The heritability of blood-based biomarkers related to risk of Alzheimer's disease in a population-based sample of early old-age men.

INTRODUCTION: Despite their increased application, the heritability of Alzheimer's disease (AD)-related blood-based biomarkers remains unexplored. METHODS: Plasma amyloid beta 40 (Aß40), Aß42, the Aß42/40 ratio, total tau (t-tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (µ = 67.0, SD = 2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them. RESULTS: Additive genetics explained 44% to 52% of Aß42, Aß40, t-tau, and NfL. The Aß42/40 ratio was not heritable. Aß40 and Aß42 were genetically near identical (rg  = 0.94). Both Aß40 and Aß42 were genetically correlated with NfL (rg  = 0.35 to 0.38), but genetically unrelated to t-tau. DISCUSSION: Except for Aß42/40, plasma biomarkers are heritable. Aß40 and Aß42 share mostly the same genetic influences, whereas genetic influences on plasma t-tau and NfL are largely unique in early old-age men. The absence of genetic associations between the Aßs and t-tau is not consistent with the amyloid cascade hypothesis.

A randomized, double-blind, placebo-controlled, repeated-dose pilot study of the safety, tolerability, and preliminary effects of a cannabidiol (CBD)- and cannabigerol (CBG)-based beverage powder to support recovery from delayed onset muscle soreness (DOMS).

BACKGROUND: Cannabinoid-containing products are marketed to athletes as promoting recovery, in spite of a lack of data on their safety and effects. This randomized, double-blind, placebo-controlled, repeated-dose pilot study tested the safety, tolerability, and preliminary effects on recovery of a formulation containing cannabidiol (CBD; 35 mg), cannabigerol (CBG; 50 mg), beta caryophyllene (BCP; 25 mg), branched-chain amino acids (BCAAs; 3.8 g), and magnesium citrate (420 mg). METHODS: Exercise-trained individuals (N = 40) underwent an experimental induction of delayed onset muscle soreness (DOMS) and completed follow-up visits 24-, 48-, and 72-hours post-DOMS. Participants were randomized to active or placebo formulation, and consumed the formulation twice per day for 3.5 days. RESULTS: There was one adverse event (AE) in the active group (diarrhea) and two AEs in placebo (dry mouth; eye rash/swollen eye). There was 100% self-reported compliance with formulation consumption across the two groups. For the primary outcome of interest, the estimate of effect for ratings of average soreness/discomfort 72 hours post-DOMS between active and placebo groups was -1.33 (85% confidence interval = -2.55, -0.10), suggesting moderate evidence of a treatment difference. The estimate of effect for the outcome of ratings of interference of soreness, discomfort, or stiffness on daily activities at work or home 48 hours post-DOMS was -1.82 (95% confidence interval = -3.64, -0.01), indicating a treatment difference of potential clinical importance. There was no significant effect between active and placebo groups on objective measures of recovery, sleep quality, or mood disturbance. CONCLUSIONS: The tested formulation reduced interference of DOMS on daily activities, demonstrating its improvement on a functional aspect of recovery.

A double-blind, randomized, placebo-controlled study of the safety and effects of CBN with and without CBD on sleep quality.

The present study sought to determine the effects of cannabinol (CBN) alone and in combination with cannabidiol (CBD) on sleep quality. This was a double-blind, randomized, placebo-controlled study conducted between May and November 2022. Participants were randomized to receive either (a) placebo, (b) 20 mg CBN, (c) 20 mg CBN + 10 mg CBD, (d) 20 mg CBN + 20 mg CBD, or (e) 20 mg CBN + 100 mg CBD for seven consecutive nights. Participants were 18-55 years of age who self-rated sleep quality as "very poor" or "poor." The primary endpoint was sleep quality, while secondary endpoints included sleep onset latency, number of awakenings, wake after sleep onset (WASO), overall sleep disturbance, and daytime fatigue. In a modified intent-to-treat analyses (N = 293), compared to placebo, 20 mg CBN demonstrated a nonsignificant but potentially meaningful effect on sleep quality (OR [95% CI] = 2.26 [0.93, 5.52], p = .082) and significantly reduced number of awakenings (95% CI [-0.96, -0.05], p = .025) and overall sleep disturbance (95% CI [-2.59, -0.14], p = .023). There was no difference from placebo among any group for sleep onset latency, WASO, or daytime fatigue (all p > .05). Individuals receiving 20 mg CBN demonstrated reduced nighttime awakenings and overall sleep disturbance relative to placebo, with no impact on daytime fatigue. The addition of CBD did not positively augment CBN treatment effects. No differences were observed for latency to sleep onset or WASO. Findings suggest 20 mg of CBN taken nightly may be helpful for improving overall sleep disturbance, including the number of times one wakes up throughout the night, without impacting daytime fatigue. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A Two-Phase, Dose-Ranging, Placebo-Controlled Study of the Safety and Preliminary Test of Acute Effects of Oral Δ8-Tetrahydrocannabivarin in Healthy Participants.

Introduction: Tetrahydrocannabivarin (THCV) is an understudied cannabinoid that appears to have effects that vary as a function of dose. No human study has evaluated the safety and nature of effects in a wide range of THCV doses. Methods: This was a two-phase, dose-ranging, placebo-controlled trial of the Δ8 isomer of oral THCV in healthy adults. Phase 1 utilized an unblinded, single-ascending dose design (n=3). Phase 2 used a double-blind, randomized, within-participant crossover design (n=18). Participants received single acute doses of placebo and 12.5, 25, 50, 100, and 200 mg of THCV. Safety measures and subjective and cognitive effects were assessed predose and up to 8 h postdose. Results: Most adverse events (AEs; 55/60) were mild. Euphoric mood was the most common AE. The 12.5, 25, and 200 mg doses produced significantly lower minimum times to complete the digit vigilance test (ps=0.01). The 25 mg dose showed elevations on mean ratings of "energetic" at 1-, 2-, and 4-h postdose, but the maximum postdose rating for this dose did not achieve statistical significance relative to placebo ([95% confidence interval]=3.2 [-0.5 to 6.9], p=0.116). The 100 and 200 mg doses showed elevations on ratings of "feel a drug effect" and "like the drug effect." Almost all urine drug screens (78/79) at 8 h postdose in the active THCV conditions tested positive for tetrahydrocannabinol (THC). Conclusion: All THCV doses displayed a favorable safety profile. Several THCV doses showed a preliminary signal for improved sustained attention, but the effect was not dose dependent. Though mild and not associated with impairment, THC-like effects were observed at higher THCV doses. Oral THCV-containing products could lead to positive urine drug screens for THC. ClinicalTrials.gov ID: NCT05210634.

Oral Cannabidiol Treatment in Two Postmenopausal Women with Osteopenia: A Case Series.

Introduction: Cannabidiol (CBD), a nonintoxicating cannabinoid, may be involved in bone remodeling, but human studies are limited. In this case series, we explored the effects of oral CBD administration on bone turnover. Materials and Methods: Two postmenopausal women with osteopenia (T-score=-1 to -2.5) were randomized to receive 100 or 300 mg CBD daily (oral, bis in die [twice per day]) for 12 weeks. Serum markers of bone resorption (carboxyl-terminal collagen crosslinks [CTx]) and bone formation (procollagen type 1 N-terminal propeptide [P1NP], bone-specific alkaline phosphatase [BSAP], and osteocalcin [OC]); safety measures; plasma concentrations of CBD and metabolites; sleep disturbance; symptoms of depression, anxiety, and stress; and quality of life, were assessed. Results: CBD was well tolerated, with no clinically significant change in vital signs, hematology, chemistry, or urinalysis, and no adverse events reported. Reductions (% change vs. baseline) in CTx (-8.5%, -28.1%), P1NP (-9.9%, -39.5%), BSAP (-12.7%, -74.8%), and OC (-16.0%, -6.7%) were observed after 12 weeks of oral administration of 100 or 300 mg CBD daily, respectively. The two participants self-reported consuming 95.3% and 98.8% of CBD doses, respectively. CBD and select metabolites were measurable in plasma after 4 and 12 weeks of CBD treatment. No notable changes in sleep disturbance, depression, anxiety, stress, or quality of life were observed. Conclusions: CBD was well tolerated after 12 weeks of twice-daily oral administration and was associated with reduction in measured markers of bone turnover. Compliance with CBD treatment was good. Large-scale randomized clinical trials into the bone protective effects of CBD in postmenopausal women are warranted.

Sex Differences in the Safety and Subjective Effects of Two Oral Δ9-Tetrahydrocannabinol-Containing Cannabis Products over Multiple Doses Among Healthy Adults.

Introduction: A growing number of females report consuming cannabis products. There is a paucity of data on sex differences in safety and subjective effects after repeated use of varying oral doses of Δ9-tetrahydrocannabinol (THC; the primary psychoactive constituent of cannabis). Materials and Methods: Data were from two randomized, double-blind, placebo-controlled, multiple-dose, between-subject trials of two THC-containing oral cannabis products. Healthy adults received placebo, low-dose THC (∼2.5 or ∼5 mg per dose), or high-dose THC (∼7.5 or ∼10 mg per dose) twice daily for 7 days. There were 38 males (8 placebo, 17 low-dose THC, 13 high-dose THC) and 46 females (8 placebo, 17 low-dose THC, 21 high-dose THC). Analyses compared adverse events (AEs) and subjective effects between males and females, by THC dose. Results: In the placebo and low-dose THC groups, there were no sex differences in the relative rate of AEs. In the high-dose THC group, females versus males reported 3.08 (95% confidence interval [CI]=1.31-8.33) times as many AEs. There were no significant interactions of sex×low-dose THC group for any subjective effect. In the high-dose THC group, females versus males reported greater "relaxed" ratings (b=15.14, 95% CI=1.44-28.84, p=0.027), whereas in the placebo group, males versus females reported greater ratings of "liking the effect" (b=-30.01, 95% CI=2.77-57.26, p=0.028). Although analyses were underpowered to assess the sex×THC dose×day interaction, the initial sex disparity in AEs and some subjective effects in the high-dose THC group appeared to shrink after the first day. Conclusions: In this exploratory analysis, sex differences in some responses to oral THC were nuanced. Females appeared more sensitive than males to AEs and some subjective effects at higher but not lower doses. Males reported higher ratings than females on some subjective effects in response to placebo. Initial sex differences in response to higher doses of oral THC tended to diminish over 7 days of dosing. If replicated, findings could help inform sex-specific dosing strategies of medical cannabis products and could help educate medical cannabis patients on any temporality of effects.

Sex Differences in the Pharmacokinetics of Cannabidiol and Metabolites Following Oral Administration of a Cannabidiol-Dominant Cannabis Oil in Healthy Adults.

Introduction: Oral cannabidiol (CBD) product use is increasingly growing among women; however, there is a lack of data on sex differences in the pharmacokinetics (PKs) of CBD and its primary metabolites, 7-hydroxy-CBD (7-OH-CBD) and 7-carboxy-CBD (7-COOH-CBD), after repeated doses. Materials and Methods: The present study is a secondary analysis of data from a randomized, double-blind, placebo-controlled multiple-dose trial of a commercially available, CBD-dominant oral cannabis product. Healthy participants (n=17 males and 15 females) were randomized to receive 120 to 480 mg of CBD daily for 7 days. Dosing groups were pooled for all analyses due to sample size limitations. Analyses compared plasma PK parameters by sex, day, and sex×day. Results: For raw PK parameters for CBD and metabolites, there were no statistically significant effects of sex×day or sex (all p-values >0.05). For metabolite-to-parent ratios (MPRs) of AUC0-t, there were significant effects of the sex×day interactions for 7-OH-CBD (F=6.89, p=0.016) and 7-COOH-CBD (F=5.96, p=0.021). For 7-OH-CBD, follow-up analyses showed significant simple effects of day within females (t=4.13, p<0.001), but not within males (t=0.34, p=0.73), such that 7-OH-CBD MPRs increased significantly from day 1 to 7 for females, but not for males. For 7-COOH-CBD, follow-up analyses revealed significant simple effects of day within females (t=8.24, p<0.001) and males (t=5.20, p<0.001), therefore 7-COOH-CBD MPRs increased significantly from day 1 to 7 in both sexes, but the increase was significantly greater among females than among males. Within dosing days, there were no statistically significant simple effects of sex on MPRs of 7-OH-CBD or 7-COOH-CBD. Conclusions: Females exhibited greater relative exposure to CBD metabolites in plasma over time, which may reflect sex differences in CBD metabolism or elimination. Further research assessing the safety implications of higher relative exposure to CBD metabolites over longer periods of time is warranted to mirror typical consumer use patterns.

Longitudinal Relationship between the Introduction of Medicinal Cannabis and Polypharmacy: An Australian Real-World Evidence Study.

Background: Recent studies recommend medicinal cannabis (MC) as a potential treatment for chronic pain (CP) when conventional therapies are not successful; however, data from Australia is limited. This real-world evidence study explored how the introduction of MC related to concomitant medication use over time. Long-term safety also was examined. Methods: Data were collected by the Emerald Clinics (a network of seven clinics located across Australia) as part of routine practice from Jan 2020 toJan 2021. Medications were classified by group: antidepressants, benzodiazepines, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and total number of medications. Adverse events (AEs) were collected at each visit and subsequently coded using the Medical Dictionary for Regulatory Activities version 23 into the system organ class (SOC) and preferred term (PT). A total of 535 patients were analyzed. Results: The most common daily oral dose was 10 mg for delta-9-tetrahydrocannabinol (THC) and 15 mg for cannabidiol (CBD). With the introduction of MC, patients' total number of medications consumed decreased over the course of one year; significant reductions in NSAIDs, benzodiazepines, and antidepressants were observed (p < .001). However, the number of prescribed opioid medications did not differ from baseline to the end of one year (p = .49). Only 6% of patients discontinued MC treatment during the study. A total of 600 AEs were reported in 310 patients during the reporting period and 97% of them were classified as nonserious. Discussion. Though observational in nature, these findings suggest MC is generally well-tolerated, consistent with the previous literature, and may reduce concomitant use of some medications. Due to study limitations, concomitant medication reductions cannot be causally attributed to MC. Nevertheless, these data underscore early signals that warrant further exploration in randomized trials.

A double-blind, randomized, placebo-controlled test of the effects of cannabidiol on fear elicited by a 10% carbon dioxide-enriched air breathing challenge.

OBJECTIVE: A single administration of cannabidiol (CBD) can reduce anxiety during social anxiety inductions. No study, however, has evaluated the impact of CBD on fear responding among humans. METHOD: A double-blind, randomized, placebo-controlled trial was undertaken to address this gap in the literature. Specifically, the current study tested a single oral administration of CBD (either 150 mg, 300 mg, or 600 mg), compared to placebo, for reducing fear reactivity to a well-established 5-min administration of 10% carbon dioxide (CO2)-enriched air biological challenge. CBD was administered 90 min prior to the challenge. Participants were 61 healthy young adults who self-reported fear continuously during the challenge. Heart rate also was continuously monitored, and panic symptoms were self-reported using the Diagnostic Sensations Questionnaire immediately following the procedure. RESULTS: Results indicated no effect of condition on self-reported fear, panic symptoms, or heart rate. CONCLUSION: This is the first study to document that CBD does not reduce fear reactivity in humans, thereby representing an important extension to research on the effects of CBD.

Medical cannabis authorization patterns, safety, and associated effects in older adults.

BACKGROUND: Use of medical cannabis is increasing among older adults. However, few investigations have examined cannabis use in this population. METHODS: We assessed the authorization patterns, safety, and effects of medical cannabis in a sub-analysis of 201 older adults (aged ≥ 65 years) who completed a 3-month follow-up during this observational study of patients who were legally authorized a medical cannabis product (N = 67). Cannabis authorization patterns, adverse events (AEs), Edmonton Symptom Assessment Scale-revised (ESAS-r), and Brief Pain Inventory Short Form (BPI-SF) data were collected. RESULTS: The most common symptoms for which medical cannabis was authorized were pain (159, 85.0%) and insomnia (9, 4.8%). At baseline and at the 3-month follow-up, cannabidiol (CBD)-dominant products were authorized most frequently (99, 54%), followed by balanced products (76, 42%), and then delta-9-tetrahydrocannabinol (THC)-dominant products (8, 4.4%). The most frequent AEs were dizziness (18.2%), nausea (9.1%), dry mouth (9.1%), and tinnitus (9.1%). Significant reductions in ESAS-r scores were observed over time in the domains of drowsiness (p = .013) and tiredness (p = .031), but not pain (p = .106) or well-being (p = .274). Significant reductions in BPI-SF scores over time were observed for worst pain (p = .010), average pain (p = .012), and overall pain severity (p = 0.009), but not pain right now (p = .052) or least pain (p = .141). CONCLUSIONS: Overall, results suggest medical cannabis was safe, well-tolerated, and associated with clinically meaningful reductions in pain in this sample of older adults. However, the potential bias introduced by the high subject attrition rate means that all findings should be interpreted cautiously and confirmed by more rigorous studies.

Cognitive Reserve and Related Constructs: A Unified Framework Across Cognitive and Brain Dimensions of Aging.

Cognitive reserve and related constructs are valuable for aging-related research, but consistency and clarification of terms is needed as there is still no universally agreed upon nomenclature. We propose a new set of definitions for the concepts of reserve, maintenance, and resilience, and we invoke parallel concepts for each that are applicable to cognition and to brain. Our definitions of reserve and resilience correspond reasonably well to dictionary definitions of these terms. We demonstrate logical/methodological problems that arise from incongruence between commonly used conceptual and operational definitions. In our view, cognitive reserve should be defined conceptually as one's total cognitive resources at a given point in time. IQ and education are examples of common operational definitions (often referred to as proxies) of cognitive reserve. Many researchers define cognitive reserve conceptually as a property that allows for performing better than expected cognitively in the face of aging or pathology. Performing better than expected is demonstrated statistically by interactions in which the moderator is typically IQ or education. The result is an irreconcilable situation in which cognitive reserve is both the moderator and the moderation effect itself. Our proposed nomenclature resolves this logical inconsistency by defining performing better than expected as cognitive resilience. Thus, in our usage, we would test the hypothesis that high cognitive reserve confers greater cognitive resilience. Operational definitions (so-called proxies) should not conflate factors that may influence reserve-such as occupational complexity or engagement in cognitive activities-with cognitive reserve itself. Because resources may be depleted with aging or pathology, one's level of cognitive reserve may change over time and will be dependent on when assessment takes place. Therefore, in addition to cognitive reserve and cognitive resilience, we introduce maintenance of cognitive reserve as a parallel to brain maintenance. If, however, education is the measure of reserve in older adults, it precludes assessing change or maintenance of reserve. Finally, we discuss consideration of resistance as a subcategory of resilience, reverse causation, use of residual scores to assess performing better than expected given some adverse factor, and what constitutes high vs. low cognitive reserve across different studies.

Cognitive practice effects delay diagnosis of MCI: Implications for clinical trials.

INTRODUCTION: Practice effects (PEs) on cognitive tests obscure decline, thereby delaying detection of mild cognitive impairment (MCI). Importantly, PEs may be present even when there are performance declines, if scores would have been even lower without prior test exposure. We assessed how accounting for PEs using a replacement-participants method impacts incident MCI diagnosis. METHODS: Of 889 baseline cognitively normal (CN) Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 722 returned 1 year later (mean age = 74.9 ± 6.8 at baseline). The scores of test-naïve demographically matched "replacement" participants who took tests for the first time were compared to returnee scores at follow-up. PEs-calculated as the difference between returnee follow-up scores and replacement participants scores-were subtracted from follow-up scores of returnees. PE-adjusted cognitive scores were then used to determine if individuals were below the impairment threshold for MCI. Cerebrospinal fluid amyloid beta, phosphorylated tau, and total tau were used for criterion validation. In addition, based on screening and recruitment numbers from a clinical trial of amyloid-positive individuals, we estimated the effect of earlier detection of MCI by accounting for cognitive PEs on a hypothetical clinical trial in which the key outcome was progression to MCI. RESULTS: In the ADNI sample, PE-adjusted scores increased MCI incidence by 19% (P < .001), increased proportion of amyloid-positive MCI cases (+12%), and reduced proportion of amyloid-positive CNs (-5%; P's < .04). Additional calculations showed that the earlier detection and increased MCI incidence would also substantially reduce necessary sample size and study duration for a clinical trial of progression to MCI. Cost savings were estimated at ≈$5.41 million. DISCUSSION: Detecting MCI as early as possible is of obvious importance. Accounting for cognitive PEs with the replacement-participants method leads to earlier detection of MCI, improved diagnostic accuracy, and can lead to multi-million-dollar cost reductions for clinical trials.

Associations between depression and cardiometabolic health: A 27-year longitudinal study.

BACKGROUND: Clarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems. METHODS: The study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse ('baseline') and the longitudinal Vietnam Era Twin Study of Aging ('follow-up'). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)]. RESULTS: Total depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07-1.57), erectile dysfunction (OR 1.32, 95% CI 1.10-1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04-1.53), and sleep apnea (OR 1.40, 95% CI 1.13-1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09-1.60). CONCLUSIONS: A history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.

Paradoxical cognitive trajectories in men from earlier to later adulthood.

Because longitudinal studies of aging typically lack cognitive data from earlier ages, it is unclear how general cognitive ability (GCA) changes throughout the life course. In 1173 Vietnam Era Twin Study of Aging (VETSA) participants, we assessed young adult GCA at average age 20 and current GCA at 3 VETSA assessments beginning at average age 56. The same GCA index was used throughout. Higher young adult GCA and better GCA maintenance were associated with stronger specific cognitive abilities from age 51 to 73. Given equivalent GCA at age 56, individuals who had higher age 20 GCA outperformed those whose GCA remained stable in terms of memory, executive function, and working memory abilities from age 51 to 73. Thus, paradoxically, despite poorer maintenance of GCA, high young adult GCA still conferred benefits. Advanced predicted brain age and the combination of elevated vascular burden and APOE-ε4 status were associated with poorer maintenance of GCA. These findings highlight the importance of distinguishing between peak and current GCA for greater understanding of cognitive aging.

Higher cerebrospinal fluid tau is associated with history of traumatic brain injury and reduced processing speed in Vietnam-era veterans: A Department of Defense Alzheimer's Disease Neuroimaging Initiative (DOD-ADNI) study.

INTRODUCTION:  Our goal was to determine whether cognitive and cerebrospinal fluid (CSF) markers of tau and amyloid beta 1-42 (Aß42) differ between Vietnam-era veterans with and without history of traumatic brain injury (TBI) and whether TBI moderates the association between CSF markers and neurocognitive functioning. METHODS:  A total of 102 male participants (52 TBI, 50 military controls [MCs]; mean age = 68) were included. Levels of CSF Aß42, tau phosphorylated at the threonine 181 position (p-tau), and total tau (t-tau) were quantified. Group differences in CSF markers and cognition as well as the moderating effect of TBI on CSF and cognition associations were explored. RESULTS:  Relative to MCs, the TBI group showed significantly higher p-tau (P = .01) and t-tau (P = .02), but no differences in amyloid (P = .09). TBI history moderated the association between CSF tau and performance on a measure of processing speed (t-tau: P  = .04; p-tau: P  = .02). DISCUSSION:  Tau accumulation may represent a mechanism of dementia risk in older veterans with remote TBI.

12-year prediction of mild cognitive impairment aided by Alzheimer's brain signatures at mean age 56.

Neuroimaging signatures based on composite scores of cortical thickness and hippocampal volume predict progression from mild cognitive impairment to Alzheimer's disease. However, little is known about the ability of these signatures among cognitively normal adults to predict progression to mild cognitive impairment. Towards that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: (i) a validated MRI-derived Alzheimer's disease signature based on cortical thickness and hippocampal volume in cognitively normal middle-aged adults would predict progression to mild cognitive impairment; and (ii) a novel grey matter mean diffusivity signature would be a better predictor than the thickness/volume signature. This cohort study was part of the Vietnam Era Twin Study of Aging. Concurrent analyses compared cognitively normal and mild cognitive impairment groups at each of three study waves (ns = 246-367). Predictive analyses included 169 cognitively normal men at baseline (age = 56.1, range = 51-60). Our previously published thickness/volume signature derived from independent data, a novel mean diffusivity signature using the same regions and weights as the thickness/volume signature, age, and an Alzheimer's disease polygenic risk score were used to predict incident mild cognitive impairment an average of 12 years after baseline (follow-up age = 67.2, range = 61-71). Additional analyses adjusted for predicted brain age difference scores (chronological age minus predicted brain age) to determine if signatures were Alzheimer-related and not simply ageing-related. In concurrent analyses, individuals with mild cognitive impairment had higher (worse) mean diffusivity signature scores than cognitively normal participants, but thickness/volume signature scores did not differ between groups. In predictive analyses, age and polygenic risk score yielded an area under the curve of 0.74 (sensitivity = 80.00%; specificity = 65.10%). Prediction was significantly improved with addition of the mean diffusivity signature (area under the curve = 0.83; sensitivity = 85.00%; specificity = 77.85%; P = 0.007), but not with addition of the thickness/volume signature. A model including both signatures did not improve prediction over a model with only the mean diffusivity signature. Results held up after adjusting for predicted brain age difference scores. The novel mean diffusivity signature was limited by being yoked to the thickness/volume signature weightings. An independently derived mean diffusivity signature may thus provide even stronger prediction. The young age of the sample at baseline is particularly notable. Given that the brain signatures were examined when participants were only in their 50 s, our results suggest a promising step towards improving very early identification of Alzheimer's disease risk and the potential value of mean diffusivity and/or multimodal brain signatures.

Authorization Patterns, Safety, and Effectiveness of Medical Cannabis in Quebec.

Introduction: Despite increasing demand for data, little is known about the authorization patterns, safety, and effectiveness of medical cannabis products. Materials and Methods: We conducted a 2 year observational study of adult patients who were legally authorized a medical cannabis product from a single licensed producer; we captured and analyzed authorized cannabis use patterns by cannabinoid profile (tetrahydrocannabinol [THC]-dominant; cannabidiol [CBD]-dominant; and balanced (THC:CBD) and clinical outcomes using standardized outcome measures every 3 months for 12 months at a network of medical cannabis clinics in Quebec, Canada. Results: We recruited 585 patients (average age 56.5 years), of whom 61% identified as female and 85% reported pain as their primary complaint. Over 12 months, there was a significant increase in the number of products authorized (Z=2.59, p=0.01). The proportion of authorizations for a THC-dominant or CBD-dominant product increased relative to the proportion of authorizations for a balanced (THC:CBD) product (all p<0.01). Symptom improvement over time was observed for pain, tiredness, drowsiness, anxiety, and well-being. Patients authorized THC-dominant products exhibited less symptom improvement for anxiety and well-being relative to those authorized CBD-dominant or balanced (THC:CBD) products. Medical cannabis was well tolerated across all product profiles. Conclusion: These real-world data reveal changes in medical cannabis authorization patterns and suggest that symptom improvement may vary by cannabinoid profile over 12 months of follow-up.

MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction.

INTRODUCTION: The locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression. METHODS: Participants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction. RESULTS: Heritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction. DISCUSSION: Reduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

Delineation of Apathy Subgroups in Parkinson's Disease: Differences in Clinical Presentation, Functional Ability, Health-related Quality of Life, and Caregiver Burden.

BACKGROUND: Apathy is a prevalent, multidimensional neuropsychiatric condition in Parkinson's disease (PD). Several authors have proposed apathy subtypes in PD, but no study has examined the classification of PD patients into distinct apathy subtypes, nor has any study examined the clinical utility of doing so. OBJECTIVES: The current study used a data-driven approach to explore the existence and associated clinical characteristics of apathy subtypes in PD. METHOD: The Apathy Scale (AS) was administered to 157 non-demented individuals with PD. Participants were classified into apathy subgroups through cluster analysis. Differences among apathy subtypes on external clinical indicators were explored across apathy subgroups. RESULTS: Individuals with PD were classified into three subgroups: a Non-Apathetic group with low levels of apathy symptoms, a Low Interest/Energy group, characterized by elevated symptoms of low interest/energy and minimal low initiation/emotional indifference symptoms, and a Low Initiation group, characterized by an absence of low interest/energy symptoms and elevated levels of low initiation/emotional indifference symptoms. Both Low Interest/Energy and Low Initiation groups exhibited worse depression, fatigue, anxiety, health-related quality of life, and caregiver burden than the Non-Apathetic subgroup. The Low Initiation group exhibited worse overall cognition, emotional well-being, state anxiety, communicative ability, and functional ability than the Low Interest/Energy group. Importantly, disease-related characteristics did not differ across apathy symptom subgroups. CONCLUSIONS: Non-demented PD patients can be separated into distinct apathy symptom subgroups, which are differentially associated with important clinical variables. Apathy subgroup membership may reflect disruption to different neural systems independent of disease progression.