BDNF Val66Met moderates episodic memory decline and tau biomarker increases in early sporadic Alzheimer's disease.

OBJECTIVE: Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been shown to moderate rates of cognitive decline in preclinical sporadic Alzheimer's disease (AD; i.e., Aß + older adults), and pre-symptomatic autosomal dominant Alzheimer's disease (ADAD). In ADAD, Met66 was also associated with greater increases in CSF levels of total-tau (t-tau) and phosphorylated tau (p-tau181). This study sought to determine the extent to which BDNF Val66Met is associated with changes in episodic memory and CSF t-tau and p-tau181 in Aß + older adults in early-stage sporadic AD. METHOD: Aß + Met66 carriers (n = 94) and Val66 homozygotes (n = 192) enrolled in the Alzheimer's Disease Neuroimaging Initiative who did not meet criteria for AD dementia, and with at least one follow-up neuropsychological and CSF assessment, were included. A series of linear mixed models were conducted to investigate changes in each outcome over an average of 2.8 years, covarying for CSF Aß42, APOE ε4 status, sex, age, baseline diagnosis, and years of education. RESULTS: Aß + Met66 carriers demonstrated significantly faster memory decline (d = 0.33) and significantly greater increases in CSF t-tau (d = 0.30) and p-tau181 (d = 0.29) compared to Val66 homozygotes, despite showing equivalent changes in CSF Aß42. CONCLUSIONS: These findings suggest that reduced neurotrophic support, which is associated with Met66 carriage, may increase vulnerability to Aß-related tau hyperphosphorylation, neuronal dysfunction, and cognitive decline even prior to the emergence of dementia. Additionally, these findings highlight the need for neuropsychological and clinicopathological models of AD to account for neurotrophic factors and the genes which moderate their expression.

Daily Cannabidiol Administration for 10 Weeks Modulates Hippocampal and Amygdalar Resting-State Functional Connectivity in Cannabis Users: A Functional Magnetic Resonance Imaging Open-Label Clinical Trial.

Introduction: Cannabis use is associated with brain functional changes in regions implicated in prominent neuroscientific theories of addiction. Emerging evidence suggests that cannabidiol (CBD) is neuroprotective and may reverse structural brain changes associated with prolonged heavy cannabis use. In this study, we examine how an ∼10-week exposure of CBD in cannabis users affected resting-state functional connectivity in brain regions functionally altered by cannabis use. Materials and Methods: Eighteen people who use cannabis took part in a ∼10 weeks open-label pragmatic trial of self-administered daily 200 mg CBD in capsules. They were not required to change their cannabis exposure patterns. Participants were assessed at baseline and post-CBD exposure with structural magnetic resonance imaging (MRI) and a functional MRI resting-state task (eyes closed). Seed-based connectivity analyses were run to examine changes in the functional connectivity of a priori regions-the hippocampus and the amygdala. We explored if connectivity changes were associated with cannabinoid exposure (i.e., cumulative cannabis dosage over trial, and plasma CBD concentrations and Δ9-tetrahydrocannabinol (THC) plasma metabolites postexposure), and mental health (i.e., severity of anxiety, depression, and positive psychotic symptom scores), accounting for cigarette exposure in the past month, alcohol standard drinks in the past month and cumulative CBD dose during the trial. Results: Functional connectivity significantly decreased pre-to-post the CBD trial between the anterior hippocampus and precentral gyrus, with a strong effect size (d=1.73). Functional connectivity increased between the amygdala and the lingual gyrus pre-to-post the CBD trial, with a strong effect size (d=1.19). There were no correlations with cannabinoids or mental health symptom scores. Discussion: Prolonged CBD exposure may restore/reduce functional connectivity differences reported in cannabis users. These new findings warrant replication in a larger sample, using robust methodologies-double-blind and placebo-controlled-and in the most vulnerable people who use cannabis, including those with more severe forms of Cannabis Use Disorder and experiencing worse mental health outcomes (e.g., psychosis, depression).

Effects of cannabinoids on resting state functional brain connectivity: A systematic review.

Cannabis products are widely used for medical and non-medical reasons worldwide and vary in content of cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Resting state functional connectivity offers a powerful tool to investigate the effects of cannabinoids on the human brain. We systematically reviewed functional neuroimaging evidence of connectivity during acute cannabinoid administration. A pre-registered (PROSPERO ID: CRD42020184264) systematic review of 13 studies comprising 318 participants (mean age of 25 years) was conducted and reported using the PRISMA checklist. During THC and THCv exposure vs placebo reduced connectivity with the NAcc was widely reported. Limited evidence shows that such effects are offset by co-administration of CBD. NAcc-frontal region connectivity was associated with intoxication levels. Cannabis intoxication vs placebo was associated with lower striatal-ACC connectivity. CBD and CBDv vs placebo were associated with both higher and lower connectivity between striatal-prefrontal/other regions. Overall, cannabis and cannabinoids change functional connectivity in the human brain during resting state as a function of the type of cannabinoid examined.