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Background: Clinical demand for quick, cheap, precise and accurate 25-hydroxyvitamin D (25(OH)D) results has led to the development of a variety of assay methods. Lack of standardization of these methods has resulted in intermethod disagreement and challenged whether current assays recognize 25(OH)D2 and 25(OH)D3 equally. Methods: We studied 172 patient samples from hip fracture cases using DiaSorin (DS) and IDS radioimmunoassays and the Nichols Advantage-automated protein binding assay (NA-CLPBA) in comparison to high-performance liquid chromatography (HPLC). 52 patient samples were analysed before and after three months treatment with 1000 IU of daily ergocalciferol (vitamin D2). Results: Linear regression analysis in pre-treatment samples demonstrated a positive Y-intercept for each immunoassay compared with HPLC, and a slope that varied from 0.64 (IDS) to 0.97 (DS, NA-CLPBA). Bland Altman analysis demonstrated that all the three assays had a proportional positive bias relative to HPLC at values from 20 to 50 nmol/L. Regression analysis of post-treatment samples demonstrated a slope that was not significantly different from zero for the IDS and NA-CLPBA and 0.2 for the DS method, with a positive intercept for all assays of between 8 and 22, indicating less than 50% of 25(OH)D2 measured by HPLC was detected. Conclusions: These results demonstrate the need for assay-specific decision limits for 25(OH)D3 in order to define appropriate thresholds for treatment institution. Treatment with vitamin D2 may not be accurately monitored with any of the three commercial assays studied. Clinicians and biochemists who continue to use 25(OH)D assays need to be urgently informed of these issues. [ABSTRACT FROM AUTHOR]

The North American epidemic of overeating, combined with a sedentary lifestyle, has led to a growing prevalence of obesity, diabetes, and the 'metabolic syndrome' in children. Excessive caloric intake does not imply adequate nutrition, and vitamin-deficiency syndromes still occur in some American children. Here we describe cases of scurvy and vitamin D deficiency in 2 children with cognitive disorders. Thorough dietary histories suggested the diagnosis in each patient and, had they been obtained at presentation, would likely have obviated invasive diagnostic workup, unnecessary stress to the patients and their families, and significant functional disability. Overnutrition and malnutrition may coexist, particularly among those with abnormal cognition or autistic spectrum disorders. Classic nutritional deficiencies must not be omitted from the differential diagnosis. A comprehensive dietary history and screening for vitamin deficiencies in at-risk children are important aspects of preventive health care and are essential for prompt diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Older adults living with multiple long-term conditions (MLTC, also known as multimorbidity) and frailty are more likely to experience a deterioration in their health requiring specialist referral or hospital admission than individuals without these syndromes. However, this group of older people are underserved by research meaning that there is a limited evidence base for their care. This study therefore aimed (1) to determine if it is feasible to recruit and collect quantitative data to describe the health and lifestyle of older adults living with MLTC, frailty and a recent deterioration in health and (2) to assess if taking part in research is acceptable to this group of older adults., Methods: Participants were approached and recruited for this study via an Older People's Medicine Day Unit in Newcastle upon Tyne, UK. The study took a mixed methods approach, involving quantitative and qualitative data collection. To determine the feasibility of carrying out research in this group, we quantified recruitment rate and collected data on the health and lifestyle, including diet and physical activity, of the participants. Qualitative semi-structured interviews were undertaken to assess acceptability. Two separate interviews were carried out focusing on involving older adults in research and the participants' experiences of taking part in the research. Interviews were analysed using thematic analysis., Results: Fifty patients were approached to participate in the study with twenty-nine (58%) successfully recruited. It was feasible to collect information to describe the health and lifestyle of these older adults who demonstrated very low levels of physical activity. Participants reported that taking part in the research was acceptable to them with interview analysis generating three themes (1) developing a meaningful partnership, (2) enabling factors to participation: research at home with flexible delivery and (3) social and psychological benefits of research participation., Conclusions: It is feasible and acceptable to recruit and carry out research with this underserved group of older adults. Participants found taking part in this research to be acceptable and reported overall positive experiences of their involvement in the study and indicated that they would be willing to contribute to further research in the future., (© 2024. The Author(s).)

This study aimed to: (1) validate a natural language processing (NLP) system developed for the home health care setting to identify signs and symptoms of Alzheimer's disease and related dementias (ADRD) documented in clinicians' free-text notes; (2) determine whether signs and symptoms detected via NLP help to identify patients at risk of a new ADRD diagnosis within four years after admission. This study applied NLP to a longitudinal dataset including medical record and Medicare claims data for 56,652 home health care patients and Cox proportional hazard models to the subset of 24,874 patients admitted without an ADRD diagnosis. Selected ADRD signs and symptoms were associated with increased risk of a new ADRD diagnosis during follow-up, including: motor issues; hoarding/cluttering; uncooperative behavior; delusions or hallucinations; mention of ADRD disease names; and caregiver stress. NLP can help to identify patients in need of ADRD-related evaluation and support services., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A new era of disease-modifying therapy for Alzheimer's disease (AD) arrived in 2021 following the Food and Drug Administration's (FDA) decision to grant accelerated approval for aducanumab, an anti-β-amyloid (Aβ) monoclonal antibody designed to target Aβ aggregates, a biological component of AD. More recently, trial outcomes for lecanemab and donanemab, two additional antibodies of this drug class, have shown favorable and significant slowing of metrics for cognitive and functional decline. Lecanemab and donanemab have since received similar FDA approval to aducanumab in January 2023 and July 2024, respectively. Given that these therapies are a clearly emerging tool in the repertoire of clinicians treating AD and related dementias, a critical dialogue has been ongoing regarding the potential impacts and place for these therapies. Here, we seek to contextualize this debate by first considering factors involved in theoretically extrapolating current randomized control trial outcomes to estimate meaningful clinical impacts. In the process of this exercise, we outline a generally useful concept termed Summative Treatment-Associated Benefit measuring Long-term Efficacy/Effectiveness Area as a metric of summative benefits of treatment over the life course of an individual. Second, we consider current real-world factors, such as conditions of FDA approval and other points involved in clinical decision-making that will influence and/or temper the actual impacts of this drug class., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Jin and Noble.)

This manuscript describes and summarizes the Dominantly Inherited Alzheimer Network Observational Study (DIAN Obs), highlighting the wealth of longitudinal data, samples, and results from this human cohort study of brain aging and a rare monogenic form of Alzheimer's disease (AD). DIAN Obs is an international collaborative longitudinal study initiated in 2008 with support from the National Institute on Aging (NIA), designed to obtain comprehensive and uniform data on brain biology and function in individuals at risk for autosomal dominant AD (ADAD). ADAD gene mutations in the amyloid protein precursor ( APP ), presenilin 1 ( PSEN1 ), or presenilin 2 ( PSEN2 ) genes are deterministic causes of ADAD, with virtually full penetrance, and a predictable age at symptomatic onset. Data and specimens collected are derived from full clinical assessments, including neurologic and physical examinations, extensive cognitive batteries, structural and functional neuro-imaging, amyloid and tau pathological measures using positron emission tomography (PET), flurordeoxyglucose (FDG) PET, cerebrospinal fluid and blood collection (plasma, serum, and whole blood), extensive genetic and multi-omic analyses, and brain donation upon death. This comprehensive evaluation of the human nervous system is performed longitudinally in both mutation carriers and family non-carriers, providing one of the deepest and broadest evaluations of the human brain across decades and through AD progression. These extensive data sets and samples are available for researchers to address scientific questions on the human brain, aging, and AD.

Objective: Hearing loss has been identified as a major modifiable risk factor for cognitive decline. The Early Age-Related Hearing Loss Investigation (EARHLI) study will assess the mechanisms linking early age-related hearing loss (ARHL) and cognitive impairment., Study Design: Randomized, controlled, single-site, early phase II, superiority trial., Setting: Tertiary academic medical center., Participants: One hundred fifty participants aged 55 to 75 years with early ARHL (severity defined as borderline to moderate) and amnestic mild cognitive impairment will be included., Interventions: Participants will be randomized 1:1 to a best practice hearing intervention or a health education control., Main Outcome Measures: The primary study outcome is cognition measured by the Alzheimer Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite. Secondary outcomes include additional measures of cognition, social engagement, and brain organization/connectivity., Results: Trial enrollment will begin in early 2024., Conclusions: After its completion in 2028, the EARHLI trial should offer evidence on the effect of hearing treatment versus a health education control on cognitive performance, social engagement, and brain organization/connectivity in 55- to 75-year-old community-dwelling adults with early ARHL and amnestic mild cognitive impairment., Competing Interests: Conflicts of interest: J.S.G.: Alcon (advisory board)., (Copyright © 2024, Otology & Neurotology, Inc.)

Introduction: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains., Methods: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo., Results: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo., Discussion: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity., Highlights: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: The American College of Clinical Pharmacy (ACCP) Pharmacotherapy Didactic Curriculum Toolkit has been used by colleges and schools of pharmacy as a guide for curricular development and revisions since its inaugural publication in 2009. The toolkit was last revised and updated by the 2019 Publications Committee., Objectives: The 2023 ACCP Publications Committee was charged with reviewing the 2019 Update to the ACCP Pharmacotherapy Didactic Curriculum Toolkit to determine any necessary revisions/updates., Methods: The committee revised tier classifications, shifting the focus of the 2023 toolkit to content within the Pharm.D. curriculum. Multiple literature sources were reviewed to assess conditions for inclusion in the 2023 toolkit, and external feedback was solicited from various practice disciplines. All topics were voted on by a simple majority rule during virtual meetings or by electronic votes., Results: There are a total of 231 topics in the 2023 toolkit, a decrease of 77 (23.2%) from the 2019 edition. Topics in each tier are as follows: 68 as tier 1 (29%), 111 as tier 2 (48%), and 52 as tier 3 (23%). Although some topics were removed completely, others were combined with other line items or revised, which may further minimize curricular overload. Similar to the 2016 and 2019 toolkits, many tier 2 topics remain in the 2023 toolkit, emphasizing the continued need for additional training through postgraduate residencies or fellowships (or "on-the-job" equivalent experiences), board certifications, and various certificate training programs., Conclusion: The 2023 ACCP Pharmacotherapy Didactic Curriculum Toolkit is designed to assist individual faculty and colleges and schools of pharmacy with curricular development and revisions. It will continue to be reviewed every 3 years to identify needed revisions on the basis of the pharmacist's evolving role, advances in therapeutics and pharmacy practice, and changes to accreditation standards and recognized professional competencies., Competing Interests: Conflicts of Interest: All other authors declare no conflicts of interest.

Introduction: We examined the association of clinical, microbiological, and host response features of periodontitis with MRI markers of atrophy/cerebrovascular disease in the Washington Heights Inwood Columbia Aging Project (WHICAP) Ancillary Study of Oral Health., Methods: We analyzed 468 participants with clinical periodontal data, microbial plaque and serum samples, and brain MRIs. We tested the association of periodontitis features with MRI features, after adjusting for multiple risk factors for Alzheimer's disease/Alzheimer's disease-related dementia (AD/ADRD)., Results: In fully adjusted models, having more teeth was associated with lower odds for infarcts, lower white matter hyperintensity (WMH) volume, higher entorhinal cortex volume, and higher cortical thickness. Higher extent of periodontitis was associated with lower entorhinal cortex volume and lower cortical thickness. Differential associations emerged between colonization by specific bacteria/serum antibacterial IgG responses and MRI outcomes., Discussion: In an elderly cohort, clinical, microbiological, and serological features of periodontitis were associated with MRI findings related to ADRD risk. Further investigation of causal associations is warranted., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Studies suggest distinct differences in the development, presentation, progression, and response to treatment of Alzheimer's disease (AD) between females and males. We investigated sex differences in cognition, neuroimaging, and fluid biomarkers in dominantly inherited AD (DIAD)., Methods: Three hundred twenty-five mutation carriers (55% female) and one hundred eighty-six non-carriers (58% female) of the Dominantly Inherited Alzheimer Network Observational Study were analyzed. Linear mixed models and Spearman's correlation explored cross-sectional sex differences in cognition, cerebrospinal fluid (CSF) biomarkers, Pittsburgh compound B positron emission tomography ( 11 C-PiB PET) and structural magnetic resonance imaging (MRI)., Results: Female carriers performed better than males on delayed recall and processing speed despite similar hippocampal volumes. As the disease progressed, symptomatic females revealed higher increases in MRI markers of neurodegeneration and memory impairment. PiB PET and established CSF AD markers revealed no sex differences., Discussion: Our findings suggest an initial cognitive reserve in female carriers followed by a pronounced increase in neurodegeneration coupled with worse performance on delayed recall at later stages of DIAD., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Many older adults live with the combination of multiple long-term conditions (MLTC) and frailty and are at increased risk of a deterioration in health requiring interaction with healthcare services. Low skeletal muscle strength is observed in individuals living with MLTC and is central to physical frailty. Resistance exercise (RE) is the best available treatment for improving muscle strength, but little is known about the attitudes and barriers to RE in this group of older adults. This study therefore aimed to explore the knowledge of and attitudes towards RE, as well as the barriers and enabling factors, in older adults living with MLTC, frailty and a recent deterioration in health., Methods: Fourteen participants aged 69-92 years (10 women) from the Lifestyle in Later Life - Older People's Medicine (LiLL-OPM) study were recruited from an Older People's Medicine Day Unit in Newcastle, UK. Participants were invited to take part in a semi-structured interview exploring their knowledge and attitudes as well as barriers and enabling factors to RE. Data were analysed using thematic analysis., Results: The analysis generated three themes (1) a lack of awareness and understanding of RE, (2) a self-perceived inability to perform RE; physical and psychological barriers and (3) willingness to perform RE under expert guidance. There was a general lack of awareness and understanding of RE, with most participants having never heard of the term and being unaware of its potential benefits. When RE was described, participants stated that they would be willing to try RE, but it was apparent that an individualised approach underpinned by expert guidance would be required to support engagement., Conclusions: Older adults living with MLTC, frailty and a recent deterioration in health lack awareness and understanding of RE. Despite a range of barriers, this group appear willing to engage in RE if they are appropriately supported. There is a need to co-design and deliver effective strategies, including education, to raise awareness and understanding of RE, as well as promote engagement in RE, in this group of older adults., (© 2023. The Author(s).)

Art activities for people with dementia have a range of therapeutic benefits including psychosocial wellbeing and enhanced quality of life. Successful art programs promote social engagement, are inclusive and empowering, and enable opportunity for people with dementia to express themselves verbally and non-verbally. The COVID-19 pandemic and associated social distancing precautions have impacted the capacity of art galleries and museums to deliver in-person programs. However, they have also provided a new opportunity. This paper explores the potential benefits, challenges, and future directions for research relating to the online delivery of gallery-facilitated art activities for people with dementia. The evidence revealed that increased digitisation of programs increased access for participants, however, the majority of the research was published before the pandemic. Nevertheless, COVID-19 has necessitated many museums and galleries to engage with people with dementia online. Future research is needed to improve the usability of online delivery platforms and a comparison of online and onsite delivery is recommended, particularly to evaluate benefits to people living in rural and remote areas where access to museums and galleries may be limited., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: This study explores the perspectives of workers and managers on workplace programs and interventions that seek to promote mental wellbeing, and prevent and treat mental health conditions The results contributed supporting evidence for the development of the WHO's first global guidelines for mental health and work, which provide evidence-based recommendations to support the implementation of workplace mental health programs and supports, to improve their acceptability, appropriateness, and uptake., Methods: An international online survey was used to examine the values and preferences among workers and managers related to workplace mental health prevention, protection, promotion, and support programs and services. The survey was made available in English, French, and Spanish and recruitment consisted of convenience sampling. Descriptive statistics were used to analyse the survey data. Rapid thematic qualitative analysis was used to analyse the results of open-ended questions., Results: N = 451 responses representing all WHO regions were included in the analysis. These results provide a unique international perspective on programs and supports for mental health at work, from the standpoint of workers and managers. Results suggest that workers value interventions developed in consultation with workers (including indicated, selective and universal interventions), increased training and capacity building among managers, and targeted interventions to address the pervasive impact of stigma on perceptions about mental health at work and help-seeking., Conclusion: The findings of this study seek to reflect the perspectives of workers and their managers, and therein to promote improved access, availability and uptake of mental health programs and supports at work and-ultimately- to support the potential of workplaces as environments that promote and support mental health., Competing Interests: JKM, JN, PAC, GM and AG declared that no competing interests exist. EEM has received funding from Otsuka-Lundbeck for patient educational activities. RWL has received honoraria for ad hoc speaking or advising/consulting, or received research funds, from: Abbvie, Asia-Pacific Economic Cooperation, Bausch, BC Leading Edge Foundation, Brain Canada, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, CAN-BIND Solutions, Carnot, Grand Challenges Canada, Healthy Minds Canada, Janssen, Lundbeck, Medscape, Michael Smith Foundation for Health Research, MITACS, Neurotorium, Ontario Brain Institute, Otsuka, Pfizer/Viatris, Shanghai Mental Health Center, Sunnybrook Health Sciences Centre, Unity Health, Vancouver Coastal Health Research Institute, and VGH-UBCH Foundation. This does not alter our adherence to PLOS ONE policies on sharing data and materials, (Copyright: © 2023 Murphy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Alzheimer's disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes-aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)-are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau., (© 2023. The Author(s).)

The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case-control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual's point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of 'sporadic' AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers., (© 2023. The Author(s).)

Community-dwelling older adults living with multiple long-term conditions (MLTC), frailty and a recent deterioration in health are underserved by research. This results in a limited evidence base for their care, including the potential benefits of lifestyle interventions such as structured exercise. The aims of the LiLL-OPM (Lifestyle in Later Life - Older People's Medicine) study are to determine if it is feasible to carry out a research project with these patients, describe their health and lifestyle, their attitudes to engaging in exercise and their experiences of taking part in the research. Older adults who are attending an Older People's Medicine Day Unit service in Newcastle, UK, and their informal carers will be invited to take part. The study will use mixed methods with semi-structured interviews and a health and lifestyle questionnaire, carried out in a way that is most convenient to participants, including in their own homes and with a flexible schedule of study visits. The findings from the feasibility study will provide invaluable data on how to design research, including the most suitable approaches to recruitment and data collection. This will improve the inclusion in research of older adults living with MLTC, frailty and a recent deterioration in health., (Copyright: © 2023 Hylonome Publications.)

Introduction: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD., Methods: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers., Results: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time., Discussion: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Periodontitis is a chronic inflammatory, bacterially-driven disease of the tooth-supporting tissues that shares several risk factors and elements of host response with Alzheimer's disease and related dementias (ADRD). Epidemiological studies have identified relatively consistent associations between adverse oral health conditions and ADRD. In this issue of the journal, a large study from the UK Biobank further explores these relationships along with MRI cognitive biomarkers. Despite its strength due to the large sample size, challenges in the study of periodontitis and neuroepidemiology markers include potential sampling bias, appropriate assessment of exposures, and the possibility of reverse causality.

Introduction: As the number of biomarkers used to study Alzheimer's disease (AD) continues to increase, it is important to understand the utility of any given biomarker, as well as what additional information a biomarker provides when compared to others., Methods: We used hierarchical clustering to group 19 cross-sectional biomarkers in autosomal dominant AD. Feature selection identified biomarkers that were the strongest predictors of mutation status and estimated years from symptom onset (EYO). Biomarkers identified included clinical assessments, neuroimaging, cerebrospinal fluid amyloid, and tau, and emerging biomarkers of neuronal integrity and inflammation., Results: Three primary clusters were identified: neurodegeneration, amyloid/tau, and emerging biomarkers. Feature selection identified amyloid and tau measures as the primary predictors of mutation status and EYO. Emerging biomarkers of neuronal integrity and inflammation were relatively weak predictors., Discussion: These results provide novel insight into our understanding of the relationships among biomarkers and the staging of biomarkers based on disease progression., (© 2022 the Alzheimer's Association.)

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

As prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and "sporadic" late-onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy-confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n = 310) and autopsy-confirmed LOAD participants (n = 163) before and after symptom onset (estimated/observed). LOAD participants declined more rapidly in the presymptomatic (preclinical) period and performed more poorly at symptom onset than ADAD participants on a cognitive composite. After symptom onset, however, the younger ADAD MCs declined more rapidly. The similar but not identical cognitive trajectories (declining but at different rates) for ADAD and LOAD suggest common AD pathologies but with some differences., (© 2021 the Alzheimer's Association.)

Purpose: Sarcopenia and the frailty phenotype both indicate older adults at risk of adverse health outcomes and yet are not widely assessed in practice. We developed the Newcastle SarcScreen to enable assessment of these two ageing syndromes during clinical care. In the setting of our Older People's Medicine Day Unit, our aims were to describe the implementation of the SarcScreen and to examine the typical values obtained., Methods: The SarcScreen comprised height, weight, questions (three on the Fried frailty phenotype and five on the SARC-F questionnaire), grip strength and gait speed. We analysed data from 552 patients completing the SarcScreen. We expressed grip strength as Z-scores (number of standard deviations above the mean expected for a patient's age and sex)., Results: It was possible to implement the SarcScreen. In 552 patients (65.9% females) with mean age 80.1 (7.7) years, grip strength was feasible in 98.2% and gait speed in 82.1%. Gait speed was typically not assessed due to mobility impairment. Most patients had weak grip strength (present in 83.8%), slow gait speed (88.8%) and the frailty phenotype (66.2%). We found a high prevalence of probable sarcopenia and the frailty phenotype across all age groups studied. This was reflected by low grip strength Z-scores, especially at younger ages: those aged 60-69 had grip strength 2.7 standard deviations (95% CI 2.5-2.9) below that expected., Conclusion: It is possible to implement an assessment of sarcopenia and the frailty phenotype as part of the routine outpatient care of older people., (© 2022. The Author(s).)

Background: This study reports on the changes in stress, anxiety, and depressive symptoms of subscribers after 3 months using Text4Hope, a supportive text messaging program designed to provide support during the pandemic., Methods: Standardized self-report measures were used to evaluate perceived stress (measured with the Perceived Stress Scale-10 [PSS-10]), anxiety (measured with the General Anxiety Disorder Scale 7 [GAD-7]), and depressive symptoms (measured with the Patient Health Questionnaire [PHQ-9]), at baseline and 3rd month ( n = 373)., Results: After 3 months of using Text4Hope, subscribers' self-reports revealed significant ( p < 0.001) mean score reductions compared with baseline on: the GAD-7 by 22.7%, PHQ-9 by 10.3%, and PSS-10 scores by 5.7%. Reductions in inferred prevalence rates for moderate to high symptoms were also observed, with anxiety demonstrating the largest reduction (15.7%)., Conclusions: Observed Text4Hope-related reductions in psychological distress during COVID-19 indicate that Text4Hope is an effective, convenient, and accessible means of implementing a population-level psychological intervention.

Background: Approximately 1 in 3 Canadians will experience an addiction or mental health challenge at some point in their lifetime. Unfortunately, there are multiple barriers to accessing mental health care, including system fragmentation, episodic care, long wait times, and insufficient support for health system navigation. In addition, stigma may further reduce an individual's likelihood of seeking support. Digital technologies present new and exciting opportunities to bridge significant gaps in mental health care service provision, reduce barriers pertaining to stigma, and improve health outcomes for patients and mental health system integration and efficiency. Chatbots (ie, software systems that use artificial intelligence to carry out conversations with people) may be explored to support those in need of information or access to services and present the opportunity to address gaps in traditional, fragmented, or episodic mental health system structures on demand with personalized attention. The recent COVID-19 pandemic has exacerbated even further the need for mental health support among Canadians and called attention to the inefficiencies of our system. As health care workers and their families are at an even greater risk of mental illness and psychological distress during the COVID-19 pandemic, this technology will be first piloted with the goal of supporting this vulnerable group., Objective: This pilot study seeks to evaluate the effectiveness of the Mental Health Intelligent Information Resource Assistant in supporting health care workers and their families in the Canadian provinces of Alberta and Nova Scotia with the provision of appropriate information on mental health issues, services, and programs based on personalized needs., Methods: The effectiveness of the technology will be assessed via voluntary follow-up surveys and an analysis of client interactions and engagement with the chatbot. Client satisfaction with the chatbot will also be assessed., Results: This project was initiated on April 1, 2021. Ethics approval was granted on August 12, 2021, by the University of Alberta Health Research Board (PRO00109148) and on April 21, 2022, by the Nova Scotia Health Authority Research Ethics Board (1027474). Data collection is anticipated to take place from May 2, 2022, to May 2, 2023. Publication of preliminary results will be sought in spring or summer 2022, with a more comprehensive evaluation completed by spring 2023 following the collection of a larger data set., Conclusions: Our findings can be incorporated into public policy and planning around mental health system navigation by Canadian mental health care providers-from large public health authorities to small community-based, not-for-profit organizations. This may serve to support the development of an additional touch point, or point of entry, for individuals to access the appropriate services or care when they need them, wherever they are., International Registered Report Identifier (irrid): PRR1-10.2196/33717., (©Jasmine M Noble, Ali Zamani, MohamadAli Gharaat, Dylan Merrick, Nathanial Maeda, Alex Lambe Foster, Isabella Nikolaidis, Rachel Goud, Eleni Stroulia, Vincent I O Agyapong, Andrew J Greenshaw, Simon Lambert, Dave Gallson, Ken Porter, Debbie Turner, Osmar Zaiane. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 25.07.2022.)

Background: Hyperphosphorylation of tau leads to conformational changes that destabilize microtubules and hinder axonal transport in Alzheimer's disease (AD). However, it remains unknown whether white matter (WM) decline due to AD is associated with specific Tau phosphorylation site(s)., Methods: In autosomal dominant AD (ADAD) mutation carriers (MC) and non-carriers (NC) we compared cerebrospinal fluid (CSF) phosphorylation at tau sites (pT217, pT181, pS202, and pT205) and total tau with WM measures, as derived from diffusion tensor imaging (DTI), and cognition. A WM composite metric, derived from a principal component analysis, was used to identify spatial decline seen in ADAD., Results: The WM composite explained over 70% of the variance in MC. WM regions that strongly contributed to the spatial topography were located in callosal and cingulate regions. Loss of integrity within the WM composite was strongly associated with AD progression in MC as defined by the estimated years to onset (EYO) and cognitive decline. A linear regression demonstrated that amyloid, gray matter atrophy and phosphorylation at CSF tau site pT205 each uniquely explained a reduction in the WM composite within MC that was independent of vascular changes (white matter hyperintensities), and age. Hyperphosphorylation of CSF tau at other sites and total tau did not significantly predict WM composite loss., Conclusions: We identified a site-specific relationship between CSF phosphorylated tau and WM decline within MC. The presence of both amyloid deposition and Tau phosphorylation at pT205 were associated with WM composite loss. These findings highlight a primary AD-specific mechanism for WM dysfunction that is tightly coupled to symptom manifestation and cognitive decline., (Copyright © 2022. Published by Elsevier Inc.)

Aim: We sought to replicate findings from published genome-wide association studies (GWAS), linking specific candidate gene loci with periodontitis-related clinical/microbial traits., Materials and Methods: In the published GWAS, a total of 2196 single nucleotide polymorphisms associated with periodontitis-related traits at a p ≤ 5 × 10 -6 and mapped to 136 gene loci. The replication cohort included 1124 individuals, 65-98 years old (67% female, 45% Hispanic, 30% Black, 23% White) with available genome-wide genotypes and full-mouth periodontal status. Microbial profiles using checkerboard DNA-DNA hybridization and 16SrRNA sequencing were available from 912 and 739 participants, respectively., Results: Using gene-specific p-values after linkage disequilibrium pruning, the following gene/phenotype associations replicated successfully: CLEC19A with edentulism and %teeth with pocket depth (PD) ≥4 mm; IL37, HPVC1, TRPS1, ABHD12B, LDLRAD4 (C180rF1), TGM3, and GRK5 with %teeth with PD ≥4 mm; DAB2IP with presence of PD ≥6 mm; KIAA1715(LNPK), ROBO2, RAB28, LINC01017, NELL1, LDLRAD4(C18orF1), and CRYBB2P1 with %teeth with clinical attachment level (CAL) ≥3 mm; RUNX2 and LAMA2 with %teeth with CAL ≥5 mm; and KIAA1715(LNPK) with high colonization by Aggregatibacter actinomycetemcomitans. In addition, CLEC19A, IQSEC1, and EMR1 associated with microbial abundance based on checkerboard data, LBP and NCR2 with abundance based on sequencing data, and NCR2 with microbial diversity based on sequencing data., Conclusions: Several gene loci identified in published GWAS as associated with periodontitis-related phenotypes replicated successfully in an elderly cohort., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The physicochemical properties of complex drug formulations, including liposomes, suspensions, and emulsions, are important for understanding drug release mechanisms, quality control, and regulatory assessment. It is ideal to characterize these complex drug formulations in their native hydrated state. This article describes the characterization of complex drug formulations in a frozen-hydrated state using cryogenic scanning electron microscopy (cryo-SEM). In comparison to other techniques, such as optical microscopy or room-temperature scanning electron microscopy, cryo-SEM combines the advantage of studying hydrated samples with high-resolution imaging capability. Detailed information regarding cryo-fixation, cryo-fracture, freeze-etching, sputter-coating, and cryo-SEM imaging is included in this article. A multivesicular liposomal complex drug formulation is used to illustrate the impact of different cryogenic sample preparation conditions. In addition to drug formulations, this approach can also be applied to biological samples (e.g., cells, bacteria) and soft-matter samples (e.g., hydrogels). © Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Basic Protocol 1: Cryo-fixation to preserve the native structure of samples using planchettes Alternate Protocol: Cryo-fixation to preserve the native structure of biological samples on sapphire disks Basic Protocol 2: Sample preparation for cross-sectional cryo-SEM imaging Basic Protocol 3: Cryo-SEM imaging and microanalysis., (© Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Insights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid β (Aβ) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP., Methods: We did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer's disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer's disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in Aβ biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF Aβ1-42 (Aβ42), and levels of Aβ1-40 (Aβ40)., Findings: Cortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p<0·0001), despite similar progression on the clinical dementia rating (p>0·7), and CSF Aβ42 levels (codon-based grouping: p=0·49; domain-based grouping: p=0·095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses., Interpretation: Autosomal dominant Alzheimer's disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer's disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer's disease, including those using Aβ PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer's disease, our results suggest that CSF and PET measures of Aβ levels are not interchangeable and might reflect different Aβ-driven pathobiological processes., Funding: National Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development., Competing Interests: Declaration of interests JPC has served on medical advisory boards for Otsuka Pharmaceuticals and Humana Healthcare, outside of the submitted work. APS has served on medical advisory boards for Janssen Pharmaceuticals and Biogen, outside of the submitted work. SMS reports consulting to Eisai, Novartis, Genentech, F Hoffmann-La Roche, Gemvax, Avid Radiopharmaceuticals, and Eli Lilly, outside of the submitted work. SMS also serves on steering committees for major biomarker and clinical trials and consortia such as the Alzheimer's Disease Neuroimaging Initiative, the Dominantly Inherited Alzheimer Network (DIAN), Alzheimer's Clinical Trial Consortium, Global Alzheimer's Platform- Network, and Longitudinal Early-onset Alzheimer's disease study, and is a project arm leader for the Dominantly Inherited Alzheimer's Network-Treatment Unit (DIAN-TU) study, outside of the submitted work. WEK is a co-inventor of Pittsburgh-Compound-B (PiB) and, as such, has a financial interest in a license agreement held by GE Healthcare and the University of Pittsburgh (PA, USA) based on the PiB-PET technology used in this manuscript. GE Healthcare provided no grant support for this study and had no role in the design or interpretation of results or preparation of this manuscript. AMF has received research funding from the National Institutes of Health and National Institute on Aging, Biogen, Centene, Fujirebio, and Roche Diagnostics, outside of the submitted work. AMF is a member of the scientific advisory boards for Roche Diagnostics, Genentech, and AbbVie, and also consults for Araclon and Grifols, DiademRes, DiamiR, and Otsuka Pharmaceuticals, outside of the submitted work. RJB has equity ownership interest in C2N Diagnostics and receives royalty income based on technology (ie, stable isotope labelling kinetics and a blood plasma assay) licensed by Washington University (WA, USA) to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US non-provisional patent application “Cerebrospinal fluid (CSF) tau rate of phosphorylation measurement to define stages of Alzheimer's disease and monitor brain kinases/phosphatases activity.” RJB has received honoraria from Janssen and Pfizer as a speaker, and from Merck and Pfizer as an advisory board member. RJB has been an invited speaker, advisory board member, and consultant for F Hoffman La Roche, an invited speaker and consultant for AC Immune and Janssen, and a consultant for Amgen and Eisai, outside of the submitted work. AMG has consulted for Eisai, Biogen, Pfizer, AbbVie, Cognition Therapeutics, and GSK, outside of the submitted work. AMG also served on the Scientific Advisory Board of Denali Therapeutics (from 2015 to 2018), outside of the submitted work. RAS and KAJ are involved in public-private partnership clinical trials sponsored by the National Institutes of Health and Eli Lilly, which owns the distribution rights to flortaucipir, but they do not have any personal financial relationship with Eli Lilly. NG-R reports grants from Biogen, Abbvie, and Lilly, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Home health care (HHC) clinicians serving individuals with Alzheimer's disease and related dementias (ADRD) do not always have information about the person's ADRD diagnosis, which may be used to improve the HHC plan of care. This retrospective cohort study examined characteristics of 56,652 HHC patients with varied documentation of ADRD diagnoses. Data included clinical assessments and Medicare claims for a 6-month look-back period and 4-year follow-up. Nearly half the sample had an ADRD diagnosis observed in the claims either prior to or following the HHC admission. Among those with a prior diagnosis, 63% did not have it documented on the HHC assessment; the diagnosis may not have been known to the HHC team or incorporated into the care plan. Patients with ADRD had heightened risk for adverse outcomes (e.g., urinary tract infection and aspiration pneumonia). Interoperable data across health care settings should include ADRD-specific elements about diagnoses, symptoms, and risk factors.

Purpose of Review: Concussion is a complex injury that may present as a variety of clinical profiles, which can overlap and reinforce one another. This review summarizes the medical management of patients with concussion and persistent post-concussive symptoms (PPCS)., Recent Findings: Management of concussion and PPCS relies on identifying underlying symptom generators. Treatment options include sub-symptom threshold aerobic exercise, cervical physical therapy, vestibular therapy, vision therapy, cognitive rehabilitation, cognitive behavioral therapy, pharmacological management, or a combination of treatments. Evidence-based treatments have emerged to treat post-concussion symptom generators for sport-related concussion and for patients with PPCS., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: Concussion produces a variety of signs and symptoms. Most patients recover within 2-4 weeks, but a significant minority experiences persistent post-concussive symptoms (PPCS), some of which may be from associated cervical or persistent neurologic sub-system (e.g., vestibular) dysfunction. This review provides evidence-based information for a pertinent history and physical examination of patients with concussion., Recent Findings: The differential diagnosis of PPCS is based on the mechanism of injury, a thorough medical history and concussion-pertinent neurological and cervical physical examinations. The concussion physical examination focuses on elements of autonomic function, oculomotor and vestibular function, and the cervical spine. Abnormalities identified on physical examination can inform specific forms of rehabilitation to help speed recovery. Emerging data show that there are specific symptom generators after concussion that can be identified by a thorough history, a pertinent physical examination, and adjunct tests when indicated., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Medical students need to understand core neuroscience principles as a foundation for their required clinical experiences in neurology. In fact, they need a solid neuroscience foundation for their clinical experiences in all other medical disciplines also because the nervous system plays such a critical role in the function of every organ system. Because of the rapid pace of neuroscience discoveries, it is unrealistic to expect students to master the entire field. It is also unnecessary, as students can expect to have ready access to electronic reference sources no matter where they practice. In the preclerkship phase of medical school, the focus should be on providing students with the foundational knowledge to use those resources effectively and interpret them correctly. This article describes an organizational framework for teaching the essential neuroscience background needed by all physicians. This is particularly germane at a time when many medical schools are reassessing traditional practices and instituting curricular changes such as competency-based approaches, earlier clinical immersion, and increased emphasis on active learning. This article reviews factors that should be considered when developing the preclerkship neuroscience curriculum, including goals and objectives for the curriculum, the general topics to include, teaching and assessment methodology, who should direct the course, and the areas of expertise of faculty who might be enlisted as teachers or content experts. These guidelines were developed by a work group of experienced educators appointed by the Undergraduate Education Subcommittee (UES) of the American Academy of Neurology (AAN). They were then successively reviewed, edited, and approved by the entire UES, the AAN Education Committee, and the AAN Board of Directors., (© 2021 American Academy of Neurology.)

Introduction: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease., Methods: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non-carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status., Results: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R 2  = 0.95), fluorodeoxyglucose (R 2  = 0.93), and atrophy (R 2  = 0.95) in mutation carriers compared to non-carriers., Discussion: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions., (© 2021 the Alzheimer's Association.)

Objective: Where traditional approaches fall short, widely accessible and accepted, yet under leveraged, digital technologies such as text messaging present novel opportunities to solve a range of health care solutions. The following provides a preliminary analysis of the Text4Support program, a text-messaging intervention using the principles of cognitive behavioral therapy, which seeks to support the health and well-being of individuals seeking support for addiction or mental health concerns. The goal of this study was to assess whether the Text4Support program improved the perceived overall mental well-being of participants. Methods: The evaluation analyzes survey responses of individuals who were enrolled in the Text4Support program beginning in July 2019, who had completed the 6-months program by May 2020. Participants were asked to provide responses to three surveys during their time in the program-at baseline, 12-weeks and 6-months, which included questions documenting demographic information, general satisfaction with the program, and a participants' level of "global distress" through use of the Clinical Outcomes Routine Evaluation System (CORE-10)-a validated brief 10-item assessment and outcome measurement tool used to assess conditions including anxiety, depression, physical problems, and risk to self. Results and Conclusions: This data set did not include a large enough sample of participants to reach statistical significance. Nevertheless, the study provides some preliminary analysis, and identifies opportunities for the future analysis and research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Noble, Vuong, Surood, Urichuk, Greenshaw and Agyapong.)

Introduction: A biphasic model for brain structural changes in preclinical Alzheimer's disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti-amyloid clinical trials., Methods: In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity-a novel marker of cortical microstructure-changes in 389 participants from the Dominantly Inherited Alzheimer Network., Results: In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations., Discussion: These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials., (© 2020 the Alzheimer's Association.)

Objective: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD)., Methods: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease., Results: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year)., Conclusion: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)