Horizon, Moderna, Pfizer, Protalix, PTC Therapeutics, Reneo, Retrophin/Travere therapeutics, Shire, and Ultragenyx, as well as received speaker fees from Cycle Pharmaceuticals, Leadiant and Recordati. MCM II received consulting payments from BioMarin, Horizon Therapeutics, Rhythm Pharmaceuticals, Applied Therapeutics, Cycle Therapeutics, and Ultragenyx. ALSP received speaker fees from BioMarin. JCR received consulting payments from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, and Nutricia, speaker fees from Applied Pharma Research, Merck Serono, BioMarin Pharmaceutical, Vitaflo, Cambrooke, PIAM, LifeDiet, and Nutricia, as well as travel support from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, Cambrooke, PIAM, and Nutricia. SS received consulting payments, research grants, speaker fees, and travel support from BioMarin and participated as clinical trials investigator for BioMarin. ASV received consulting payments from BioMarin, Horizon Therapeutics, and Ultragenyx and participated as clinical trial investigator for Acadia, Alexion, BioMarin, Genzyme, Homology Medicines, Kaleido, Mallinckrodt, and Ultragenyx. JV received consulting payments from BioMarin, LogicBio Pharmaceuticals, Sangamo Therapeutics, Orphan Labs, Synlogic Therapeutics, Sanofi, Axcella Health, Agios Pharmaceuticals, and Applied Therapeutics as well as travel grants from BioMarin and LogicBio Pharmaceuticals. MW received consulting payments, speaker fees, and travel support from BioMarin, and participated as clinical trial investigator for Mallinckrodt, Roche, Wave, Cycle Therapeutics, and Intrabio. ACM participated in strategic advisory boards and received honoraria as a consultant and as a speaker for Merck Serono, BioMarin, Nestlé Health Science (SHS), Applied Pharma Research, Actelion, Retrophin, Censa, PTC Therapeutics, and Arla Food. Funding Information: Ideally, access to (neuro)psychological/psychiatric support should assist adolescents with identifying, understanding, and reporting of PKU-specific challenges (Table 3), offering individualized recommendations on managing these challenges. Although there is no replacement for mental health services for patients with identified needs, psychosocial support from PKU peers, e.g., through PKU camps, virtual social events, etc., can at least in the short-term help to improve metabolic control by providing individuals an opportunity to participate in supportive PKU-related educational activities potentially reducing perceived social isolation [91]. In addition to PKU camps, which may be very specific to certain regions or countries, HCPs should consider encouraging involvement in local, regional, national and international PKU patient/family advocacy and social support organizations, introducing adolescents and young adults to national/international patient registries [92,93]. Besides support from PKU peers, patients can benefit from non-PKU peer support, although some adolescents and young adults with PKU may not disclose to others and may avoid eating in with others or eating in public due to potential feelings of anxiety or feelings of being ashamed of their disease. In addition, patients with PKU of all ages, but particularly vulnerable adolescents and young adults, can benefit from having the opportunity to learn about and practice strategies that help promote feelings of empowerment and self-efficacy that can be used in both familiar and unfamiliar environments where they may experience peer pressure and feel the need to ‘fit in’. For example, a role-play approach involving behavioral rehearsal, self-monitoring, goal setting, and training in problem-solving skills with emphasis on initiation and inhibition (i.e., how to say no) could be provided by parents, PKU peers, or even members of the PKU team. These types of activities can be used to teach adolescents with PKU how to react in social situations, such as dining out, helping to avoid indulging and increased risk-taking behavior, a hallmark of the adolescent period [94].This work was supported by BioMarin Pharmaceutical Inc.The content of this manuscript was based on preparatory pre-meeting activities and presentations and discussions during two advisory board meetings that were coordinated and funded by BioMarin Pharmaceutical Inc. All authors or their institutions received funding from BioMarin to attend at least one or both meetings. Additional disclosures: BKB received consulting payments from BioMarin, Shire, Genzyme, Alexion, Horizon Therapeutics, Denali Therapeutics, JCR Pharma, Moderna, Aeglea BioTherapeutics, SIO Gene Therapies, Taysha Gene Therapy, Ultragenyx, and Inventiva Pharma, participated as clinical trial investigator for BioMarin, Shire, Denali Therapeutics, Homology Medicines, Ultragenyx, and Moderna as well as received speaker fees from BioMarin, Shire, Genzyme, and Horizon Therapeutics. AH received consulting payments from BioMarin, Chiesi, Shire, Genzyme, Amicus, and Ultragenyx, participated as clinical trial investigator for Ultragenyx as well as received speaker fees from Alexion, Amicus, BioMarin, Genzyme, Nutricia, Sobi, and Takeda. ABQ received consulting payments from BioMarin, speaker fees from BioMarin, Nutricia, Vitaflo, Sanofi, Takeda, Recordati, and travel support from Vitaflo. SEC received consulting payments and speaker fees from BioMarin as well as consulting payments from Synlogic Therapeutics. COH was clinical trial investigator for BioMarin and received consulting and speaker payments from BioMarin. SCJH received consulting payments and travel support from BioMarin and Homology Medicines. NL received consulting payments from Alnylam, Amicus, Astellas, BioMarin, BridgeBio, Chiesi, Genzyme/Sanofi, HemoShear, Horizon Therapeutics, Jaguar, Moderna, Nestle, PTC Therapeutics, Reneo, Shire, Synlogic, and Ultragenyx, participated as clinical trial investigator for Aeglea, Amicus, Astellas, BioMarin, Genzyme/Sanofi, Homology, Horizon, Moderna, Pfizer, Protalix, PTC Therapeutics, Reneo, Retrophin/Travere therapeutics, Shire, and Ultragenyx, as well as received speaker fees from Cycle Pharmaceuticals, Leadiant and Recordati. MCM II received consulting payments from BioMarin, Horizon Therapeutics, Rhythm Pharmaceuticals, Applied Therapeutics, Cycle Therapeutics, and Ultragenyx. ALSP received speaker fees from BioMarin. JCR received consulting payments from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, and Nutricia, speaker fees from Applied Pharma Research, Merck Serono, BioMarin Pharmaceutical, Vitaflo, Cambrooke, PIAM, LifeDiet, and Nutricia, as well as travel support from Applied Pharma Research, Merck Serono, BioMarin, Vitaflo, Cambrooke, PIAM, and Nutricia. SS received consulting payments, research grants, speaker fees, and travel support from BioMarin and participated as clinical trials investigator for BioMarin. ASV received consulting payments from BioMarin, Horizon Therapeutics, and Ultragenyx and participated as clinical trial investigator for Acadia, Alexion, BioMarin, Genzyme, Homology Medicines, Kaleido, Mallinckrodt, and Ultragenyx. JV received consulting payments from BioMarin, LogicBio Pharmaceuticals, Sangamo Therapeutics, Orphan Labs, Synlogic Therapeutics, Sanofi, Axcella Health, Agios Pharmaceuticals, and Applied Therapeutics as well as travel grants from BioMarin and LogicBio Pharmaceuticals. MW received consulting payments, speaker fees, and travel support from BioMarin, and participated as clinical trial investigator for Mallinckrodt, Roche, Wave, Cycle Therapeutics, and Intrabio. ACM participated in strategic advisory boards and received honoraria as a consultant and as a speaker for Merck Serono, BioMarin, Nestlé Health Science (SHS), Applied Pharma Research, Actelion, Retrophin, Censa, PTC Therapeutics, and Arla Food. Publisher Copyright: © 2022 The Authors Background: Early treated patients with phenylketonuria (PKU) often become lost to follow-up from adolescence onwards due to the historical focus of PKU care on the pediatric population and lack of programs facilitating the transition to adulthood. As a result, evidence on the management of adolescents and young adults with PKU is limited. Methods: Two meetings were held with a multidisciplinary international panel of 25 experts in PKU and comorbidities frequently experienced by patients with PKU. Based on the outcomes of the first meeting, a set of statements were developed. During the second meeting, these statements were voted on for consensus generation (≥70% agreement), using a modified Delphi approach. Results: A total of 37 consensus recommendations were developed across five areas that were deemed important in the management of adolescents and young adults with PKU: (1) general physical health, (2) mental health and neurocognitive functioning, (3) blood Phe target range, (4) PKU-specific challenges, and (5) transition to adult care. The consensus recommendations reflect the personal opinions and experiences from the participating experts supported with evidence when available. Overall, clinicians managing adolescents and young adults with PKU should be aware of the wide variety of PKU-associated comorbidities, initiating screening at an early age. In addition, management of adolescents/young adults should be a joint effort between the patient, clinical center, and parents/caregivers supporting adolescents with gradually gaining independent control of their disease during the transition to adulthood. Conclusions: A multidisciplinary international group of experts used a modified Delphi approach to develop a set of consensus recommendations with the aim of providing guidance and offering tools to clinics to aid with supporting adolescents and young adults with PKU. publishersversion published

Introduction: Sodium selenate increases tau dephosphorylation through protein phosphatase 2 activation. Here we report an open-label Phase 1b study of sodium selenate as a disease-modifying treatment for behavioral variant frontotemporal dementia (bvFTD). Methods: Twelve participants with bvFTD received sodium selenate (15 mg, three times a day) for 52 weeks. Safety assessments were carried out throughout the trial. Primary outcomes were frequency of adverse events (AEs), serious adverse events (SAEs), and discontinuations. Secondary outcomes of potential efficacy included cognitive and behavioral assessments, magnetic resonance imaging (MRI) whole brain volume, and cerebrospinal fluid (CSF) and blood total tau (t-tau), phosphorylated tau (p-tau), and neurofilament light (NfL) levels, which were measured at baseline and at week 52. Results: Sodium selenate was safe and well tolerated. All participants completed the study, and the majority (64.7%) of reported AEs were mild. One SAE occurred, which was not treatment related. Small declines in MRI and cognitive and behavioral measures were observed over the treatment period. There was no evidence for change in CSF protein levels (t-tau, p-tau, or NfL). Further analysis showed two distinct groups when measuring disease progression markers over the course of the study-one (n = 4) with substantial brain atrophy (2.5% to 6.5% reduction) and cognitive and behavioral decline over the 12-month treatment period, and the second group (n = 7) with no detectable change in cognitive and behavioral measures and less brain atrophy (0.3% to 1.7% reduction). Conclusion: Sodium selenate is safe and well tolerated in patients with bvFTD. Randomized-controlled trials are warranted to investigate potential efficacy.

Supplemental material, sj-pdf-1-anp-10.1177_00048674211058684 for Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives by Dhamidhu Eratne, Shorena Janelidze, Charles B Malpas, Samantha Loi, Mark Walterfang, Antonia Merritt, Ibrahima Diouf, Kaj Blennow, Henrik Zetterberg, Brandon Cilia, Cassandra Wannan, Chad Bousman, Ian Everall, Andrew Zalesky, Mahesh Jayaram, Naveen Thomas, Samuel F Berkovic, Oskar Hansson, Dennis Velakoulis, Christos Pantelis and Alexander Santillo in Australian & New Zealand Journal of Psychiatry

Supplemental material, sj-docx-1-anp-10.1177_00048674211025715 for Development of a suspicion index for secondary schizophrenia using the Delphi method by Olivier Bonnot, Jose Luis Insua, Mark Walterfang, Juan Vincente Torres and Stefan Armin Kolb in Australian & New Zealand Journal of Psychiatry

Genome and exome sequencing has been extensively successful in identifying disease causing gene mutations and variants in GWAS. However, there has been little success in deducing the pertinent genomic variants that significantly modify disease progression and fully account for phenotype. One reason is that current use of genome-wide association study (GWAS) utilize narrow sense heritability estimates and do not include assessment of epistasis and other components of broad-sense heritability1-2 . Here we report investigation of genetic variants that modify the causal gene of a monogenic disease and ultimately regulate its onset and progression in individuals. Niemann-Pick type C (NP-C) disease, a rare monogenic Mendelian disease, is one of more than 6,000 Mendelian diseases for which there is no cure. Most NP-C patients with the NPC1 gene mutation are diagnosed as late infants and die before or during adolescence, yet survival of some to adulthood provides a testbed for elucidating genes that alleviate the primary mutation. Therefore, we collected whole-genome sequences of pediatric and adult-onset patients. We then developed a pipeline that integrates mathematical models of genetic polymorphisms, augmented Bayesian biological networks, clinical records, and semantic ontologies of GWAS data. The tool that we developed analyzes sequencing data, identifies genome-wide interactions, and has scripts that control for confounding factors using heterogeneous data harmonization and modularity-based clustering. Our approach mitigates the statistical challenge of sample sizes inherent to current GWAS methodology. There are a large number of modifying genes that appear to function in epistatic networks of disease-modifying variants whose genetic effects together explain the heritability NP-C in its various manifestations. 1- Kim, S. et al. Genes with high network connectivity are enriched for disease heritability. Am. J. Hum. Genet. (2019). 2- Escala-Garcia, M. et al. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis. Nat. Commun. (2020). Keywords: system biology, network, genome, GWAS, Bayesian Acknowledgments: Ara Parseghian Medical Research Fund ABOUT THE AUTHOR(S) Eliatan Niktab - I’m a Ph.D. candidate at Victoria University and a member of Quantitative Methods, Machine Learning, and Functional Genomics group at Genomics England Clinical Interpretation Partnership (GeCIP). I’m trained to investigate diverse, complex and multifeature data including human genomics, proteomics, and metabolomics by developing mathematical models and statistical analyses. My Ph.D. dissertation utilizes such models for investigating the rare neurodegenerative Niemann-Pick type C (NPC) disease. I’m mostly practiced in genome-scale algorithm design, using deep neural networks for genetic variant discovery, Baysian modeling, and GPU-accelerated software development.Stephen Sturley, Ph.D. Professor Sturley’s group uses a multidisciplinary approach that integrates genetics, biochemistry and cell biology. He is specialized in applying yeast as a model organism to understand human lipid metabolism. Particular emphasis and success of his lab has been attained with regard to cholesterol, sphingolipid and fatty acid homeostasis underlying lipotoxicity with particular reference to neurodegeneration, obesity, and diabetes. Their use of yeast to identify genetic modifiers of recessive disorders such as Niemann- Pick Type C (NPC) resulted in the identification of histone deacetylase inhibitors as a candidate therapy, for which this drug was further tested in murine models of NPC disease and now in clinical trial in human patients.Mark Walterfang, M.D., Ph.D. FRANZCP Professor Walterfang has significant experience in clinical neuropsychiatry and general adult psychiatry with expertise in managing comorbid psychiatric and neurological disorders, neurodegenerative disorders, neurometabolic disorders, and atypical dementias. Clinical experience is the basis of his success in research, starting with 13 published papers from his Ph.D. that have been cited more than 500 times. He has since published over 130 papers in major psychiatric, metabolic, neurological and neuroimaging journals. Ingrid Winship, MBChB, MD, Ph.D., FRACP, FACD The focus of her research is the relationship between genotype and phenotype with particular emphasis on human diseases. In the last two decades, her research has helped to frame the questions, define the phenotypes, and via statistical analyses associated genotype and phenotype. At the other end of the translational pipeline, her research has translated the discoveries and knowledge into clinical protocols and policies, which has changed the way patients are treated in medical practice via new drug targets and biomarkers to monitor the onset and progression of the disease. Paul Atkinson, Ph.D. Professor Atkinson is a cell biologist who has long investigated ER-related events in specification of membrane protein synthesis and transport. His studies have included ER, Golgi and plasma membrane specific glycosylation structure determined by multidimensional NMR. Specific membrane glycoproteins studies utilised model systems including membrane maturing viruses. More recently he has utilized yeast gene knockout libraries to investigate epistatic network contribution to phenotype in ER related events. Andrew Munkacsi, Ph.D. Munkacsi lab studies the genetics, cell biology, and biochemistry of intracellular lipid transport to identify novel targets to treat the defective transport of cholesterol and sphingolipids underlying human disease. His group uses a unique combination of unbiased, high- throughput systems biology approaches in yeast genomic screens based on synthetic lethality, gene expression, protein localization, and protein-protein interactions, as well as exome and genome sequencing of human patients. Dr. Munkacsi successfully used these genome-wide yeast screens to identify unsuspected and precise targets to treat neurodegenerative diseases such as Alzheimer’s disease and Niemann- Pick Type C (NPC) disease, of which a subset have progressed to clinical trials.

Additional file 1: Appendix. Biological Specimens.

Purpose of review: Niemann-Pick disease type C (NP-C) is a neurovisceral disorder that may be more prevalent than earlier estimates. Diagnosis of NP-C is often delayed; a key aim for clinical practice is to reduce this delay. Recently, substantial progress has been made in the field of NP-C screening and diagnosis, justifying an update to the existing recommendations for clinical practice. Recent findings: New biomarker profiling and genetic analysis technologies are included as first-line diagnostic tests for NP-C. Most diagnoses can now be confirmed by combination of biomarker and genetic analyses. Filipin staining may facilitate diagnosis in uncertain cases. Recommendations are provided for psychiatrists, neuro-ophthalmologists, and radiologists, and on screening within specific at-risk patient cohorts. The NP-C diagnostic algorithm has been updated and simplified. Summary: This publication provides expert recommendations for clinicians who may see patients presenting with the signs and symptoms of NP-C, including general practitioners, pediatricians, neurologists, and psychiatrists.

Objective: Cognitive impairment in Parkinson disease (PD) places a high burden on patients and the pathophysiological mechanisms that differentiate patients with cognitive impairment from those without it are still incompletely understood. Methods: We conducted a resting-state seed region-of-interest approach to investigate functional connectivity (FC) of important subdivisions of the caudate nucleus, putamen and thalamus in controls (n=33), cognitively unimpaired subjects (PD-CU, n=33), PD subjects with mild cognitive impairment (PD-MCI, n=22) and subjects with dementia (PDD, n=17). We then investigated how the morphology of these structures differed between groups. Results: PD-CU subjects, compared to controls, displayed increased and decreased FC of caudate, putamen and thalamic subdivisions. PD-MCI subjects demonstrated reduced FC of the mediodorsal thalamus with the paracingulate cortex, compared to PD-CU, and reduced FC of the mediodorsal thalamus with the posterior cingulate cortex compared to PDD. Extensive volumetric and surface-based deflation was found in subjects with dementia. Conclusions: Our research suggests that cognitive impairment and dementia in PD may be associated with a breakdown in FC of the mediodorsal thalamus with para- and posterior cingulate regions of the brain, respectively. Significance: Cognitive impairment and dementia in PD may relate to pathophysiological changes in FC of the mediodorsal thalamus.

Supplemental material, Online_Supp for A pilot study of the utility of cerebrospinal fluid neurofilament light chain in differentiating neurodegenerative from psychiatric disorders: A ‘C-reactive protein’ for psychiatrists and neurologists? by Dhamidhu Eratne, Samantha M Loi, Nirbaanjot Walia, Sarah Farrand, Qiao-Xin Li, Shiji Varghese, Mark Walterfang, Andrew Evans, Ramon Mocellin, Kunal Dhiman, Veer Gupta, Charles B Malpas, Steven Collins, Colin L Masters and Dennis Velakoulis in Australian & New Zealand Journal of Psychiatry

Table S1. Comparison of disability scales. (DOCX 45 kb)

Supplemental material, APY766120_Appendix for Huntington’s disease: Managing neuropsychiatric symptoms in Huntington’s disease by Samantha M Loi, Mark Walterfang, Dennis Velakoulis and Jeffrey CL Looi in Australasian Psychiatry

To describe the development, design and function of an innovative international clinical research network for neuroimaging research, based in Australia, within a joint state health service/medical school. This Australian, US, Scandinavian Imaging Exchange (AUSSIE) network focuses upon identifying neuroimaging biomarkers for neuropsychiatric and neurodegenerative disease.We describe a case study of the iterative development of the network, identifying characteristic features and methods which may serve as potential models for virtual clinical research networks. This network was established to analyse clinically-derived neuroimaging data relevant to neuropsychiatric and neurodegenerative disease, specifically in relation to subcortical brain structures.The AUSSIE network has harnessed synergies from the individual expertise of the component groups, primarily clinical neuroscience researchers, to analyse a variety of clinical data.AUSSIE is an active virtual clinical research network, analogous to a connectome, which is embedded in health care and has produced significant research, advancing our understanding of neuropsychiatric and neurodegenerative disease through the lens of neuroimaging.

Hippocampal pathology is central to Alzheimer's disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1). We conducted shape analysis of hippocampi segmented from structural T1 MRI images on clinically diagnosed dementia patients and controls. The subjects included 19 AD and 35 FTLD patients [13 frontotemporal dementia (FTD), 13 semantic dementia (SD), and 9 progressive nonfluent aphasia (PNFA)] and 21 controls. Compared to controls, SD displayed severe atrophy of the whole left hippocampus. PNFA and FTD also displayed atrophy on the left side, restricted to the hippocampal head in FTD. Finally, AD displayed most atrophy in left hippocampal body with relative sparing of the hippocampal head. Consistent with neuropathological studies, most atrophic deformation was found in CA1 and subiculum areas in FTLD and AD.

Hippocampal pathology is central to Alzheimer’s disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1).

Chorea-acanthocytosis (ChAc) is an uncommon autosomal recessive disorder due to mutations of the VPS13A gene, which encodes for the membrane protein chorein. ChAc presents with progressive limb and orobuccal chorea, but there is often a marked dysexecutive syndrome. ChAc may first present with neuropsychiatric disturbance such as obsessive-compulsive disorder (OCD), suggesting a particular role for disruption to striatal structures involved in non-motor frontostriatal loops, such as the head of the caudate nucleus. Two previous studies have suggested a marked reduction in volume in the caudate nucleus and putamen, but did not examine morphometric change.

Topiramate is a sulfamate-substituted monosaccharide anticonvulsant that is associated with anorexia and weight loss and has been used to treat binge eating disorder and bulimia nervosa. This report describes a man with frontotemporal dementia, behavioural variant, associated with abnormal eating behaviour which appeared to respond to topiramate. We review the physiological basis of abnormal eating behaviour in frontotemporal dementia and explore possible mechanisms of action by which topiramate may modify eating behaviour in this condition.

Functional deficits seen in several neurodegenerative disorders have been linked with dysfunction in fronto-striatal circuits and with associated shape alterations in striatal structures. The severity of visible white matter changes (WMC) on MRI has been found to correlate with poorer performance on measures of gait and balance. This study aimed to determine whether striatal volume and shape changes were correlated with gait dysfunction.

Objective To evaluate the accuracy of the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) to screen for major depression among people with physical health problems. Design Systematic review and individual participant data meta-analysis. Data sources Medline, Medline In-Process and Other Non-Indexed Citations, PsycInfo, and Web of Science (from inception to 25 October 2018). Review methods Eligible datasets included HADS-D scores and major depression status based on a validated diagnostic interview. Primary study data and study level data extracted from primary reports were combined. For HADS-D cut-off thresholds of 5-15, a bivariate random effects meta-analysis was used to estimate pooled sensitivity and specificity, separately, in studies that used semi-structured diagnostic interviews (eg, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders), fully structured interviews (eg, Composite International Diagnostic Interview), and the Mini International Neuropsychiatric Interview. One stage meta-regression was used to examine whether accuracy was associated with reference standard categories and the characteristics of participants. Sensitivity analyses were done to assess whether including published results from studies that did not provide raw data influenced the results. Results Individual participant data were obtained from 101 of 168 eligible studies (60%; 25 574 participants (72% of eligible participants), 2549 with major depression). Combined sensitivity and specificity was maximised at a cut-off value of seven or higher for semi-structured interviews, fully structured interviews, and the Mini International Neuropsychiatric Interview. Among studies with a semi-structured interview (57 studies, 10 664 participants, 1048 with major depression), sensitivity and specificity were 0.82 (95% confidence interval 0.76 to 0.87) and 0.78 (0.74 to 0.81) for a cut-off value of seven or higher, 0.74 (0.68 to 0.79) and 0.84 (0.81 to 0.87) for a cut-off value of eight or higher, and 0.44 (0.38 to 0.51) and 0.95 (0.93 to 0.96) for a cut-off value of 11 or higher. Accuracy was similar across reference standards and subgroups and when published results from studies that did not contribute data were included. Conclusions When screening for major depression, a HADS-D cut-off value of seven or higher maximised combined sensitivity and specificity. A cut-off value of eight or higher generated similar combined sensitivity and specificity but was less sensitive and more specific. To identify medically ill patients with depression with the HADS-D, lower cut-off values could be used to avoid false negatives and higher cut-off values to reduce false positives and identify people with higher symptom levels. Fil: Wu, Yin. School Of Medicine; Canadá. Lady Davis Institute For Medical Research; Canadá Fil: Levis, Brooke. Keele University; Reino Unido Fil: Sun, Ying. Lady Davis Institute For Medical Research; Canadá Fil: He, Chen. Lady Davis Institute For Medical Research; Canadá Fil: Krishnan, Ankur. Lady Davis Institute For Medical Research; Canadá Fil: Neupane, Dipika. Lady Davis Institute For Medical Research; Canadá Fil: Bhandari, Parash Mani. Lady Davis Institute For Medical Research; Canadá Fil: Negeri, Zelalem. Université Mcgill; Canadá. Lady Davis Institute For Medical Research; Canadá Fil: Benedetti, Andrea. Centre Universitaire de Santé Mcgill; Canadá Fil: Thombs, Brett D.. Mcgill Faculty Of Medicine And Health Sciences; Canadá. Lady Davis Institute For Medical Research; Canadá Fil: Daray, Federico Manuel. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina