Neuropsychiatric Symptoms of Alzheimer's Disease: An Anatomic-Genetic Framework for Treatment Development.

BACKGROUND: Despite the burden on patients and caregivers, there are no approved therapies for the neuropsychiatric symptoms of Alzheimer's disease (NPS-AD). This is likely due to an incomplete understanding of the underlying mechanisms. OBJECTIVE: To review the neurobiological mechanisms of NPS-AD, including depression, psychosis, and agitation. METHODS: Understanding that genetic encoding gives rise to the function of neural circuits specific to behavior, we review the genetics and neuroimaging literature to better understand the biological underpinnings of depression, psychosis, and agitation. RESULTS: We found that mechanisms involving monoaminergic biosynthesis and function are likely key elements of NPS-AD and while current treatment approaches are in line with this, the lack of effectiveness may be due to contributions from additional mechanisms including neurodegenerative, vascular, inflammatory, and immunologic pathways. CONCLUSION: Within an anatomic-genetic framework, development of novel effective biological targets may engage targets within these pathways but will require a better understanding of the heterogeneity in NPS-AD.

Altered Angular Gyrus Resting State Functional Connectivity Associated with Financial Capacity in Mild Cognitive Impairment.

BACKGROUND: Financial capacity (FC) is a complex ability commonly impaired in older individuals with cognitive impairment; however, the underlying neural mechanisms are not well understood. OBJECTIVE: To assess resting state functional connectivity using functional magnetic resonance imaging (rs-fMRI) in individuals with mild cognitive impairment (MCI) and impaired FC compared to cognitively normal older adults. METHODS: rs-fMRI scans were obtained from individuals with MCI (N = 17) and normal older adults (N = 15). All participants completed the Financial Capacity Instrument Short Form (FCI-SF) and neuropsychological assessments. Based on previous findings, the left angular gyrus (lAG) was used as the seed region. Connectivity correlation coefficients were calculated for each seed-based connection that showed significantly altered connectivity. A Pearson's correlation was calculated between the connectivity correlation values from relevant regions and FC and other cognitive measures. RESULTS: A total of 26 brain regions showed significantly increased functional connectivity with the lAG. Of these regions, 14 were identified as relevant to higher-level cognitive function for analysis. Pearson's correlations showed a significant negative correlation between the FCI-SF total score and increased connectivity between the IAG and the right temporal fusiform cortex (rTFC) (r = -0.455, p = 0.009). CONCLUSION: Results showed a significant correlation between FC and increased functional connectivity between the lAG and the rTFC in cognitively normal older adults compared to participants with MCI. These exploratory findings suggest that cognitive functions play important roles in FC as the functional connectivity between the lAG and rTFC was not associated with other tests of executive or visuospatial cognition.

Study rationale and baseline data for pilot trial of dronabinol adjunctive treatment of agitation in Alzheimer's dementia (THC-AD).

Agitation is a common complication of Alzheimer's dementia (Agit-AD) associated with substantial morbidity, high healthcare service utilization, and adverse emotional and physical impact on care partners. There are currently no FDA-approved pharmacological treatments for Agit-AD. We present the study design and baseline data for an ongoing multisite, three-week, double-blind, placebo-controlled, randomized clinical trial of dronabinol (synthetic tetrahydrocannabinol [THC]), titrated to a dose of 10 mg daily, in 80 participants to examine the safety and efficacy of dronabinol as an adjunctive treatment for Agit-AD. Preliminary findings for 44 participants enrolled thus far show a predominately female, white sample with advanced cognitive impairment (Mini Mental Status Examination mean 7.8) and agitation (Neuropsychiatric Inventory-Clinician Agitation subscale mean 14.1). Adjustments to study design in light of the COVID-19 pandemic are described. Findings from this study will provide guidance for the clinical utility of dronabinol for Agit-AD. ClinicalTrials.gov Identifier: NCT02792257.

Cannabinoids for Agitation in Alzheimer's Disease.

Agitation is a common neuropsychiatric symptom of Alzheimer's disease (AD) that greatly impacts quality of life and amplifies caregiver burden. Agitation in AD may be associated with volume loss in the anterior cingulate cortex, posterior cingulate cortex, insula, amygdala, and frontal cortex, as well as with degeneration of monoaminergic neurotransmission, disrupted circadian rhythms, and frailty. Current pharmacologic options have troubling safety concerns and only modest efficacy. There is increasing interest in cannabinoids as promising agents due to preclinical and early clinical research that suggest cannabinoids can elicit anxiolytic, antidepressant, and/or anti-inflammatory effects. Cannabinoids may relieve agitation by regulating neurotransmitters, improving comorbidities and circadian rhythms, and increasing cerebral circulation. Here we discuss the possible contributory mechanisms for agitation in AD and the therapeutic relevance of cannabinoids, including CBD and THC.