Sex differences in the association between tau PET and cognitive performance in a non-Hispanic White cohort with preclinical AD.

INTRODUCTION: We investigated how the associations between tau and cognitive measures differ by sex in the preclinical Alzheimer's disease (AD) stage. METHODS: A total of 343 cognitively unimpaired, amyloid-positive individuals (205 women, 138 men) who self-identified as non-Hispanic White from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study were included. We assessed sex-stratified associations between 18 F-flortaucipir positron emission tomography (PET) standardized uptake value ratio (SUVR) in the meta-temporal region and Preclinical Alzheimer's Cognitive Composite (PACC) and Computerized Cognitive Composite (C3) components. RESULTS: We observed that higher tau level was significantly associated with worse cognitive performance only in women: PACC and its components except for Mini-Mental State Examination (MMSE) and C3 components: First Letter Name Recall (FNLT) and One-Card Learning Reaction Time (OCL RT). These associations except for FNLT were apolipoprotein E (APOE) ε4 independent. DISCUSSION: Women show stronger associations between tau PET and cognitive outcomes in preclinical AD. These findings have important implications for sex-specific tau-targeted preventive AD clinical trials. HIGHLIGHTS: The tau positron emission tomography (PET) signal in the meta-temporal region was associated with poor cognitive performance in preclinical Alzheimer's disease (AD). After sex stratification, the associations between regional tau PET and cognitive outcomes were observed only in women. The associations between tau PET and some cognitive outcomes were independent of apolipoprotein E (APOE) ε4.

Connections between reproductive health and cognitive aging among women enrolled in the HCHS/SOL and SOL-INCA.

INTRODUCTION: Reproductive health history may contribute to cognitive aging and risk for Alzheimer's disease, but this is understudied among Hispanic/Latina women. METHODS: Participants included 2126 Hispanic/Latina postmenopausal women (44 to 75 years) from the Study of Latinos-Investigation of Neurocognitive Aging. Survey linear regressions separately modeled the associations between reproductive health measures (age at menarche, history of oral contraceptive use, number of pregnancies, number of live births, age at menopause, female hormone use at Visit 1, and reproductive span) with cognitive outcomes at Visit 2 (performance, 7-year change, and mild cognitive impairment [MCI] prevalence). RESULTS: Younger age at menarche, oral contraceptive use, lower pregnancies, lower live births, and older age at menopause were associated with better cognitive performance. Older age at menarche was protective against cognitive change. Hormone use was linked to lower MCI prevalence. DISCUSSION: Several aspects of reproductive health appear to impact cognitive aging among Hispanic/Latina women.

Flortaucipir tau PET findings from former professional and college American football players in the DIAGNOSE CTE research project.

INTRODUCTION: Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD: We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS: Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups. DISCUSSION: Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

Moving Beyond Depression: Mood Symptoms Across the Spectrum Relate to Tau Pathology in Older Women at Risk for Alzheimer's Disease.

We examined how symptoms across the mood spectrum relate to Alzheimer's disease (AD) biomarkers in older women at high risk for AD. Participants included 25 women aged 65+ with mild cognitive deficits and elevated AD genetic risk. The Profile of Mood States Questionnaire measured mood symptoms and a total mood disturbance (TMD) score. Tau burden in the meta-temporal region of interest was measured using MK-6240 Tau positron emission tomography (PET) imaging. A subset (n = 12) also had p-Tau181, and Aß40/42 levels measured in plasma. Higher TMD scores related to higher tau PET standardized uptake value ratio (SUVR). Greater negative mood symptoms correlated with higher tau PET SUVR, while greater vigor correlated with lower SUVR. Similar results were seen with plasma p-Tau181 levels, but not with Aß40/42 levels. In conclusion, positive and negative mood symptoms related to tau pathology in older women at high risk for AD, highlighting a role of mental well-being in AD risk.

Intersections of Modifiable Risks: Loneliness is Associated with Poor Subjective Sleep Quality in Older Women at Risk for Alzheimer's Disease.

We examined the relationship between subjective and objective sleep outcomes and loneliness in older women at risk for Alzheimer's disease (AD). Our sample consisted of 39 participants (aged 65+) with mild cognitive deficits who completed the UCLA Loneliness Scale, the Pittsburgh Sleep Quality Index (PSQI), and an at home sleep test, to determine presence of obstructive sleep apnea. Based on sleep quality scores, individuals categorized as "poor sleepers" had significantly higher loneliness scores than "good sleepers." However, total loneliness scores did not significantly differ between groups with or without sleep apnea. We found that higher loneliness was significantly associated to lower habitual sleep efficiency and sleep duration and was also influenced by use of sleep medication. Our findings suggest that increased loneliness relates to worse subjective sleep quality, but not to sleep apnea. These findings suggest that combined interventions targeting loneliness and sleep quality may be important for older women.

Pandemic ethics and beyond: Creating space for virtues in the social professions.

BACKGROUND: During the pandemic, social and health care professionals operated in 'crisis conditions'. Some existing rules/protocols were not operational, many services were closed/curtailed, and new 'blanket' rules often seemed inappropriate or unfair. These experiences provide fertile ground for exploring the role of virtues in professional life and considering lessons for professional ethics in the future. RESEARCH DESIGN AND AIM: This article draws on an international qualitative survey conducted online in May 2020, which aimed to explore the ethical challenges experienced by social workers during Covid-19. PARTICIPANTS AND RESEARCH CONTEXT: 607 social workers responded from 54 countries, giving written online responses. This article first summarises previously published findings from the survey regarding the range of ethical challenges experienced, then develops a new analysis of social workers' accounts of ethically challenging situations from a virtue ethics perspective. This analysis took a narrative ethics approach, treating respondents' accounts as stories featuring the tellers as moral agents, with implicit or explicit implications for their professional ethical identity and character. The article is illustrated with accounts from the 41 UK respondents, drawing particularly on two case examples. ETHICAL CONSIDERATIONS: Ethical approval was gained from Durham University and anonymity was ensured for participants. FINDINGS/RESULTS: This article explores the nature of the ethical space created during the pandemic showing how practitioners were able to draw more on 'inner resources' and professional discretion than usual, displaying virtues such as professional wisdom, care, respectfulness and courage as they took account of the specific contexts of their work, rather than simply adhering to blanket rules. CONCLUSION: Exploring practice through a virtue ethical lens provides valuable lessons for 'building back better' in social and health care professions.

Sex differences in plasma p-tau181 associations with Alzheimer's disease biomarkers, cognitive decline, and clinical progression.

Studies have shown that women on the Alzheimer's disease (AD) continuum have more pathological tau in the brain and cerebrospinal fluid (CSF), than men. Some studies have found that higher levels of tau biomarkers are more strongly associated with clinical AD, cognitive decline and neurodegeneration in women than in men. Despite major developments in the use of plasma tau phosphorylated at threonine 181 (p-tau181) as an AD biomarker, it is unknown whether these sex differences apply to plasma p-tau181. In 1060 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (47% women, 73.8 ± 7.6 years old), we examined sex differences in plasma p-tau181 levels and their association with other biomarkers, cognitive decline and incident AD. Linear regressions tested for an effect of sex on plasma p-tau181 levels and for plasma p-tau181 × sex interactions on CSF p-tau181, as well as entorhinal cortex tau, cortical amyloid-ß (Aß) deposition, and brain glucose metabolism, quantified using PET imaging. Linear mixed effects models tested for a sex × baseline plasma p-tau181 interaction on change in cognition over time. Finally, Cox models tested for a sex × plasma p-tau181 interaction on the risk of AD dementia in participants who were free of dementia at baseline. Despite similar plasma p-tau181 levels between sexes, women had lower brain glucose metabolism, greater brain Aß and entorhinal cortex tau deposition, higher CSF p-tau181 and faster cognitive decline in relation to higher baseline plasma p-tau181 levels compared with men. Among Aß positive, dementia-free participants, women had higher rates of incident AD dementia associated with increasing baseline plasma p-tau181 levels, relative to men. Our results suggest that sex may impact the clinical interpretation of plasma p-tau181 concentrations. If replicated, these findings could have important implications for the use of plasma p-tau181 as an accessible AD biomarker and screening tool for preventive and therapeutic clinical trials.

Neurophysiology, Neuropsychology, Epilepsy, 2022: Hills We Have Climbed and the Hills Ahead. Cognition and Sensory Systems in Healthy and Diseased Subjects.

This article summarizes selected presentations from a session titled "Cognition and Sensory Systems in Healthy and Diseased Subjects", held to highlight and honor the work of Dr. Marilyn Jones-Gotman. The session was part of a two-day symposium, "Neurophysiology, Neuropsychology, Epilepsy, 2022: Hills We Have Climbed and the Hills Ahead". The session presented research on epilepsy and sensory systems by colleagues and former trainees of Dr. Jones-Gotman. The extended summaries provide an overview of historical and current work in the neuropsychology of epilepsy, neuropsychological and neuroimaging approaches to understanding brain organization, sex differences in brain mechanisms underlying neurological disorders, dietary influences on brain function and cognition, and expertise in olfactory training and language experiences and their implications for brain organization and structure.

Articulation Rate, Pauses, and Disfluencies in Professional Fighters: Potential Speech Biomarkers for Repetitive Head Injury.

OBJECTIVE: As part of a larger study dedicated to identifying speech and language biomarkers of neurological decline associated with repetitive head injury (RHI) in professional boxers and mixed martial artists (MMAs), we examined articulation rate, pausing, and disfluency in passages read aloud by participants in the Professional Athletes Brain Health Study. SETTING: A large outpatient medical center specializing in neurological care. PARTICIPANTS, DESIGN, AND MAIN MEASURES: Passages read aloud by 60 boxers, 40 MMAs, and 55 controls were acoustically analyzed to determine articulation rate (the number of syllables produced per second), number and duration of pauses, and number and duration of disfluencies in this observational study. RESULTS: Both boxers and MMAs differed from controls in articulation rate, producing syllables at a slower rate than controls by nearly half a syllable per second on average. Boxers produced significantly more pauses and disfluencies in passages read aloud than MMAs and controls. CONCLUSIONS: Slower articulation rate in both boxers and MMA fighters compared with individuals with no history of RHI and the increased occurrence of pauses and disfluencies in the speech of boxers suggest changes in speech motor behavior that may relate to RHI. These speech characteristics can be measured in everyday speaking conditions and by automatic recognition systems, so they have the potential to serve as effective, noninvasive clinical indicators for RHI-associated neurological decline.

A simple genetic stratification method for lower cost, more expedient clinical trials in early Alzheimer's disease: A preliminary study of tau PET and cognitive outcomes.

INTRODUCTION: Identifying individuals who are most likely to accumulate tau and exhibit cognitive decline is critical for Alzheimer's disease (AD) clinical trials. METHODS: Participants (N = 235) who were cognitively normal or with mild cognitive impairment from the Alzheimer's Disease Neuroimaging Initiative were stratified by a cutoff on the polygenic hazard score (PHS) at 65th percentile (above as high-risk group and below as low-risk group). We evaluated the associations between the PHS risk groups and tau positron emission tomography and cognitive decline, respectively. Power analyses estimated the sample size needed for clinical trials to detect differences in tau accumulation or cognitive change. RESULTS: The high-risk group showed faster tau accumulation and cognitive decline. Clinical trials using the high-risk group would require a fraction of the sample size as trials without this inclusion criterion. DISCUSSION: Incorporating a PHS inclusion criterion represents a low-cost and accessible way to identify potential participants for AD clinical trials.

Comparison of the telephone-Montreal Cognitive Assessment (T-MoCA) and Telephone Interview for Cognitive Status (TICS) as screening tests for early Alzheimer's disease.

INTRODUCTION: Remote screening for cognitive impairment associated with Alzheimer's disease (AD) has grown in importance with the expected rise in prevalence of AD in an aging population and with new potential treatment options. METHODS: The Telephone Interview for Cognitive Status (TICS) and new telephone adaptation of the Montreal Cognitive Assessment (T-MoCA) were administered to participants independently classified through in-person clinical evaluation as cognitively normal (CN; n = 167), mild cognitive impairment (MCI; n = 25), or dementia (n = 23). Cerebrospinal fluid AD biomarkers were measured (n = 79). RESULTS: TICS and T-MoCA were highly correlated (r = 0.787; P < 0.001): groups differed on both (CN

Improved multimodal prediction of progression from MCI to Alzheimer's disease combining genetics with quantitative brain MRI and cognitive measures.

INTRODUCTION: There is a pressing need for non-invasive, cost-effective tools for early detection of Alzheimer's disease (AD). METHODS: Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Cox proportional models were conducted to develop a multimodal hazard score (MHS) combining age, a polygenic hazard score (PHS), brain atrophy, and memory to predict conversion from mild cognitive impairment (MCI) to dementia. Power calculations estimated required clinical trial sample sizes after hypothetical enrichment using the MHS. Cox regression determined predicted age of onset for AD pathology from the PHS. RESULTS: The MHS predicted conversion from MCI to dementia (hazard ratio for 80th versus 20th percentile: 27.03). Models suggest that application of the MHS could reduce clinical trial sample sizes by 67%. The PHS alone predicted age of onset of amyloid and tau. DISCUSSION: The MHS may improve early detection of AD for use in memory clinics or for clinical trial enrichment. HIGHLIGHTS: A multimodal hazard score (MHS) combined age, genetics, brain atrophy, and memory. The MHS predicted time to conversion from mild cognitive impairment to dementia. MHS reduced hypothetical Alzheimer's disease (AD) clinical trial sample sizes by 67%. A polygenic hazard score predicted age of onset of AD neuropathology.

White matter hyperintensities in former American football players.

INTRODUCTION: The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players. METHODS: A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60. RESULTS: In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function. DISCUSSION: In older former football players, WMH may have unique presentations, risk factors, and etiologies. HIGHLIGHTS: Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.

Olfactory bulb volume and cortical thickness evolve during sommelier training.

Brain plasticity is essential for experts to acquire the abilities they need. Sommeliers are olfaction experts who display differences in olfactory regions in the brain that correlate with greater olfactory abilities. While most studies on this topic are cross-sectional, we used a longitudinal design and invited 17 sommelier students at the start and end of their training then to compare them to 17 control students to study the effects of training-related brain plasticity. After a year and a half, 5 sommelier students and 4 control students dropped out, leading to 12 sommelier students versus 13 controls. We used magnetic resonance imaging to measure cortical thickness and olfactory bulb volume, as this structure plays a crucial role in olfactory processing. We used the Sniffin' Sticks test to evaluate olfactory performance. During training, olfactory bulb volume increased in sommelier students while there was no significant change in the control group. We also observed that thickness of right entorhinal cortex increased, and cortical thickness decreased in other cerebral regions. Our olfactory tests did not reveal any significant changes in sommelier students. In conclusion, this is the first longitudinal study to report an increase in olfactory bulb volume in olfaction experts in line with the notion of effects of ecological training-related brain plasticity. The mixed results about cortical thickness might be explained by a "overproduction-pruning" model of brain plasticity, according to which the effects of training-related plasticity are non-linear and simultaneously involve different processes.

Story Memory Impairment Rates and Association with Hippocampal Volumes in a Memory Clinic Population.

OBJECTIVE: Story memory tasks are among the most commonly used memory tests; however, research suggests they may be less sensitive to memory decline and have a weaker association with hippocampal volumes than list learning tasks. To examine its utility, we compared story memory to other memory tests on impairment rates and association with hippocampal volumes. METHOD: Archival records from 1617 older adults (Mage = 74.41, range = 65-93) who completed the Wechsler Memory Scale - 4th edition (WMS-IV) Logical Memory (LM), Hopkins Verbal Learning Test - Revised (HVLT-R), and Brief Visuospatial Memory Test - Revised (BVMT-R) as part of a clinical neuropsychological evaluation were reviewed. Scores >1.5 SD below age-adjusted means were considered impaired, and frequency distributions were used to examine impairment rates. A subset of participants (n = 179) had magnetic resonance imaging (MRI) data that underwent image quality assessment. Partial correlations and linear regression analyses, accounting for age, education, and total intracranial volume (TIV), examined associations between memory raw scores and hippocampal volumes. RESULTS: For delayed recall, nearly half of the sample was impaired on HVLT-R (48.8%) and BVMT-R (46.1%), whereas a little more than a third was impaired on LM (35.7%). Better performance on all three measures was related to larger hippocampal volumes (r's =. 26-.43, p's < .001). Individually adding memory scores to regression models predicting hippocampal volumes improved the model fit for all measures. CONCLUSIONS: Despite findings suggesting that story memory is less sensitive to memory dysfunction, it was not differentially associated with hippocampal volumes compared to other memory measures. Results support assessing memory using different formats and modalities in older adults.

Sex differences for phenotype in pathologically defined dementia with Lewy bodies.

INTRODUCTION: Sex differences in dementia with Lewy bodies (DLB) have been reported in clinically defined cohorts; however, clinical diagnostic accuracy in DLB is suboptimal and phenotypic differences have not been assessed in pathologically confirmed participants. METHODS: Core DLB features were compared across 55 women and 156 men with pathologically defined DLB in the National Alzheimer's Coordinating Center. These analyses were repeated for 55 women and 55 men matched for age, education and tau burden. RESULTS: In the total sample, women died older, had fewer years of education, had higher tau burden but were less likely to be diagnosed with dementia and clinical DLB. In the matched sample, visual hallucinations continued to be less common in women, and fewer women met clinical DLB criteria. DISCUSSION: Sex impacts clinical manifestations of underlying pathologies in DLB. Despite similar underlying Lewy body pathology, women are less likely to manifest core DLB features and may be clinically underdiagnosed.

Sex-dependent autosomal effects on clinical progression of Alzheimer's disease.

Sex differences in the manifestations of Alzheimer's disease are under intense investigation. Despite the emerging importance of polygenic predictions for Alzheimer's disease, sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on Alzheimer's disease can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Relative to sex-mismatched scores, sex-matched polygenic hazard scores showed significantly stronger associations with age-at-disease-onset, clinical progression, amyloid deposition, neurofibrillary tangles, and composite neuropathological scores, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores, showed lower predictive power than polygenic hazard scores with no evidence for sex differences. Our results indicate that revealing sex-dependent genetic architecture requires the consideration of temporal processes of Alzheimer's disease. This has strong implications not only for the genetic underpinning of Alzheimer's disease but also for how we estimate sex-dependent polygenic effects for clinical use.

Sex Differences in Cognitive Changes in De Novo Parkinson's Disease.

OBJECTIVE: To evaluate the sex differences in cognitive course over 4 years in Parkinson's disease (PD) patients with and without mild cognitive impairment (MCI) compared to controls. METHODS: Four-year longitudinal cognitive scores of 257 cognitively intact PD, 167 PD-MCI, and 140 controls from the Parkinson's Progression Markers Initiative were included. Longitudinal scores of men and women, and PD with and without MCI were compared. RESULTS: Women had better verbal memory, men had better visuospatial function. There was no interaction between sex, diagnostic group, and/or time (4-year follow-up period). CONCLUSIONS: Sex differences in cognitive course in de novo PD are similar to healthy aging. Cognitive decline rates in PD with and without MCI are similar for the first 4 years of PD.

Awareness of Psychiatric Symptoms in a Mixed Clinical Sample of Older Adults.

OBJECTIVE: This study examined the neuropsychological correlates and impact on caregiver distress of reduced awareness of mood symptoms in patients with suspected neurodegenerative disease. METHOD: Records from a clinical sample of older adults were examined (N = 940). RESULTS: More than one-third of patient and caregiver ratings of mood symptoms did not agree (comparing patient and caregiver self-report measures); 27.9% of patients were unaware of depression (UoD) and 16.6% of patients were unaware of anxiety (UoA). The UoD group exhibited poorer verbal memory and executive abilities and the UoA group exhibited poorer verbal memory than those with preserved awareness. Unawareness was not associated with caregiver distress. CONCLUSIONS: These findings highlight the importance of capturing informant report in clinical practice with older adults suspected of cognitive impairment. Unawareness of mood symptoms was related to memory dysfunction and-to a lesser extent-to executive abilities and may have implications for addressing patient and caregiver needs for disorders affecting these cognitive systems.

The Relationship Between Fighting Style, Cognition, and Regional Brain Volume in Professional Combatants: A Preliminary Examination Using Brief Neurocognitive Measures.

OBJECTIVE: Repetitive head impacts (RHIs) in combat sports are associated with cognitive decline and brain volume reduction. While fighting style differences between boxers, mixed martial artists (MMAs), and martial artists (MAs) have resulted in a broader spectrum of injury, the effects of RHIs on MAs relative to other fighters have not yet been explored. This study aimed to determine a differential effect of fighting style on cognition and brain. SETTING: A large outpatient medical center specializing in neurological care. PARTICIPANTS, DESIGN, AND MAIN MEASURES: In total, 40 MAs, 188 boxers, and 279 MMAs were compared on baseline measures of subcortical regional brain volumes, after controlling for total brain volumes, and cognitive performance. RESULTS: Significant differences between MAs, MMAs, and boxers were observed in subcortical brain structure volumes and cognitive measures. MMAs and MAs consistently had larger volumes and higher scores than boxers. Fighting style significantly moderated the relationship between the number of professional fights and the volumes of various subcortical brain structures and performance on a measure of processing speed at baseline. CONCLUSIONS: Differences in RHIs across fighting styles may be of clinical significance. Exploring changes over time within the MA, boxer, and MMA cohorts may provide insight into longer-term discrepancies in subcortical regional brain volumes and cognitive functioning across fighting styles.