Relationships of Cognitive Measures with Cerebrospinal Fluid but Not Imaging Biomarkers of Alzheimer Disease Vary between Black and White Individuals.

OBJECTIVE: Biomarkers of Alzheimer disease vary between groups of self-identified Black and White individuals in some studies. This study examined whether the relationships between biomarkers or between biomarkers and cognitive measures varied by racialized groups. METHODS: Cerebrospinal fluid (CSF), amyloid positron emission tomography (PET), and magnetic resonance imaging measures were harmonized across four studies of memory and aging. Spearman correlations between biomarkers and between biomarkers and cognitive measures were calculated within each racialized group, then compared between groups by standard normal tests after Fisher's Z-transformations. RESULTS: The harmonized dataset included at least one biomarker measurement from 495 Black and 2,600 White participants. The mean age was similar between racialized groups. However, Black participants were less likely to have cognitive impairment (28% vs 36%) and had less abnormality of some CSF biomarkers including CSF Aß42/40, total tau, p-tau181, and neurofilament light. CSF Aß42/40 was negatively correlated with total tau and p-tau181 in both groups, but at a smaller magnitude in Black individuals. CSF Aß42/40, total tau, and p-tau181 had weaker correlations with cognitive measures, especially episodic memory, in Black than White participants. Correlations of amyloid measures between CSF (Aß42/40, Aß42) and PET imaging were also weaker in Black than White participants. Importantly, no differences based on race were found in correlations between different imaging biomarkers, or in correlations between imaging biomarkers and cognitive measures. INTERPRETATION: Relationships between CSF biomarkers but not imaging biomarkers varied by racialized groups. Imaging biomarkers performed more consistently across racialized groups in associations with cognitive measures. ANN NEUROL 2024;95:495-506.

Cross-Platform Synaptic Network Analysis of Human Entorhinal Cortex Identifies TWF2 as a Modulator of Dendritic Spine Length.

Proteomic studies using postmortem human brain tissue samples have yielded robust assessments of the aging and neurodegenerative disease(s) proteomes. While these analyses provide lists of molecular alterations in human conditions, like Alzheimer's disease (AD), identifying individual proteins that affect biological processes remains a challenge. To complicate matters, protein targets may be highly understudied and have limited information on their function. To address these hurdles, we sought to establish a blueprint to aid selection and functional validation of targets from proteomic datasets. A cross-platform pipeline was engineered to focus on synaptic processes in the entorhinal cortex (EC) of human patients, including controls, preclinical AD, and AD cases. Label-free quantification mass spectrometry (MS) data (n = 2260 proteins) was generated on synaptosome fractionated tissue from Brodmann area 28 (BA28; n = 58 samples). In parallel, dendritic spine density and morphology was measured in the same individuals. Weighted gene co-expression network analysis was used to construct a network of protein co-expression modules that were correlated with dendritic spine metrics. Module-trait correlations were used to guide unbiased selection of Twinfilin-2 (TWF2), which was the top hub protein of a module that positively correlated with thin spine length. Using CRISPR-dCas9 activation strategies, we demonstrated that boosting endogenous TWF2 protein levels in primary hippocampal neurons increased thin spine length, thus providing experimental validation for the human network analysis. Collectively, this study describes alterations in dendritic spine density and morphology as well as synaptic proteins and phosphorylated tau from the entorhinal cortex of preclinical and advanced stage AD patients.SIGNIFICANCE STATEMENT Proteomic studies can yield vast lists of molecules that are altered under various experimental or disease conditions. Here, we provide a blueprint to facilitate mechanistic validation of protein targets from human brain proteomic datasets. We conducted a proteomic analysis of human entorhinal cortex (EC) samples spanning cognitively normal and Alzheimer's disease (AD) cases with a comparison of dendritic spine morphology in the same samples. Network integration of proteomics with dendritic spine measurements allowed for unbiased discovery of Twinfilin-2 (TWF2) as a regulator of dendritic spine length. A proof-of-concept experiment in cultured neurons demonstrated that altering Twinfilin-2 protein level induced corresponding changes in dendritic spine length, thus providing experimental validation for the computational framework.

Analysis of seizure-cluster circadian periodicity from a long-term, open-label safety study of diazepam nasal spray.

OBJECTIVE: Seizure clusters require prompt medical treatment to minimize possible progression to status epilepticus, increased health care use, and disruptions to daily life. Isolated seizures may exhibit cyclical patterns, including circadian and longer rhythms. However, little is known about the cyclical patterns in seizure clusters. This post hoc analysis of data from a long-term, phase 3, open-label, repeat-dose safety study of diazepam nasal spray modeled the periodicity of treated seizure clusters. METHODS: Mixed-effects cosinor analysis evaluated circadian rhythmicity, and single component cosinors using 12 and 24 h were used to calculate cosinor parameters (e.g., midline statistic of rhythm, wave ampitude, and acrophase [peak]). Analysis was completed for the full cohort and a consistent cohort of participants with two or more seizure clusters in each of four, 3-month periods. The influence of epilepsy type on cosinor parameters was also analyzed. RESULTS: Seizure-cluster events plotted across 24 h showed a bimodal distribution with acrophases (peaks) at ~06:30 and ~18:30. A 12-h plot showed a single peak at ~06:30. Cosinor analyses of the full and consistent cohort aligned, with acrophases for both models predicting peak seizure activity at ~23:30 on a 24-h scale and ~07:30 on a 12-h scale. The consistent cohort was associated with increases in baseline and peak seizure-cluster activity. Analysis by epilepsy type identified distinct trends. Seizure clusters in the focal epilepsy group peaked in the evening (acrophase 19:19), whereas events in the generalized epilepsy group peaked in the morning (acrophase 04:46). Together they compose the bimodal clustering observed over 24 h. SIGNIFICANCE: This analysis of seizure clusters treated with diazepam nasal spray demonstrated that seizure clusters occur cyclically in 12- and 24-h time frames similar to that reported with isolated seizures. Further elucidation of these patterns may provide important information for patient care, ranging from improved patient-centered outcomes to seizure-cluster prediction.

Gut- and oral-dysbiosis differentially impact spinal- and bulbar-onset ALS, predicting ALS severity and potentially determining the location of disease onset.

BACKGROUND: Prior studies on the role of gut-microbiome in Amyotrophic Lateral Sclerosis (ALS) pathogenesis have yielded conflicting results. We hypothesized that gut- and oral-microbiome may differentially impact two clinically-distinct ALS subtypes (spinal-onset ALS (sALS) vs. bulbar-onset ALS (bALS), driving disagreement in the field. METHODS: ALS patients diagnosed within 12 months and their spouses as healthy controls (n = 150 couples) were screened. For eligible sALS and bALS patients (n = 36) and healthy controls (n = 20), 16S rRNA next-generation sequencing was done in fecal and saliva samples after DNA extractions to examine gut- and oral-microbiome differences. Microbial translocation to blood was measured by blood lipopolysaccharide-binding protein (LBP) and 16S rDNA levels. ALS severity was assessed by Revised ALS Functional Rating Scale (ALSFRS-R). RESULTS: sALS patients manifested significant gut-dysbiosis, primarily driven by increased fecal Firmicutes/Bacteroidetes-ratio (F/B-ratio). In contrast, bALS patients displayed significant oral-dysbiosis, primarily driven by decreased oral F/B-ratio. For sALS patients, gut-dysbiosis (a shift in fecal F/B-ratio), but not oral-dysbiosis, was strongly associated with greater microbial translocation to blood (r = 0.8006, P < 0.0001) and more severe symptoms (r = 0.9470, P < 0.0001). In contrast, for bALS patients, oral-dysbiosis (a shift in oral F/B-ratio), but not gut-dysbiosis, was strongly associated with greater microbial translocation to blood (r = 0.9860, P < 0.0001) and greater disease severity (r = 0.9842, P < 0.0001). For both ALS subtypes, greater microbial translocation was associated with more severe symptoms (sALS: r = 0.7924, P < 0.0001; bALS: r = 0.7496, P = 0.0067). Importantly, both sALS and bALS patients displayed comparable oral-motor deficits with associations between oral-dysbiosis and severity of oral-motor deficits in bALS but not sALS. This suggests that oral-dysbiosis is not simply caused by oral/bulbar/respiratory symptoms but represents a pathological driver of bALS. CONCLUSIONS: We found increasing gut-dysbiosis with worsening symptoms in sALS patients and increasing oral-dysbiosis with worsening symptoms in bALS patients. Our findings support distinct microbial mechanisms underlying two ALS subtypes, which have been previously grouped together as a single disease. Our study suggests correcting gut-dysbiosis as a therapeutic strategy for sALS patients and correcting oral-dysbiosis as a therapeutic strategy for bALS patients.

Longitudinal optical coherence tomography study of optic atrophy in secondary progressive multiple sclerosis: Results from a clinical trial cohort.

BACKGROUND: Limited prospective information exists regarding spectral-domain optical coherence tomography (SD-OCT) in secondary progressive multiple sclerosis (SPMS). OBJECTIVE: Document cross-sectional and longitudinal retinal nerve fiber layer (RNFL) and macular ganglion cell plus inner plexiform layer (GCIPL) features of an SPMS clinical trial cohort. METHODS: Prospective, observational study using a 2-year randomized placebo-controlled SPMS trial cohort with yearly SD-OCT testing. Post hoc analysis determined influences of optic neuritis (ON), disease duration, and baseline SD-OCT on annualized atrophy rates and on correlations between OCT and brain atrophy. RESULTS: Mean RNFL and GCIPL values of patients ( n = 47, mean age = 59 years, mean disease duration = 30 years) were significantly lower among eyes with prior ON than those without (no history of ON (NON)). Annualized RNFL (-0.31 µm/year) and GCIPL (-0.29 µm/year) atrophy rates did not differ between ON and NON eyes. Baseline RNFL thickness >75 µm was associated with greater annualized RNFL atrophy (-0.85 µm/year). Neither RNFL nor GCIPL atrophy correlated with whole-brain atrophy. CONCLUSION: This study suggests that eyes with and without ON history may be pooled for atrophy analysis in SPMS clinical trials using SD-OCT. Low baseline RNFL, small retinal atrophy rates, and lack of correlation with whole-brain atrophy in this population are important trial design considerations.

Surgery is associated with ventricular enlargement as well as cognitive and functional decline.

INTRODUCTION: In preclinical studies, surgery/anesthesia contribute to cognitive decline and enhance neuropathologic changes underlying Alzheimer's disease (AD). Nevertheless, the link between surgery, anesthesia, apolipoprotein E ε4 (APOE ε4), and AD remains unclear. METHODS: We performed a retrospective cohort analysis of two prospective longitudinal aging studies. Mixed-effects statistical models were used to assess the relationship between surgical/anesthetic exposure, the APOE genotype, and rate of change in measures of cognition, function, and brain volumes. RESULTS: The surgical group (n = 182) experienced a more rapid rate of deterioration compared with the nonsurgical group (n = 345) in several cognitive, functional, and brain magnetic resonance imaging measures. Furthermore, there was a significant synergistic effect of anesthesia/surgery exposure and presence of the APOE ε4 allele in the decline of multiple cognitive and functional measures. DISCUSSION: These data provide insight into the role of surgical exposure as a risk factor for cognitive and functional decline in older adults.

Quantifying Putative Retinal Gliosis in Preclinical Alzheimer's Disease.

Purpose: Neuroinflammation plays a significant role in the pathology of Alzheimer's disease (AD). Mouse models of AD and postmortem biopsy of patients with AD reveal retinal glial activation comparable to central nervous system immunoreactivity. We hypothesized that the surface area of putative retinal gliosis observed in vivo using en face optical coherence tomography (OCT) imaging will be larger in patients with preclinical AD versus controls. Methods: The Spectralis II instrument was used to acquire macular centered 20 × 20 and 30 × 25-degrees spectral domain OCT images of 76 participants (132 eyes). A cohort of 22 patients with preclinical AD (40 eyes, mean age = 69 years, range = 60-80 years) and 20 control participants (32 eyes, mean age = 66 years, range = 58-82 years, P = 0.11) were included for the assessment of difference in surface area of putative retinal gliosis and retinal nerve fiber layer (RNFL) thickness. The surface area of putative retinal gliosis and RNFL thickness for the nine sectors of the Early Treatment Diabetic Retinopathy Study (ETDRS) map were compared between groups using generalized linear mixed models. Results: The surface area of putative retinal gliosis was significantly greater in the preclinical AD group (0.97 ± 0.55 mm2) compared to controls (0.68 ± 0.40 mm2); F(1,70) = 4.41, P = 0.039; Cohen's d = 0.61. There was no significant difference between groups for RNFL thickness in the 9 ETDRS sectors, P > 0.05. Conclusions: Our analysis shows greater putative retinal gliosis in preclinical AD compared to controls. This demonstrates putative retinal gliosis as a potential biomarker for AD-related neuroinflammation.

Baseline levels and longitudinal changes in plasma Aß42/40 among Black and white individuals.

Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C2N Diagnostics' PrecivityAD test for Aß42 and Aß40. Compared to white individuals, Black individuals had higher average plasma Aß42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aß40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aß42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups.

Population fraction of Parkinson's disease attributable to preventable risk factors.

Parkinson's disease is the fastest-growing neurologic disease with seemingly no means of prevention. Intrinsic risk factors (age, sex, and genetics) are inescapable, but environmental factors are not. We identified repeated blows to the head in sports/combat as a potential new risk factor. 23% of PD cases in females were attributable to pesticide/herbicide exposure, and 30% of PD in males were attributable to pesticides/herbicides, military-related chemical exposures, and repeated blows to the head, and therefore could have potentially been prevented.

Population fraction of Parkinson's disease attributable to preventable risk factors.

Parkinson's disease is the fastest growing neurologic disease with seemingly no means for prevention. Intrinsic risk factors (age, sex, genetics) are inescapable, but environmental factors are not. We studied population attributable fraction and estimated fraction of PD that could be reduced if modifiable risk factors were eliminated. Assessing several known risk factors simultaneously in one study, we demonstrate that all were operative and independent, underscoring etiological heterogeneity within a single population. We investigated repeated blows to head in sports or combat as a potential new risk factor, and found it was associated with two-fold increased risk of PD. Considering modifiable risk factors, 23% of PD cases in females were attributable to pesticides/herbicides exposure, and 30% of PD cases in males was attributable to pesticides/herbicides, Agent Orange/chemical warfare, and repeated blows to the head. Thus, one-in-three cases of PD in males, and one-in-four cases in females could have potentially been prevented.

Patients with sporadic FTLD exhibit similar increases in lysosomal proteins and storage material as patients with FTD due to GRN mutations.

Loss of function progranulin (GRN) mutations are a major autosomal dominant cause of frontotemporal dementia (FTD). Patients with FTD due to GRN mutations (FTD-GRN) develop frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A) and exhibit elevated levels of lysosomal proteins and storage material in frontal cortex, perhaps indicating lysosomal dysfunction as a mechanism of disease. To investigate whether patients with sporadic FTLD exhibit similar signs of lysosomal dysfunction, we compared lysosomal protein levels, transcript levels, and storage material in patients with FTD-GRN or sporadic FTLD-TDP type A. We analyzed samples from frontal cortex, a degenerated brain region, and occipital cortex, a relatively spared brain region. In frontal cortex, patients with sporadic FTLD-TDP type A exhibited similar increases in lysosomal protein levels, transcript levels, and storage material as patients with FTD-GRN. In occipital cortex of both patient groups, most lysosomal measures did not differ from controls. Frontal cortex from a transgenic mouse model of TDP-opathy had similar increases in cathepsin D and lysosomal storage material, showing that TDP-opathy and neurodegeneration can drive these changes independently of progranulin. To investigate these changes in additional FTLD subtypes, we analyzed frontal cortical samples from patients with sporadic FTLD-TDP type C or Pick's disease, an FTLD-tau subtype. All sporadic FTLD groups had similar increases in cathepsin D activity, lysosomal membrane proteins, and storage material as FTD-GRN patients. However, patients with FTLD-TDP type C or Pick's disease did not have similar increases in lysosomal transcripts as patients with FTD-GRN or sporadic FTLD-TDP type A. Based on these data, accumulation of lysosomal proteins and storage material may be a common aspect of end-stage FTLD. However, the unique changes in gene expression in patients with FTD-GRN or sporadic FTLD-TDP type A may indicate distinct underlying lysosomal changes among FTLD subtypes.

Effect of Vascular Comorbidity on Visual and Disability Outcomes in a Secondary Progressive Multiple Sclerosis Clinical Trial Cohort.

BACKGROUND: Vascular comorbidity (VC) is associated with multiple sclerosis (MS) disease progression and visual dysfunction. The longitudinal effect of VC in people with secondary progressive MS (SPMS) is unclear. This study explored the impact of VC on standard clinical, MRI, and visual outcomes in people with SPMS enrolled in a clinical trial. METHODS: Data were extracted from a 2-year randomized controlled trial (N = 51) testing the supplement lipoic acid in people with SPMS who underwent annual Expanded Disability Status Scales, Timed 25-Foot Walk tests, MRIs, visual acuity testing, and retinal nerve fiber layer (RNFL) and ganglion cell/inner plexiform layer (GCIPL) thicknesses per optical coherence tomography (OCT). Post hoc linear mixed-effects regression analysis compared baseline and annualized outcomes between participants without VC (VC-) and with 1 or more VCs (VC+) (hypertension, dyslipidemia, obesity, diabetes, peripheral or cardiovascular disease, tobacco use). RESULTS: The VC- (n = 19) and VC+ (n = 28) participants were similar in age, sex, and MS disease duration and had comparable MS disability, mobility, and brain atrophy at baseline and throughout the 2-year parent study. The VC+ participants had worse baseline visual acuity than those in the VC- group by 0.13 logMAR (P = .041). No significant differences were detected in RNFL or GCIPL baseline thickness or atrophy between groups. CONCLUSIONS: In an SPMS cohort, VC had an inconsistent effect on standard clinical, MRI, and exploratory OCT outcomes, suggesting that the effect of VC may not be evident in smaller cohort studies. Using a more refined definition of VC in future, adequately powered investigations may help effectively elucidate and account for the interaction between vascular risk burden and MS disability.

Influence of Subject-Specific Effects in Longitudinal Modelling of Cognitive Decline in Alzheimer's Disease.

BACKGROUND: Accurate longitudinal modelling of cognitive decline is a major goal of Alzheimer's disease and related dementia (ADRD) research. However, the impact of subject-specific effects is not well characterized and may have implications for data generation and prediction. OBJECTIVE: This study seeks to address the impact of subject-specific effects, which are a less well-characterized aspect of ADRD cognitive decline, as measured by the Alzheimer's Disease Assessment Scale's Cognitive Subscale (ADAS-Cog). METHODS: Prediction errors and biases for the ADAS-Cog subscale were evaluated when using only population-level effects, robust imputation of subject-specific effects using model covariances, and directly known individual-level effects fit during modelling as a natural control. Evaluated models included pre-specified parameterizations for clinical trial simulation, analogous mixed-effects regression models parameterized directly, and random forest ensemble models. Assessment used a meta-database of Alzheimer's disease studies with validation in simulated synthetic cohorts. RESULTS: All models observed increases in variance under imputation leading to increased prediction error. Bias decreased with imputation except under the pre-specified parameterization, which increased in the meta-database, but was attenuated under simulation. Known fitted subject effects gave the best prediction results. CONCLUSION: Subject-specific effects were found to have a profound impact on predicting ADAS-Cog. Reductions in bias suggest imputing random effects assists in calculating results on average, as when simulating clinical trials. However, reduction in error emphasizes population-level effects when attempting to predict outcomes for individuals. Forecasting future observations greatly benefits from using known subject-specific effects.

Dynamic Amyloid PET: Relationships to 18F-Flortaucipir Tau PET Measures.

Measuring amyloid and predicting tau status using a single amyloid PET study would be valuable for assessing brain AD pathophysiology. We hypothesized that early-frame amyloid PET (efAP) correlates with the presence of tau pathology because the initial regional brain concentrations of radioactivity are determined primarily by blood flow, which is expected to be decreased in the setting of tau pathology. Methods: The study included 120 participants (63 amyloid-positive and 57 amyloid-negative) with dynamic 18F-florbetapir PET and static 18F-flortaucipir PET scans obtained within 6 mo of each other. These subjects were predominantly cognitively intact in both the amyloid-positive (63%) and the amyloid-negative (93%) groups. Parameters for efAP quantification were optimized for stratification of tau PET positivity, assessed by either a tauopathy score or Braak regions. The ability of efAP to stratify tau positivity was measured using receiver-operating-characteristic analysis of area under the curve (AUC). Pearson r and Spearman ρ were used for parametric and nonparametric comparisons between efAP and tau PET, respectively. Standardized net benefit was used to evaluate improvement in using efAP as an additional copredictor over hippocampal volume in predicting tau PET positivity. Results: Measuring efAP within the hippocampus and summing the first 3 min of brain activity after injection showed the strongest discriminative ability to stratify for tau positivity (AUC, 0.67-0.89 across tau PET Braak regions) in amyloid-positive individuals. Hippocampal efAP correlated significantly with a global tau PET tauopathy score in amyloid-positive participants (r = -0.57, P < 0.0001). Compared with hippocampal volume, hippocampal efAP showed a stronger association with tau PET Braak stage (ρ = -0.58 vs. -0.37) and superior stratification of tau PET tauopathy score (AUC, 0.86 vs. 0.66; P = 0.002). Conclusion: Hippocampal efAP can provide additional information to conventional amyloid PET, including estimation of the likelihood of tau positivity in amyloid-positive individuals.

Racial Differences in Alzheimer's Disease Specialist Encounters Are Associated with Usage of Molecular Imaging and Dementia Medications: An Enterprise-Wide Analysis Using i2b2.

BACKGROUND: African Americans are at increased risk for Alzheimer's disease (AD) but barriers to optimal clinical care are unclear. OBJECTIVE: To comprehensively evaluate potential racial differences in the diagnosis and treatment of AD in an academic medical center. METHODS: We used the clinical informatics tool, i2b2, to analyze all patient encounters for AD or mild cognitive impairment (MCI) in the University of Alabama at Birmingham Health System over a three-year period, examining neuroimaging rates and dementia-related medication use by race and clinic site using ratio tests on contingency tables of stratified patient counts. RESULTS: Enterprise-wide, African Americans were not underrepresented among outpatients seen for AD/MCI. However, there were differences in the clinic setting where visits occurred, with African Americans overrepresented in Geriatrics and primary care clinics and underrepresented in Memory Disorders specialty clinics. There were no racial differences in the rates at which any clinic ordered PET neuroimaging tests or dementia-related medications. However, unsurprisingly, specialty clinics ordered both PET neuroimaging and dementia-related medications at a higher rate than primary care clinics, and overall across the medical enterprise, African Americans were statistically less likely to have PET neuroimaging or dementia-related medications ordered. CONCLUSION: African Americans with AD/MCI were not underrepresented at this academic medical center but were somewhat less likely to have PET neuroimaging or to be on dementia-related medications, potentially in part from underrepresentation in the specialty clinics where these orders are more likely. The reasons for this underrepresentation in specialty clinics are likely multifactorial and important to better understand.

Oxidized Products of Omega-6 and Omega-3 Long Chain Fatty Acids Are Associated with Increased White Matter Hyperintensity and Poorer Executive Function Performance in a Cohort of Cognitively Normal Hypertensive Older Adults.

BACKGROUND: Cerebrovascular disease is a common cause of dementia in older adults, and potentially preventable with early intervention. Oxylipins are produced from the oxidation of long-chain polyunsaturated fatty acids (PUFA) possessing potent vascular effects. Oxylipins generated from the cytochrome P450 pathway are enzymatically converted to diols by soluble epoxide hydrolase (sEH); sEH products have been associated with small vessel ischemic disease. Little is known about oxylipins' impact on markers of dementia risk. OBJECTIVE: An exploratory examination of the association between omega-6 and omega-3 derived oxylipins, brain MRI, and cognition. METHODS: Thirty-seven non-demented participants with controlled hypertension (mean age 65.6 years) were enrolled in a dementia prevention study investigating fish oil and lipoic acid on preserving cognitive function. Baseline associations between plasma oxylipins, white matter hyperintensity (WMH), and Trails-B were examined using linear regression. P450-derived diol/epoxide ratio was an indirect measure of sEH activity. RESULTS: Omega-6 derived 9-HODE was associated with increased WMH (p = 0.017) and reduced grey matter volume (p = 0.02). Omega-6 P450-derived diol/epoxide ratio 9,10-DiHOME/9,10-EpOME was associated with increased WMH (p = 0.035) and poorer performance on Trails-B (p = 0.05); ratio14,15-DHET/14,15-EET was associated with increased WMH (p = 0.045). Omega-3 P450-derived diol/epoxide ratio 19,20-DiHDPE/19,20-EpDPE was associated with increased WMH (p = 0.04) and poorer performance on Trails-B (p = 0.04). Arachidonic acid was associated with better performance on Trails-B (p = 0.012); Omega-3 derived 16,17-EpDPE was associated with decreased WMH (p = 0.005). CONCLUSIONS: With the exception of arachidonic acid, it was specific oxylipin products, not their parent PUFAs, that were associated with unfavorable and favorable MRI and cognitive markers of dementia risk.

Elevated levels of extracellular vesicles in progranulin-deficient mice and FTD-GRN Patients.

OBJECTIVE: The goal of this study was to investigate the effect of progranulin insufficiency on extracellular vesicles (EVs), a heterogeneous population of vesicles that may contribute to progression of neurodegenerative disease. Loss-of-function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD), and brains from GRN carriers with FTD (FTD-GRN) exhibit signs of lysosomal dysfunction. Lysosomal dysfunction may induce compensatory increases in secretion of exosomes, EVs secreted from the endolysosomal system, so we hypothesized that progranulin insufficiency would increase EV levels in the brain. METHODS: We analyzed levels and protein contents of brain EVs from Grn-/- mice, which model the lysosomal abnormalities of FTD-GRN patients. We then measured brain EVs in FTD-GRN patients. To assess the relationship of EVs with symptomatic disease, we measured plasma EVs in presymptomatic and symptomatic GRN mutation carriers. RESULTS: Grn-/- mice had elevated brain EV levels and altered EV protein contents relative to wild-type mice. These changes were age-dependent, occurring only after the emergence of pathology in Grn-/- mice. FTD-GRN patients (n = 13) had elevated brain EV levels relative to controls (n = 5). Symptomatic (n = 12), but not presymptomatic (n = 7), GRN carriers had elevated plasma EV levels relative to controls (n = 8). INTERPRETATION: These data show that symptomatic FTD-GRN patients have elevated levels of brain and plasma EVs, and that this effect is modeled in the brain of Grn-/- mice after the onset of pathology. This increase in EVs could influence FTD disease progression, and provides further support for EVs as potential FTD biomarkers.

The Sensor Technology and Rehabilitative Timing (START) Protocol: A Randomized Controlled Trial for the Rehabilitation of Mild Traumatic Brain Injury.

BACKGROUND: Clinical practice for rehabilitation after mild traumatic brain injury (mTBI) is variable, and guidance on when to initiate physical therapy is lacking. Wearable sensor technology may aid clinical assessment, performance monitoring, and exercise adherence, potentially improving rehabilitation outcomes during unsupervised home exercise programs. OBJECTIVE: The objectives of this study were to: (1) determine whether initiating rehabilitation earlier than typical will improve outcomes after mTBI, and (2) examine whether using wearable sensors during a home-exercise program will improve outcomes in participants with mTBI. DESIGN: This was a randomized controlled trial. SETTING: This study will take place within an academic hospital setting at Oregon Health & Science University and Veterans Affairs Portland Health Care System, and in the home environment. PARTICIPANTS: This study will include 160 individuals with mTBI. INTERVENTION: The early intervention group (n = 80) will receive one-on-one physical therapy 8 times over 6 weeks and complete daily home exercises. The standard care group (n = 80) will complete the same intervention after a 6- to 8-week wait period. One-half of each group will receive wearable sensors for therapist monitoring of patient adherence and quality of movements during their home exercise program. MEASUREMENTS: The primary outcome measure will be the Dizziness Handicap Inventory score. Secondary outcome measures will include symptomatology, static and dynamic postural control, central sensorimotor integration posturography, and vestibular-ocular-motor function. LIMITATIONS: Potential limitations include variable onset of care, a wide range of ages, possible low adherence and/or withdrawal from the study in the standard of care group, and low Dizziness Handicap Inventory scores effecting ceiling for change after rehabilitation. CONCLUSIONS: If initiating rehabilitation earlier improves primary and secondary outcomes post-mTBI, this could help shape current clinical care guidelines for rehabilitation. Additionally, using wearable sensors to monitor performance and adherence may improve home exercise outcomes.

Longitudinal Assessment of Balance and Gait After Concussion and Return to Play in Collegiate Athletes.

CONTEXT: In longitudinal studies tracking recovery after concussion, researchers often have not considered the timing of return to play (RTP) as a factor in their designs, which can limit the understanding of how RTP may affect the analysis and resulting conclusions. OBJECTIVE: To evaluate the recovery of balance and gait in concussed athletes using a novel linear mixed-model design that allows an inflection point to account for changes in trend that may occur after RTP. DESIGN: Cohort study. SETTING: University athletics departments, applied field setting. PATIENTS OR OTHER PARTICIPANTS: Twenty-three concussed (5 women, 18 men; age = 20.1 ± 1.3 years) and 25 healthy control (6 women, 19 men; age = 20.9 ± 1.4 years) participants were studied. Participants were referred by their team athletic trainers. MAIN OUTCOME MEASURE(S): Measures consisted of the Balance Error Scoring System (BESS) total score, sway (instrumented root mean square of mediolateral sway), single-task gait speed, gait speed while simultaneously reading a handheld article (dual-task gait speed), dual-task cost of reading on gait speed, and dual-task cost of walking on reading. RESULTS: We observed no significant effects or interactions for the BESS. Instrumented sway was worse in concussed participants, and a change in the recovery trend occurred after RTP. We observed group and time effects and group × time and group × RTP change interactions (P ≤ .046). No initial between-groups differences were found for single-task or dual-task gait. Both groups increased gait speed initially and then leveled off after the average RTP date. We noted time and RTP change effects and positive group × time interactions for both conditions (P ≤ .042) and a group × RTP change interaction for single-task gait speed (P = .005). No significant effects or interactions were present for the dual-task cost of reading on gait speed or the dual-task cost of walking on reading. CONCLUSIONS: Changes in the rate of recovery were coincident with the timing of RTP. Although we cannot suggest these changes were a result of the athletes returning to play, these findings demonstrate the need for further research to evaluate the effects of RTP on concussion recovery.

Sex and genetic differences in postoperative cognitive dysfunction: a longitudinal cohort analysis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common postoperative complication experienced by patients aged 65 years and older, and these older adults comprise more than one third of the surgical patients in the USA. Because not everyone with a history of exposure to surgery and anesthesia develops POCD, there are likely major biological risk factors involved. There are important gaps in our knowledge regarding whether genetic makeup, biological sex, or other Alzheimer's disease risk factors predispose older adults to developing POCD. We set out to determine whether biological sex and Apolipoprotein E-ε4 (APOE4) carrier status increase the risk of developing POCD in older adults. METHODS: We performed a cohort analysis of 1033 participants of prospective longitudinal aging studies. Participants underwent regular cognitive test batteries and we compared the annual rate of change over time in various cognitive measures in the women exposed to surgery and general anesthesia compared to the men exposed to surgery and general anesthesia. Mixed-effects statistical models were used to assess the relationship between biological sex, APOE4 carrier status, surgery and anesthesia exposure, and the rate of change in cognitive test scores. RESULTS: When comparing all men (n = 89) and women (n = 164) who had surgery, there were no significant sex differences in postoperative cognitive outcomes. However, men with an APOE4 allele performed significantly worse on cognitive testing following surgery and anesthesia than women APOE4 carriers, even after adjusting for age, education level, and comorbidities. CONCLUSIONS: Older men with APOE4 allele may be more vulnerable to postoperative cognitive dysfunction than older women with APOE4 allele.