Development of a smartphone screening test for preclinical Alzheimer's disease and validation across the dementia continuum.

BACKGROUND: Dementia prevalence is predicted to triple to 152 million globally by 2050. Alzheimer's disease (AD) constitutes 70% of cases. There is an urgent need to identify individuals with preclinical AD, a 10-20-year period of progressive brain pathology without noticeable cognitive symptoms, for targeted risk reduction. Current tests of AD pathology are either too invasive, specialised or expensive for population-level assessments. Cognitive tests are normal in preclinical AD. Emerging evidence demonstrates that movement analysis is sensitive to AD across the disease continuum, including preclinical AD. Our new smartphone test, TapTalk, combines analysis of hand and speech-like movements to detect AD risk. This study aims to [1] determine which combinations of hand-speech movement data most accurately predict preclinical AD [2], determine usability, reliability, and validity of TapTalk in cognitively asymptomatic older adults and [3], prospectively validate TapTalk in older adults who have cognitive symptoms against cognitive tests and clinical diagnoses of Mild Cognitive Impairment and AD dementia. METHODS: Aim 1 will be addressed in a cross-sectional study of at least 500 cognitively asymptomatic older adults who will complete computerised tests comprising measures of hand motor control (finger tapping) and oro-motor control (syllabic diadochokinesis). So far, 1382 adults, mean (SD) age 66.20 (7.65) years, range 50-92 (72.07% female) have been recruited. Motor measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 to develop an algorithm that classifies preclinical AD risk. Aim 2 comprises three sub-studies in cognitively asymptomatic adults: (i) a cross-sectional study of 30-40 adults to determine the validity of data collection from different types of smartphones, (ii) a prospective cohort study of 50-100 adults ≥ 50 years old to determine usability and test-retest reliability, and (iii) a prospective cohort study of ~1,000 adults ≥ 50 years old to validate against cognitive measures. Aim 3 will be addressed in a cross-sectional study of ~200 participants with cognitive symptoms to validate TapTalk against Montreal Cognitive Assessment and interdisciplinary consensus diagnosis. DISCUSSION: This study will establish the precision of TapTalk to identify preclinical AD and estimate risk of cognitive decline. If accurate, this innovative smartphone app will enable low-cost, accessible screening of individuals for AD risk. This will have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06114914, 29 October 2023. Retrospectively registered.

"I'm still in the lap of the gods I don't know whether I'm going to improve or not": listening to people with dementia or cognitive impairment and their support people, talking about inpatient rehabilitation experiences.

PURPOSE: People with dementia often experience poor outcomes in hospital and prolonged lengths of stay. They are sometimes labelled as having "poor rehabilitation potential". This study aimed to understand the inpatient rehabilitation experiences of people with dementia or cognitive impairment, and their support people, to inform future work to improve rehabilitation access and outcomes. MATERIALS AND METHODS: An exploratory qualitative study from an interpretivist perspective. Participants were inpatients of a geriatric rehabilitation unit in Australia, and their chosen support people. Semi-structured interviews were audio-recorded and transcribed. An analytical framework was developed and indexed to the dataset, followed by charting and thematic analysis. RESULTS: Ten people with dementia or cognitive impairment and nine support people participated (n = 19). Four themes were identified representing an interpretation of the analysis intended to inform clinical practice: Support patients to engage in the rehabilitation process; create a hospitable environment; recognise and work with care partners; and ensure staff have adequate dementia knowledge. CONCLUSIONS: Practical, emotional, process-related, and dementia-specific factors may influence the experiences of people living with dementia or cognitive impairment when participating in inpatient rehabilitation. Future research could investigate whether improvements focused on these factors might enhance quality of care for people with dementia.

People living with dementia may require tailored support to engage in the rehabilitation process effectively.Safe, kind, and comfortable environments provide a strong foundation for good rehabilitation care for people with dementia or cognitive impairment.Involving family as care partners may be essential for some people living with dementia.Dementia knowledge for the geriatric rehabilitation workforce may improve clinical outcomes.

Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease.

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.

Brief webcam test of hand movements predicts episodic memory, executive function, and working memory in a community sample of cognitively asymptomatic older adults.

INTRODUCTION: Low-cost simple tests for preclinical Alzheimer's disease are a research priority. We evaluated whether remote unsupervised webcam recordings of finger-tapping were associated with cognitive performance in older adults. METHODS: A total of 404 cognitively-asymptomatic participants (64.6 [6.77] years; 70.8% female) completed 10-second finger-tapping tests (Tasmanian [TAS] Test) and cognitive tests (Cambridge Neuropsychological Test Automated Battery [CANTAB]) online at home. Regression models including hand movement features were compared with null models (comprising age, sex, and education level); change in Akaike Information Criterion greater than 2 (ΔAIC > 2) denoted statistical difference. RESULTS: Hand movement features improved prediction of episodic memory, executive function, and working memory scores (ΔAIC > 2). Dominant hand features outperformed nondominant hand features for episodic memory (ΔAIC = 2.5), executive function (ΔAIC = 4.8), and working memory (ΔAIC = 2.2). DISCUSSION: This brief webcam test improved prediction of cognitive performance compared to age, sex, and education. Finger-tapping holds potential as a remote language-agnostic screening tool to stratify community cohorts at risk for cognitive decline.

Physiotherapy students are underprepared to work with people living with dementia: a qualitative study.

OBJECTIVES: To 1) explore physiotherapy students' experience in caring for people with dementia; 2) develop a rich understanding of their perceived preparedness to work with people with dementia upon graduation; and 3) identify opportunities to improve dementia education from the perspectives of students. DESIGN: A qualitative study comprised of semi-structured interviews via web conferencing software. Thematic analysis was undertaken, with themes/subthemes derived and a qualitative framework generated. SETTING: Three Victorian Universities in Australia. PARTICIPANTS: Physiotherapy students of entry-to-professional practice education programs (n = 17; mean age 23.7 years, 65% female), having completed at least 15 weeks of clinical placements. RESULTS: The overarching theme was that students' experience of providing care for people with dementia was variable. The three sub-themes were: 1) students experience significant challenges when working with people with dementia, 2) students experience a range of emotions when working with people with dementia, and 3) the quality of dementia learning experiences during entry-to-professional practice training is mostly inadequate. Students described the importance of the supervisor during clinical placements, and suggested incorporating 'real-life' scenario training in the classroom to assist them learn to manage the challenging symptoms of dementia. CONCLUSION: Physiotherapy students believe that entry-to-practice dementia education is insufficient. These findings have important implications for the future planning and delivery of physiotherapy dementia education. CONTRIBUTION OF THE PAPER.

Reforming allied health service provision in residential aged care to improve the rehabilitation reach: a feasibility study.

Objective My Therapy is an allied health guided, co-designed rehabilitation self-management program for residents of aged care facilities. This study aimed to determine the feasibility of implementing My Therapy in a residential aged care setting. Methods This observational study was conducted on a 30-bed wing, within a 90-bed metropolitan residential aged care facility, attached to a public health service, in Victoria, Australia. Staff and resident data were collected prospectively over 6 weeks (staff focus groups, patient surveys, and audits) to evaluate the feasibility domains of acceptability , reach and demand , practicality , integration , limited efficacy testing and adaptations . Results Twenty-six residents and five allied health staff (physiotherapy and occupational therapy) participated. My Therapy was acceptable to residents (survey) and staff (focus groups). Via initial My Therapy discussions between the resident and the therapists, to determine goals and resident preferences, My Therapy reached 26 residents (n = 26/26, 100% program reach ), with 15 residents subsequently receiving a rehabilitation program (n = 15/26, 58% program demand ). The remaining 11 residents did not participate due to resident preference or safety issues (n = 11/26, 42%). Collecting physical function outcome measures for limited efficacy testing was practical , and the cost of My Therapy was AUD$6 per resident per day, suggesting financial integration may be possible. Several adaptations were required, due to limited allied health staff, complex resident goal setting and program co-design. Conclusion My Therapy has the potential to improve the rehabilitation reach of allied health services in residential aged care. While introducing this low-cost intervention is feasible, adaptations were required for successful implementation.

Estimating presymptomatic episodic memory impairment using simple hand movement tests: A cross-sectional study of a large sample of older adults.

INTRODUCTION: Finding low-cost methods to detect early-stage Alzheimer's disease (AD) is a research priority for neuroprotective drug development. Presymptomatic Alzheimer's is associated with gait impairment but hand motor tests, which are more accessible, have hardly been investigated. This study evaluated how home-based Tasmanian (TAS) Test keyboard tapping tests predict episodic memory performance. METHODS: 1169 community participants (65.8 ± 7.4 years old; 73% female) without cognitive symptoms completed online single-key and alternate-key tapping tests and episodic memory, working memory, and executive function cognitive tests. RESULTS: All single-key (R2 adj  = 8.8%, ΔAIC = 5.2) and alternate-key (R2 adj  = 9.1%, ΔAIC = 8.8) motor features predicted episodic memory performance relative to demographic and mood confounders only (R2 adj  = 8.1%). No tapping features improved estimation of working memory. DISCUSSION: Brief self-administered online hand movement tests predict asymptomatic episodic memory impairment. This provides a potential low-cost home-based method for stratification of enriched cohorts. HIGHLIGHTS: We devised two brief online keyboard tapping tests to assess hand motor function. 1169 cognitively asymptomatic adults completed motor- and cognitive tests online. Impaired hand motor function predicted reduced episodic memory performance. This brief self-administered test may aid stratification of community cohorts.

Current evidence on the association of tongue strength with cognitive decline in older adults and the known risk factors of frailty, sarcopenia and nutritional health: a scoping review protocol.

INTRODUCTION: Evidence suggests that the pathology underlying cognitive decline leading to dementia begins 15-20 years before cognitive symptoms emerge. Thus, identifying biomarkers in this preclinical phase is critically important. Age-related decrease in muscle mass and strength, a known risk factor for sarcopenia, frailty and cognitive decline, also affects the tongue. This paper describes an a priori protocol by a multidisciplinary team to address the following questions relating to adults ≥50 years of age: (1) What is the current evidence on the association of tongue strength with cognitive decline? (2) How does tongue strength associate with frailty and sarcopenia? (3) What is the association of tongue strength with nutritional health? METHODS AND ANALYSIS: Search terms will be identified then multiple electronic databases (PubMed, PsycINFO (Ovid), Scopus, Embase (Ovid), CINAHL and Web of Science) searched systematically for peer-reviewed articles published in English that address the following inclusion criteria: (1) human studies, (2) participants ≥50 years of age and (3) studies with tongue pressure values measured in relation to at least one of the following: frailty, sarcopenia, nutritional health, cognitive function and dementia (Alzheimer's, vascular, frontotemporal and Lewy body). Grey literature also will be searched to identify additional studies, clinical trials and policy papers appropriate for inclusion. The search will be from database inception. After removing duplicates, two research team members will independently screen abstracts and identify articles for full-text review. The team will use a data charting tool for data extraction. Data will be analysed quantitatively and qualitatively. ETHICS AND DISSEMINATION: The scoping review does not require ethics approval as data will be from publicly available sources. Results will be disseminated in workshops and conferences and a peer-reviewed journal paper.

A new one-stop interdisciplinary cognitive clinic model tackles rural health inequality and halves the time to diagnosis: Benchmarked against a national dementia registry.

OBJECTIVES: Unequal access to cognitive assessments is a major barrier to timely diagnosis, especially for those living in rural or remote areas. 'One-stop' cognitive clinic models are a proposed solution, but few such clinics exist. We evaluate the implementation of a new one-stop State-wide clinic model in Tasmania, Australia, where 27% of people live in rural/remote areas. METHODS: A novel single-visit protocol has been developed, comprising interdisciplinary medical and cognitive assessments, research participation, consensus diagnosis and management plan. A cross-sectional evaluation was undertaken using the RE-AIM (reach, effectiveness, adoption, implementation, maintenance) framework and results benchmarked against the national Australian Dementia Network Registry. RESULTS: Over the first 52 consecutive weekly clinics: Reach: 130 adults were assessed (mean age [SD] 70.12 years [10.31]; 59.2% female) with 40 (36.8%) from rural/remote areas. EFFECTIVENESS: 98.5% (128/130) received a same-day diagnosis: 30.1% (n = 40) Subjective Cognitive Decline, 35.4% (46) Mild Cognitive Impairment, 33.1% (43) dementia and one case inconclusive. Adoption: 22.9% (156) of General Practitioners referred patients. IMPLEMENTATION: Nearly all 'ideal' diagnostic clinical practices were met and >90% of surveyed patients reported 'good/very good' clinic experience. The wait from referral to diagnosis was 2 months shorter than other national Registry clinics (78 vs. 133 days). CONCLUSIONS: This 'one-stop' model provides an interdisciplinary consensus cognitive diagnosis quickly and is well accepted; this may reduce health inequities especially for people living in rural/remote areas. This cognitive clinic model may be of relevance to other centres worldwide and also provides a rich data source for research studies.

Chromosomal deletions on 16p11.2 encompassing SH2B1 are associated with accelerated metabolic disease.

New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2-3 [BP2-3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10-10) and increased rates of T2D. Compared with BMI-matched controls, deletion carriers have an earlier onset of T2D, with poorer glycemic control despite higher medication usage. Cystatin C, a biomarker of kidney function, is significantly elevated in deletion carriers, suggesting increased risk of renal impairment. In a Mendelian randomization study, decreased SH2B1 expression increases T2D risk (p = 8.1 × 10-6). We conclude that people with 16p11.2 BP2-3 deletions have early, complex obesity and T2D and may benefit from therapies that enhance leptin and insulin signaling.

Investigating the associations between upper limb motor function and cognitive impairment: a scoping review.

Upper limb motor function is a potential new biomarker of cognitive impairment and may aid discrimination from healthy ageing. However, it remains unclear which assessments to use. This study aimed to explore what methods have been used and to describe associations between upper limb function and cognitive impairment. A scoping review was conducted using PubMed, CINAHL and Web of Science. A systematic search was undertaken, including synonyms for key concepts 'upper limb', 'motor function' and 'cognitive impairment'. Selection criteria included tests of upper limb motor function and impaired cognition in adults. Analysis was by narrative synthesis. Sixty papers published between 1998 and 2022, comprising 41,800 participants, were included. The most common assessment tasks were finger tapping, Purdue Pegboard Test and functional tasks such as writing. Protocols were diverse in terms of equipment used and recording duration. Most participants were recruited from clinical settings. Alzheimer's Disease was the most common cause of cognitive impairment. Results were mixed but, generally, slower speed, more errors, and greater variability in upper limb movement variables was associated with cognitive impairment. This review maps the upper limb motor function assessments used and summarises the available evidence on how these associate with cognitive impairment. It identifies research gaps and may help guide protocols for future research. There is potential for upper limb motor function to be used in assessments of cognitive impairment.

A rare human variant that disrupts GPR10 signalling causes weight gain in mice.

Disruption of brain-expressed G protein-coupled receptor-10 (GPR10) causes obesity in animals. Here, we identify multiple rare variants in GPR10 in people with severe obesity and in normal weight controls. These variants impair ligand binding and G protein-dependent signalling in cells. Transgenic mice harbouring a loss of function GPR10 variant found in an individual with obesity, gain excessive weight due to decreased energy expenditure rather than increased food intake. This evidence supports a role for GPR10 in human energy homeostasis. Therapeutic targeting of GPR10 may represent an effective weight-loss strategy.

Physiotherapy students' experiences of working with people with dementia during their clinical placements: a qualitative study.

PURPOSE: To explore the experiences of physiotherapy students on working with people with dementia during their clinical placements. METHODS: Qualitative study using a Web-based survey of students in a 2-year entry-level Masters of Physical Therapy (MPT) program. Students were asked to reflect on their experiences during clinical placements within the MPT program. Qualitative content analysis was used to analyze the survey responses. RESULTS: A total of 55 students (93%) completed the survey. Two overarching themes were mastery and inequity. Mastery described dementia care physiotherapy as a complex and potentially rewarding area of practice, requiring education and development throughout the professional continuum from student to expert. Inequity captured the barriers people with dementia experience to receiving excellent physiotherapy care. Six categories supported the themes: 1) physiotherapist characteristics for a successful therapeutic relationship; 2) communication strategies; 3) best practice physiotherapy skills and knowledge; 4) education strategies; 5) desire to work with people living with dementia; and 6) equity. CONCLUSIONS: The study found physiotherapy students' experiences were informed by the preceptors' approach to delivery of care for people living with dementia. The students also articulated areas they wish they had known before placement and provided suggestions for teaching development in this area.

Let families decide: Barriers and enablers to participation in family-assisted therapy for older people in transition care.

OBJECTIVE: To understand the barriers and enablers to participation in family-assisted therapy for older people in Transition Care. METHODS: A qualitative study, underpinned by interpretive description, was conducted at two public health services in Melbourne, Australia. Participants included patients in Transition Care, or their family members, who either participated in or chose not to participate in a family-assisted therapy trial. Semi-structured interviews were conducted, transcribed verbatim and analysed thematically. RESULTS: Forty-four participants were interviewed (17 patients and 27 family members). The unifying theme was to let families decide about participation in family-assisted therapy. The unifying theme was illustrated by three subthemes. The first, what is possible for the family now, described practical considerations including geography, paid and unpaid work structure and commitments and the presence of fit and willing social networks. The second, what is important to the family now, recognised the role of family priorities in deciding. Physical rehabilitation and extra therapy were of high importance to some families. For others, emotional support or searching for a residential aged care bed were more important at the time. Finally, how the family functions described the complexity of relationships and family history that impacted the decision to participate. CONCLUSIONS: The decision to participate in family-assisted therapy is complex and is best made by patients and their families. Clinicians offering family-assisted therapy are encouraged to avoid assuming what will or will not work for families and instead, to let families decide.

Human loss-of-function variants in the serotonin 2C receptor associated with obesity and maladaptive behavior.

Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety and depression. Here we studied the role of the serotonin 2C receptor (5-HT2CR) in weight regulation and behavior. Using exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity. Using the 5-HT2CR agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired in knock-in mice. In conclusion, we demonstrate that 5-HT2CR is involved in the regulation of human appetite, weight and behavior. Our findings suggest that melanocortin receptor agonists might be effective in treating severe obesity in individuals carrying HTR2C variants. We suggest that HTR2C should be included in diagnostic gene panels for severe childhood-onset obesity.

MicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis.

MicroRNAs (miRNAs) modulate physiological responses by repressing the expression of gene networks. We found that global deletion of microRNA-7 (miR-7), the most enriched miRNA in the hypothalamus, causes obesity in mice. Targeted deletion of miR-7 in Single-minded homolog 1 (Sim1) neurons, a critical component of the hypothalamic melanocortin pathway, causes hyperphagia, obesity and increased linear growth, mirroring Sim1 and Melanocortin-4 receptor (MC4R) haplo-insufficiency in mice and humans. We identified Snca (α-Synuclein) and Igsf8 (Immunoglobulin Superfamily Member 8) as miR-7 target genes that act in Sim1 neurons to regulate body weight and endocrine axes. In humans, MIR-7-1 is located in the last intron of HNRNPK, whose promoter drives the expression of both genes. Genetic variants at the HNRNPK locus that reduce its expression are associated with increased height and truncal fat mass. These findings demonstrate that miR-7 suppresses gene networks involved in the hypothalamic melanocortin pathway to regulate mammalian energy homeostasis.

Moving towards intelligent telemedicine: Computer vision measurement of human movement.

BACKGROUND: Telemedicine video consultations are rapidly increasing globally, accelerated by the COVID-19 pandemic. This presents opportunities to use computer vision technologies to augment clinician visual judgement because video cameras are so ubiquitous in personal devices and new techniques, such as DeepLabCut (DLC) can precisely measure human movement from smartphone videos. However, the accuracy of DLC to track human movements in videos obtained from laptop cameras, which have a much lower FPS, has never been investigated; this is a critical gap because patients use laptops for most telemedicine consultations. OBJECTIVES: To determine the validity and reliability of DLC applied to laptop videos to measure finger tapping, a validated test of human movement. METHOD: Sixteen adults completed finger-tapping tests at 0.5 Hz, 1 Hz, 2 Hz, 3 Hz and at maximal speed. Hand movements were recorded simultaneously by a laptop camera at 30 frames per second (FPS) and by Optotrak, a 3D motion analysis system at 250 FPS. Eight DLC neural network architectures (ResNet50, ResNet101, ResNet152, MobileNetV1, MobileNetV2, EfficientNetB0, EfficientNetB3, EfficientNetB6) were applied to the laptop video and extracted movement features were compared to the ground truth Optotrak motion tracking. RESULTS: Over 96% (529/552) of DLC measures were within +/-0.5 Hz of the Optotrak measures. At tapping frequencies >4 Hz, there was progressive decline in accuracy, attributed to motion blur associated with the laptop camera's low FPS. Computer vision methods hold potential for moving us towards intelligent telemedicine by providing human movement analysis during consultations. However, further developments are required to accurately measure the fastest movements.

The TAS Test project: a prospective longitudinal validation of new online motor-cognitive tests to detect preclinical Alzheimer's disease and estimate 5-year risks of cognitive decline and dementia.

BACKGROUND: The worldwide prevalence of dementia is rapidly rising. Alzheimer's disease (AD), accounts for 70% of cases and has a 10-20-year preclinical period, when brain pathology covertly progresses before cognitive symptoms appear. The 2020 Lancet Commission estimates that 40% of dementia cases could be prevented by modifying lifestyle/medical risk factors. To optimise dementia prevention effectiveness, there is urgent need to identify individuals with preclinical AD for targeted risk reduction. Current preclinical AD tests are too invasive, specialist or costly for population-level assessments. We have developed a new online test, TAS Test, that assesses a range of motor-cognitive functions and has capacity to be delivered at significant scale. TAS Test combines two innovations: using hand movement analysis to detect preclinical AD, and computer-human interface technologies to enable robust 'self-testing' data collection. The aims are to validate TAS Test to [1] identify preclinical AD, and [2] predict risk of cognitive decline and AD dementia. METHODS: Aim 1 will be addressed through a cross-sectional study of 500 cognitively healthy older adults, who will complete TAS Test items comprising measures of motor control, processing speed, attention, visuospatial ability, memory and language. TAS Test measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 (p-tau181). Aim 2 will be addressed through a 5-year prospective cohort study of 10,000 older adults. Participants will complete TAS Test annually and subtests of the Cambridge Neuropsychological Test Battery (CANTAB) biennially. 300 participants will undergo in-person clinical assessments. We will use machine learning of motor-cognitive performance on TAS Test to develop an algorithm that classifies preclinical AD risk (p-tau181-defined) and determine the precision to prospectively estimate 5-year risks of cognitive decline and AD. DISCUSSION: This study will establish the precision of TAS Test to identify preclinical AD and estimate risk of cognitive decline and AD. If accurate, TAS Test will provide a low-cost, accessible enrichment strategy to pre-screen individuals for their likelihood of AD pathology prior to more expensive tests such as blood or imaging biomarkers. This would have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05194787 , 18 January 2022. Retrospectively registered.

Obesity Due to Steroid Receptor Coactivator-1 Deficiency Is Associated With Endocrine and Metabolic Abnormalities.

CONTEXT: Genetic variants affecting the nuclear hormone receptor coactivator steroid receptor coactivator, SRC-1, have been identified in people with severe obesity and impair melanocortin signaling in cells and mice. As a result, obese patients with SRC-1 deficiency are being treated with a melanocortin 4 receptor agonist in clinical trials. OBJECTIVE: Here, our aim was to comprehensively describe and characterize the clinical phenotype of SRC-1 variant carriers to facilitate diagnosis and clinical management. METHODS: In genetic studies of 2462 people with severe obesity, we identified 23 rare heterozygous variants in SRC-1. We studied 29 adults and 18 children who were SRC-1 variant carriers and performed measurements of metabolic and endocrine function, liver imaging, and adipose tissue biopsies. Findings in adult SRC-1 variant carriers were compared to 30 age- and body mass index (BMI)-matched controls. RESULTS: The clinical spectrum of SRC-1 variant carriers included increased food intake in children, normal basal metabolic rate, multiple fractures with minimal trauma (40%), persistent diarrhea, partial thyroid hormone resistance, and menorrhagia. Compared to age-, sex-, and BMI-matched controls, adult SRC-1 variant carriers had more severe adipose tissue fibrosis (46.2% vs 7.1% respectively, P = .03) and a suggestion of increased liver fibrosis (5/13 cases vs 2/13 in controls, odds ratio = 3.4), although this was not statistically significant. CONCLUSION: SRC-1 variant carriers exhibit hyperphagia in childhood, severe obesity, and clinical features of partial hormone resistance. The presence of adipose tissue fibrosis and hepatic fibrosis in young patients suggests that close monitoring for the early development of obesity-associated metabolic complications is warranted.