Head Injury and Risk of Incident Ischemic Stroke in Community-Dwelling Adults.

BACKGROUND: While stroke is a recognized short-term sequela of traumatic brain injury, evidence about long-term ischemic stroke risk after traumatic brain injury remains limited. METHODS: The Atherosclerosis Risk in Communities Study is an ongoing prospective cohort comprised of US community-dwelling adults enrolled in 1987 to 1989 followed through 2019. Head injury was defined using self-report and hospital-based diagnostic codes and was analyzed as a time-varying exposure. Incident ischemic stroke events were physician-adjudicated. We used Cox regression adjusted for sociodemographic and cardiovascular risk factors to estimate the hazard of ischemic stroke as a function of head injury. Secondary analyses explored the number and severity of head injuries; the mechanism and severity of incident ischemic stroke; and heterogeneity within subgroups defined by race, sex, and age. RESULTS: Our analysis included 12 813 participants with no prior head injury or stroke. The median follow-up age was 27.1 years (25th-75th percentile=21.1-30.5). Participants were of median age 54 years (25th-75th percentile=49-59) at baseline; 57.7% were female and 27.8% were Black. There were 2158 (16.8%) participants with at least 1 head injury and 1141 (8.9%) participants with an incident ischemic stroke during follow-up. For those with head injuries, the median age to ischemic stroke was 7.5 years (25th-75th percentile=2.2-14.0). In adjusted models, head injury was associated with an increased hazard of incident ischemic stroke (hazard ratio [HR], 1.34 [95% CI, 1.12-1.60]). We observed evidence of dose-response for the number of head injuries (1: HR, 1.16 [95% CI, 0.97-1.40]; ≥2: HR, 1.94 [95% CI, 1.39-2.71]) but not for injury severity. We observed evidence of stronger associations between head injury and more severe stroke (National Institutes of Health Stroke Scale score ≤5: HR, 1.31 [95% CI, 1.04-1.64]; National Institutes of Health Stroke Scale score 6-10: HR, 1.64 [95% CI, 1.06-2.52]; National Institutes of Health Stroke Scale score ≥11: HR, 1.80 [95% CI, 1.18-2.76]). Results were similar across stroke mechanism and within strata of race, sex, and age. CONCLUSIONS: In this community-based cohort, head injury was associated with subsequent ischemic stroke. These results suggest the importance of public health interventions aimed at preventing head injuries and primary stroke prevention among individuals with prior traumatic brain injuries.

Sex differences in the extent of acute axonal pathologies after experimental concussion.

Although human females appear be at a higher risk of concussion and suffer worse outcomes than males, underlying mechanisms remain unclear. With increasing recognition that damage to white matter axons is a key pathologic substrate of concussion, we used a clinically relevant swine model of concussion to explore potential sex differences in the extent of axonal pathologies. At 24 h post-injury, female swine displayed a greater number of swollen axonal profiles and more widespread loss of axonal sodium channels than males. Axon degeneration for both sexes appeared to be related to individual axon architecture, reflected by a selective loss of small caliber axons after concussion. However, female brains had a higher percentage of small caliber axons, leading to more extensive axon loss after injury compared to males. Accordingly, sexual dimorphism in axonal size is associated with more extensive axonal pathology in females after concussion, which may contribute to worse outcomes.

FMR1 Protein Expression Correlates with Intelligence Quotient in Both Peripheral Blood Mononuclear Cells and Fibroblasts from Individuals with an FMR1 Mutation.

Fragile X syndrome (FXS) is the most common heritable form of intellectual disability and is caused by CGG repeat expansions exceeding 200 (full mutation). Such expansions lead to hypermethylation and transcriptional silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene. As a consequence, little or no FMR1 protein (FMRP) is produced; absence of the protein, which normally is responsible for neuronal development and maintenance, causes the syndrome. Previous studies have demonstrated the causal relationship between FMRP levels and cognitive abilities in peripheral blood mononuclear cells (PBMCs) and dermal fibroblast cell lines of patients with FXS. However, it is arguable whether PBMCs or fibroblasts would be the preferred surrogate for measuring molecular markers, particularly FMRP, to represent the cognitive impairment, a core symptom of FXS. To address this concern, CGG repeats, methylation status, FMR1 mRNA, and FMRP levels were measured in both PBMCs and fibroblasts derived from 66 individuals. The findings indicated a strong association between FMR1 mRNA expression levels and CGG repeat numbers in PBMCs of premutation males after correcting for methylation status. Moreover, FMRP expression levels from both PBMCs and fibroblasts of male participants with a hypermethylated full mutation and with mosaicism demonstrated significant association between the intelligence quotient levels and FMRP levels, suggesting that PBMCs may be preferable for FXS clinical studies, because of their greater accessibility.

Unmethylated Mosaic Full Mutation Males without Fragile X Syndrome.

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability (ID) and single gene cause of autism. Although most patients with FXS and the full mutation (FM) have complete methylation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene, some have mosaicism in methylation and/or CGG repeat size, and few have completely unmethylated FM alleles. Those with a complete lack of methylation are rare, with little literature about the cognitive and behavioral phenotypes of these individuals. A review of past literature was conducted regarding individuals with unmethylated and mosaic FMR1 FM. We report three patients with an unmethylated FM FMR1 alleles without any behavioral or cognitive deficits. This is an unusual presentation for men with FM as most patients with an unmethylated FM and no behavioral phenotypes do not receive fragile X DNA testing or a diagnosis of FXS. Our cases showed that mosaic males with unmethylated FMR1 FM alleles may lack behavioral phenotypes due to the presence of smaller alleles producing the FMR1 protein (FMRP). However, these individuals could be at a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) due to the increased expression of mRNA, similar to those who only have a premutation.

Adoptive transfer of donor-B lymphocytes: a phase I/IIa study for patients after allogeneic stem cell transplantation.

Immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is slow and patients carry a high and prolonged risk for opportunistic infections. We hypothesized that the adoptive transfer of donor B cells can foster post-HSCT immuno-reconstitution. Here we report on the results of a first-in-human phase I/IIa study aimed to evaluate the feasibility and safety of adoptively transferred donor B cells and to test their activity upon recall vaccination. GMP-grade B-cell products were generated from donor apheresis products using a two-step magnetic cell separation. 15 allo-HSCT patients were enrolled and treated after taper of immunosuppression (median day +148, range 130 to 160). Patients received four different doses of B cells (0.5x106 - 4.0x106 B-cells per kg body weight (BW)). To test the activity of infused donor memory B cells in vivo patients were vaccinated with a pentavalent vaccine 7 days after B cell transfer. We observed mobilization of plasmablasts and an increase of serum titers against vaccine antigens with a stronger response in patients receiving higher B cell numbers. The analysis of immunoglobulin VH-sequences by next-generation-sequencing revealed that plasmablasts responding to the vaccination originated from memory B cell clones from the donor. Donor B cell transfer was safe as no EBV reactivation was observed, and only low-grade GvHD occurred in 4 out of 15 patients. This pilot trial may pave the way for further studies exploring the adoptive transfer of memory B cells to reduce the frequency of infections after allo-HSCT. This trial was registered at ClinicalTrial.gov NCT02007811.

Posttraumatic Epilepsy and Dementia Risk.

Importance: Although both head injury and epilepsy are associated with long-term dementia risk, posttraumatic epilepsy (PTE) has only been evaluated in association with short-term cognitive outcomes. Objective: To investigate associations of PTE with dementia risk. Design, Setting, and Participants: The Atherosclerosis Risk in Communities (ARIC) study initially enrolled participants from 1987 to 1989 and this prospective cohort study uses data through December 31, 2019, with a median follow-up of 25 years. Data were analyzed between March 14, 2023, and January 2, 2024. The study took place in 4 US communities in Minnesota, Maryland, North Carolina, and Mississippi. Of 15 792 ARIC study participants initially enrolled, 2061 were ineligible and 1173 were excluded for missing data, resulting in 12 558 included participants. Exposures: Head injury was defined by self-report and International Classification of Diseases (ICD) diagnostic codes. Seizure/epilepsy was defined using ICD codes. PTE was defined as a diagnosis of seizure/epilepsy occurring more than 7 days after head injury. Head injury, seizure/epilepsy, and PTE were analyzed as time-varying exposures. Main Outcomes and Measures: Dementia was defined using cognitive assessments, informant interviews, and ICD and death certificate codes. Adjusted Cox and Fine and Gray proportional hazards models were used to estimate dementia risk. Results: Participants had a mean (SD) age of 54.3 (5.8) years at baseline, 57.7% were female, 28.2% were of self-reported Black race, 14.4% were ultimately categorized as having head injury, 5.1% as having seizure/epilepsy, and 1.2% as having PTE. Over a median follow-up of 25 (25th to 75th percentile, 17-30) years, 19.9% developed dementia. In fully adjusted models, compared with no head injury and no seizure/epilepsy, PTE was associated with 4.56 (95% CI, 4.49-5.95) times the risk of dementia, while seizure/epilepsy was associated with 2.61 (95% CI, 2.21-3.07) times the risk and head injury with 1.63 (95% CI, 1.47-1.80) times the risk. The risk of dementia associated with PTE was significantly higher than the risk associated with head injury alone and with nontraumatic seizure/epilepsy alone. Results were slightly attenuated in models accounting for the competing risks of mortality and stroke, but patterns of association remained similar. In secondary analyses, the increased dementia risk associated with PTE occurring after first vs second head injury and after mild vs moderate/severe injury was similar. Conclusions and Relevance: In this community-based cohort, there was an increased risk of dementia associated with PTE that was significantly higher than the risk associated with head injury or seizure/epilepsy alone. These findings provide evidence that PTE is associated with long-term outcomes and supports both the prevention of head injuries via public health measures and further research into the underlying mechanisms and the risk factors for the development of PTE, so that efforts can also be focused on the prevention of PTE after a head injury.

The human factor H protein family - an update.

Complement is an ancient and complex network of the immune system and, as such, it plays vital physiological roles, but it is also involved in numerous pathological processes. The proper regulation of the complement system is important to allow its sufficient and targeted activity without deleterious side-effects. Factor H is a major complement regulator, and together with its splice variant factor H-like protein 1 and the five human factor H-related (FHR) proteins, they have been linked to various diseases. The role of factor H in inhibiting complement activation is well studied, but the function of the FHRs is less characterized. Current evidence supports the main role of the FHRs as enhancers of complement activation and opsonization, i.e., counter-balancing the inhibitory effect of factor H. FHRs emerge as soluble pattern recognition molecules and positive regulators of the complement system. In addition, factor H and some of the FHR proteins were shown to modulate the activity of immune cells, a non-canonical function outside the complement cascade. Recent efforts have intensified to study factor H and the FHRs and develop new tools for the distinction, quantification and functional characterization of members of this protein family. Here, we provide an update and overview on the versatile roles of factor H family proteins, what we know about their biological functions in healthy conditions and in diseases.

Occupation, Retirement Age, and 20-Year Cognitive Decline: The Atherosclerosis Risk in Communities Neurocognitive Study.

INTRODUCTION: We examined the association of both midlife occupation and age at retirement with cognitive decline in the Atherosclerosis Risk in Communities (ARIC) biracial community-based cohort. METHODS: Current or most recent occupation at ARIC baseline (1987-89; ages 45-64y) was categorized based on 1980 US census major occupation groups and tertiles of the Nam-Powers-Boyd occupational status score (n=14,090). Retirement status via annual follow-up questionnaires administered ascertained in 1999-2007 was classified as occurring before or after age 70 (n=7,503). Generalized estimating equation models were used to examine associations of occupation and age at retirement with trajectories of global cognitive factor scores, assessed from visit 2 (1990-92) to visit 5 (2011-2013). Models were a priori stratified by race and sex and adjusted for demographics and comorbidities. RESULTS: Low occupational status and blue-collar occupations were associated with low baseline cognitive scores in all race-sex strata. Low occupational status and homemaker status were associated with faster decline in White women but slower decline in Black women compared to high occupational status. Retirement before age 70 was associated with slower cognitive decline in White men and women and in Black men. Results did not change substantially after accounting for attrition. CONCLUSION: Low occupational status was associated with cognitive decline in women but not in men. Earlier retirement was associated with a slower cognitive decline in White participants and in Black men. Further research should explore reasons for the observed associations and race-sex differences.

Stroke Subtype and Risk of Subsequent Hospitalization: The Atherosclerosis Risk in Communities Study

BACKGROUND AND OBJECTIVES: Risk of readmission after stroke differs by stroke (sub)type and etiology, with higher risks reported for hemorrhagic stroke and cardioembolic stroke. We examined the risk and cause of first readmission by stroke subtype over the years post incident stroke. METHODS: Atherosclerosis Risk in Communities (ARIC) study participants (n = 1,412) with first-ever stroke were followed up for all-cause readmission after incident stroke. Risk of first readmission was examined by stroke subtypes (cardioembolic, thrombotic/lacunar, and hemorrhagic [intracerebral and subarachnoid]) using Cox and Fine-Gray proportional hazards models, adjusting for sociodemographic and cardiometabolic risk factors. RESULTS: Among 1,412 participants (mean [SD] age 72.4 [9.3] years, 52.1% women, 35.3% Black), 1,143 hospitalizations occurred over 41,849 person-months. Overall, 81% of participants were hospitalized over a maximum of 26.6 years of follow-up (83% of participants with thrombotic/lacunar stroke, 77% of participants with cardioembolic stroke, and 78% of participants with hemorrhagic stroke). Primary cardiovascular and cerebrovascular diagnoses were reported for half of readmissions. Over the entire follow-up period, compared with cardioembolic stroke, readmission risk was lower for thrombotic/lacunar stroke (hazard ratio [HR] 0.82, 95% CI 0.71-0.95) and hemorrhagic stroke (HR 0.74, 95% CI 0.58-0.93) in adjusted Cox proportional hazards models. By contrast, there was no statistically significant difference among subtypes when adjusting for atrial fibrillation and competing risk of death. Compared with cardioembolic stroke, thrombotic/lacunar stroke was associated with lower readmission risk within 1 month (HR 0.66, 95% CI 0.46-0.93) and during 1 month-1 year (HR 0.78, 95% CI 0.62-0.97), and hemorrhagic stroke was associated with lower risk during 1 month-1 year (HR 0.60, 95% CI 0.41-0.87). There was no significant difference between subtypes in readmission risk during later periods. DISCUSSION: Over 26 years of follow-up, 81% of stroke participants experienced a readmission. Cardiovascular and cerebrovascular diagnoses at readmission were most common across stroke subtypes. Though cardioembolic stroke has previously been reported to confer higher risk of readmission, in this study, the readmission risk was not statistically significantly different between stroke subtypes or over different periods when accounting for the competing risk of death.

Association of Win-Loss Record With Neuropsychiatric Symptoms and Brain Health Among Professional Fighters.

OBJECTIVE: Repetitive head impacts in professional fighting commonly lead to head injuries. Increased exposure to repetitive head trauma, measured by the number of professional fights and years of fighting, has been associated with slower processing speed and smaller brain volumes. The impact of win-loss outcomes has been investigated in other sports, with several studies suggesting that individuals on losing teams experience more head injuries. Here, the authors hypothesized that fighters with a worse fight record would exhibit poorer brain health outcomes. METHODS: The Professional Fighters Brain Health Study examined changes in neuropsychiatric symptoms, regional brain volume, and cognition among professional boxers and mixed martial arts fighters. These data were used to evaluate the relationship between win-loss ratios and brain health outcomes among professional fighters (N=212) by using validated neuropsychiatric symptom and cognitive measures and MRI data. RESULTS: Retired fighters with a better record demonstrated more impulsiveness (B=0.21, df=48) and slower processing speed (B=-0.42, df=31). More successful fighters did not perform better than fighters with worse records on any neuropsychiatric or cognitive test. Retired fighters with better fight records had smaller brain volumes in the subcortical gray matter, anterior corpus callosum, left and right hippocampi, left and right amygdala, and left thalamus. More successful active fighters had a smaller left amygdala volume. CONCLUSIONS: These findings suggest that among retired fighters, a better fight record was associated with greater impulsiveness, slower processing speed, and smaller brain volume in certain regions. This study shows that even successful fighters experience adverse effects on brain health.

Associations Between Prior Head Injury, Physical Functioning, and Frailty in the Atherosclerosis Risk in Communities Study.

BACKGROUND: Older adults have the highest rates of head injury and are at the greatest risk for subsequent dysfunction, yet research on subsequent physical decline is limited. We sought to examine cross-sectional and prospective associations of head injury with physical functioning and frailty among older adults. METHODS: A total of 5 598 Atherosclerosis Risk in Communities Study participants from Visit 5 (2011-13) underwent assessments of physical functioning (Short Physical Performance Battery [SPPB], comprised of gait speed, chair stands, and balance) and frailty (defined using established criteria) were followed through Visit 7 (2018-19). Head injury was self-reported or based on ICD-9 codes. Adjusted linear and multinomial logistic regression models were used to estimate associations. Prospective models incorporated inverse probability of attrition weights to account for death or attrition. RESULTS: Participants were a mean age of 75 years, 58% were women, 22% were Black, and 27% had a prior head injury. Compared to individuals without head injury, individuals with head injury had worse physical functioning (SPPB total score, ß-coefficient = -0.22, 95% CI: -0.35 to -0.09) and were more likely to be pre-frail (OR = 1.19, 95% CI: 1.04 to 1.35) or frail (OR = 1.40, 95% CI: 1.08 to 1.80) compared to robust. Prospectively, head injury was associated with a 0.02 m/s greater decline (95% CI: -0.04 to -0.01) in gait speed over a median of 5 years. Among baseline robust individuals (n = 1 847), head injury was associated with increased odds of becoming pre-frail (OR = 1.32, 95% CI: 1.04 to 1.67) or frail (OR = 1.92, 95% CI: 1.05 to 3.51) compared to robust. CONCLUSIONS: Older adults with prior head injury had worse physical functioning and greater frailty at baseline and were more likely to become frail and walk slower over time, compared to individuals without head injury.

Prevention of peri-interventional hypothermia during endoscopic retrograde cholangiopancreatography using a forced-air heating system.

Background and study aims Perioperative hypothermia is associated with significant complications and can be prevented with forced-air heating systems (FAHS). Whether hypothermia occurs during prolonged endoscopic sedation is unclear and prevention measures are not addressed in endoscopic sedation guidelines. We hypothesized that hypothermia also occurs in a significant proportion of patients undergoing endoscopic interventions associated with longer sedation times such as endoscopic retrograde cholangiopancreaticography (ERCP), and that FAHS may prevent it. Patients and methods In this observational study, each patient received two consecutive ERCPs, the first ERCP following current standard of care without FAHS (SOC group) and a consecutive ERCP with FAHS (FAHS group). The primary endpoint was maximum body temperature difference during sedation. Results Twenty-four patients were included. Median (interquartile range) maximum body temperature difference was -0.9°C (-1.2; -0.4) in the SOC and -0.1°C (-0.2; 0) in the FAHS group ( P < 0.001). Median body temperature was lower in the SOC compared with the FAHS group after 20, 30, 40, and 50 minutes of sedation. A reduction in body temperature of > 1°C ( P < 0.001) and a reduction below 36°C ( P = 0.01) occurred more often in the SOC than in the FAHS group. FAHS was independently associated with reduced risk of hypothermia ( P = 0.006). More patients experienced freezing in the SOC group ( P = 0.004). Hemodynmaic and respiratory stability were comparable in both groups. Conclusions Hypothermia occurred in the majority of patients undergoing prolonged endoscopic sedation without active temperature control. FAHS was associated with higher temperature stability during sedation and better patient comfort.

Associations of Prior Head Injury With Mild Behavioral Impairment Domains.

OBJECTIVE: This study investigated associations of prior head injury and number of prior head injuries with mild behavioral impairment (MBI) domains. SETTING: The Atherosclerosis Risk in Communities (ARIC) Study. PARTICIPANTS: A total of 2534 community-dwelling older adults who took part in the ARIC Neurocognitive Study stage 2 examination were included. DESIGN: This was a prospective cohort study. Head injury was defined using self-reported and International Classification of Diseases, Ninth Revision ( ICD -9) code data. MBI domains were defined using the Neuropsychiatric Inventory Questionnaire (NPI-Q) via an established algorithm mapping noncognitive neuropsychiatric symptoms to the 6 domains of decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and abnormal perception/thought content. MAIN MEASURES: The primary outcome was the presence of impairment in MBI domains. RESULTS: Participants were a mean age of 76 years, with a median time from first head injury to NPI-Q administration of 32 years. The age-adjusted prevalence of symptoms in any 1+ MBI domains was significantly higher among individuals with versus without prior head injury (31.3% vs 26.0%, P = .027). In adjusted models, a history of 2+ head injuries, but not 1 prior head injury, was associated with increased odds of impairment in affective dysregulation and impulse dyscontrol domains, compared with no history of head injury (odds ratio [OR] = 1.83, 95% CI = 1.13-2.98, and OR = 1.74, 95% CI = 1.08-2.78, respectively). Prior head injury was not associated with symptoms in MBI domains of decreased motivation, social inappropriateness, and abnormal perception/thought content (all P > .05). CONCLUSION: Prior head injury in older adults was associated with greater MBI domain symptoms, specifically affective dysregulation and impulse dyscontrol. Our results suggest that the construct of MBI can be used to systematically examine the noncognitive neuropsychiatric sequelae of head injury; further studies are needed to examine whether the systematic identification and rapid treatment of neuropsychiatric symptoms after head injury is associated with improved outcomes.

Trends in Traumatic Brain Injury Mortality in the US.

This cohort study characterizes US trends in traumatic brain injury­related mortality by age, sex, and race and ethnicity.

Timing of Cognitive Test Score Decline Prior to Incident Dementia Diagnosis in Blacks and Whites: The Atherosclerosis Risk in Communities Neurocognitive Study.

INTRODUCTION: Commonly occurring dementias include those of Alzheimer's, vascular, and mixtures of these and other pathologies. They are believed to evolve over many years, but that time interval has been difficult to establish. Our objective was to determine how many years in advance of a dementia diagnosis cognitive scores begin to change. METHODS: 14,086 dementia-free ARIC participants underwent a cognitive exam at baseline visit 2 (1990-1992, mean age 57 ± 5.72), and 11,244 at visit 4 (1996-1998), 5,640 at visit 5 (2011-2013), and 3,574 at visit 6 (2016-2017) with surveillance for dementias of all-causes combined. Within 5-year intervals after each visit, we compared performance on the Delayed Word Recall Test (DWRT), the Digit Symbol Substitution Test (DSST), the Word Fluency Test (WFT), and the combined mean of three cognitive tests at baseline in participants who were diagnosed with dementia within each interval versus those who survived the interval without a dementia diagnosis. Z-scores were adjusted for demographics and education in separate regression models for each visit. We plotted adjusted z-score means by time interval following each visit. RESULTS: During follow-up 3,334, 2,821, 1,218, and 329 dementia cases were ascertained after visits 2, 4, 5, and 6, respectively. Adjusted DWRT z-scores were significantly lower 20-25 years before dementia than those who did not experience dementia within 25 years. DSST z-scores were significantly lower at 25-30 years and 3-test combination z-scores were significantly lower as early as 30-31 years before onset. The difference between dementia and non-dementia group in the visit 2 3-test combination z-score was -0.20 at 30-31 years prior to dementia diagnosis. As expected, differences between the dementia and non-dementia groups increased closer to the time of dementia occurrence, up to their widest point at 0-5 years prior to dementia diagnosis. The difference between dementia and non-dementia groups in the visit 2 3-test combination z-score at 0-5 years was -0.90. WFT z-score differences were smaller than for the DSST or DWRT and began later. Patterns were similar in Black and White participants. CONCLUSION: DWRT, DSST, and combined 3-test z-scores were significantly lower more than 20 years prior to diagnosis in the dementia group versus the non-dementia group. Findings contribute to our knowledge of the long prodromal period in Blacks and Whites.

FMR1 Carriers Report Executive Function Changes Prior to Fragile X-Associated Tremor/Ataxia Syndrome: A Longitudinal Study.

BACKGROUND: Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies has made it difficult to address this hypothesis. OBJECTIVE: To determine whether executive function deterioration experienced by premutation carriers (PC) in daily life precedes and predicts FXTAS. METHODS: This study included 66 FMR1 PC ranging from 40 to 78 years (mean, 59.5) and 31 well-matched healthy controls (HC) ages 40 to 75 (mean, 57.7) at baseline. Eighty-four participants returned for 2 to 5 follow up visits over a duration of 1 to 9 years (mean, 4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit. RESULTS: Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, increased self-report executive function problems at baseline significantly predicted later development of FXTAS. CONCLUSIONS: Executive function changes experienced by male PC represent a prodrome of the later movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association between structural brain MRI abnormalities and epilepsy in older adults.

OBJECTIVE: To determine the association between brain MRI abnormalities and incident epilepsy in older adults. METHODS: Men and women (ages 45-64 years) from the Atherosclerosis Risk in Communities study were followed up from 1987 to 2018 with brain MRI performed between 2011 and 2013. We identified cases of incident late-onset epilepsy (LOE) with onset of seizures occurring after the acquisition of brain MRI. We evaluated the relative pattern of cortical thickness, subcortical volume, and white matter integrity among participants with incident LOE after MRI in comparison with participants without seizures. We examined the association between MRI abnormalities and incident LOE using Cox proportional hazards regression. Models were adjusted for demographics, hypertension, diabetes, smoking, stroke, and dementia status. RESULTS: Among 1251 participants with brain MRI data, 27 (2.2%) developed LOE after MRI over a median of 6.4 years (25-75 percentile 5.8-6.9) of follow-up. Participants with incident LOE after MRI had higher levels of cortical thinning and white matter microstructural abnormalities before seizure onset compared to those without seizures. In longitudinal analyses, greater number of abnormalities was associated with incident LOE after controlling for demographic factors, risk factors for cardiovascular disease, stroke, and dementia (gray matter: hazard ratio [HR]: 2.3, 95% confidence interval [CI]: 1.0-4.9; white matter diffusivity: HR: 3.0, 95% CI: 1.2-7.3). INTERPRETATION: This study demonstrates considerable gray and white matter pathology among individuals with LOE, which is present prior to the onset of seizures and provides important insights into the role of neurodegeneration, both of gray and white matter, and the risk of LOE.

Open-Label Sulforaphane Trial in FMR1 Premutation Carriers with Fragile-X-Associated Tremor and Ataxia Syndrome (FXTAS).

Fragile X (FMR1) premutation is a common mutation that affects about 1 in 200 females and 1 in 450 males and can lead to the development of fragile-X-associated tremor/ataxia syndrome (FXTAS). Although there is no targeted, proven treatment for FXTAS, research suggests that sulforaphane, an antioxidant present in cruciferous vegetables, can enhance mitochondrial function and maintain redox balance in the dermal fibroblasts of individuals with FXTAS, potentially leading to improved cognitive function. In a 24-week open-label trial involving 15 adults aged 60-88 with FXTAS, 11 participants successfully completed the study, demonstrating the safety and tolerability of sulforaphane. Clinical outcomes and biomarkers were measured to elucidate the effects of sulforaphane. While there were nominal improvements in multiple clinical measures, they were not significantly different after correction for multiple comparisons. PBMC energetic measures showed that the level of citrate synthase was higher after sulforaphane treatment, resulting in lower ATP production. The ratio of complex I to complex II showed positive correlations with the MoCA and BDS scores. Several mitochondrial biomarkers showed increased activity and quantity and were correlated with clinical improvements.

Mobile eye tracking applied as a tool for customer experience research in a crowded train station.

Train stations have increasingly become crowded, necessitating stringent requirements in the design of stations and commuter navigation through these stations. In this study, we explored the use of mobile eye tracking in combination with observation and a survey to gain knowledge on customer experience in a crowded train station. We investigated the utilization of mobile eye tracking in ascertaining customers' perception of the train station environment and analyzed the effect of a signalization prototype (visual pedestrian flow cues), which was intended for regulating pedestrian flow in a crowded underground passage. Gaze behavior, estimated crowd density, and comfort levels (an individual's comfort level in a certain situation), were measured before and after the implementation of the prototype. The results revealed that the prototype was visible in conditions of low crowd density. However, in conditions of high crowd density, the prototype was less visible, and the path choice was influenced by other commuters. Hence, herd behavior appeared to have a stronger effect than the implemented signalization prototype in conditions of high crowd density. Thus, mobile eye tracking in combination with observation and the survey successfully aided in understanding customers' perception of the train station environment on a qualitative level and supported the evaluation of the signalization prototype the crowded underground passage. However, the analysis process was laborious, which could be an obstacle for its practical use in gaining customer insights.