Deep brain stimulation of the amygdala for treatment-resistant combat post-traumatic stress disorder: Long-term results.

Deep brain stimulation (DBS) holds promise for neuropsychiatric conditions where imbalance in network activity contributes to symptoms. Treatment-resistant Combat post-traumatic stress disorder (TR-PTSD) is a highly morbid condition and 50% of PTSD sufferers fail to recover despite psychotherapy or pharmacotherapy. Reminder-triggered symptoms may arise from inadequate top-down ventromedial prefrontal cortex (vmPFC) control of amygdala reactivity. Here, we report long-term data on two TR-PTSD participants from an investigation utilizing high-frequency amygdala DBS. The two combat veterans were implanted bilaterally with quadripolar electrodes targeting the basolateral amygdala. Following a randomized staggered onset, patients received stimulation with adjustments based on PTSD symptom severity for four years while psychiatric and neuropsychiatric symptoms, neuropsychological performance, and electroencephalography were systematically monitored. Evaluation of vmPFC-Amygdala network engagement was assessed with 18FDG positron emission tomography (PET). CAPS-IV scores varied over time, but improved 55% from 119 at baseline to 53 at 4-year study endpoint in participant 1; and 44%, from 68 to 38 in participant 2. Thereafter, during 5 and 1.5 years of subsequent clinical care respectively, long-term bilateral amygdala DBS was associated with additional, clinically significant symptomatic and functional improvement. There were no serious stimulation-related adverse psychiatric, neuropsychiatric, neuropsychological, neurological, or neurosurgical effects. In one subject, symptomatic improvement was associated with an intensity-dependent reduction in amygdala theta frequency power. In our two participants, FDG-PET findings were inconclusive regarding the hypothesized mechanism of suppression of amygdala hyperactivity. Our findings encourage further research to confirm and extend our preliminary observations.

Visit-To-Visit Blood Pressure Variability and Subthreshold Depressive Symptoms in Older Adults.

OBJECTIVES: Depression is related to increased risk for dementia, possibly through links with cerebrovascular disease. Blood pressure variability is an emerging risk factor for cerebrovascular disease and dementia, but relationships with affective symptoms remain understudied. DESIGN: Retrospective analysis of prospective cohort study. SETTING: Alzheimer's Disease Neuroimaging Initiative. PARTICIPANTS: 505 older adults without history of dementia or recent depression underwent three to four blood pressure measurements over 12 months and completed a self-report measure of depressive symptoms (Geriatric Depression Scale - 15 Item) at study baseline and 24-months follow-up. MEASUREMENTS: Blood pressure variability was calculated as variability independent of mean and maximum minus minimum. Regression models investigated relationships between blood pressure variability and severity of self-reported depressive symptoms at 24-months follow-up after controlling for several variables, including average blood pressure, antihypertensive use, antidepressant use, and baseline depressive symptom severity. RESULTS: Elevated diastolic blood pressure variability was related to greater total depressive symptom score at follow-up (ß = .16 [95% CI 0.02, .30]; p = 0.03), with specific contribution from increased severity of symptoms of dysphoria (odds ratio = 1.35 [95% CI 1.07, 1.75]; p = 0.02). Blood pressure variability was not significantly related to other symptom subscales, including those reflecting life satisfaction or withdrawal. CONCLUSIONS: Findings suggest that elevated diastolic blood pressure variability is related to subthreshold depressive symptomatology in older adults without history of dementia or recent depression, independent of average blood pressure. Blood pressure variability may be an understudied vascular risk factor linked with depression and cognitive impairment, with potential therapeutic implications.

Cholinergic receptor binding in unimpaired older adults, mild cognitive impairment, and Alzheimer's disease dementia.

BACKGROUND: Cholinergic neurotransmitter system dysfunction contributes to cognitive impairment in Alzheimer's disease and other syndromes. However, the specific cholinergic mechanisms and brain structures involved, time course of alterations, and relationships with specific cognitive deficits are not well understood. METHODS: This study included 102 older adults: 42 cognitively unimpaired (CU), 28 with mild cognitive impairment (MCI), and 32 with Alzheimer's disease (AD) dementia. Each participant underwent a neuropsychological assessment. Regional brain α4ß2 nicotinic cholinergic receptor binding (VT/fp) was measured using 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and PET imaging. Voxel-wise analyses of group differences were performed. Relationships between receptor binding and cognition, age, and cholinesterase inhibitor medication use were assessed using binding values in six prespecified regions of interest. RESULTS: SPM analysis showed the group VT/fp binding differences in the bilateral entorhinal cortex, hippocampus, insula, anterior cingulate, thalamus, and basal ganglia (p < .05, FWE-corrected). Pairwise comparisons revealed lower binding in the AD group compared to the CU group in similar regions. Binding in the entorhinal cortex was lower in the MCI group than in the CU group; binding in the hippocampus was lower in the AD group than in the MCI group. AD participants taking cholinesterase inhibitor medication had lower 2FA binding in the bilateral hippocampus and thalamus compared to those not taking medication. In the CU group, age was negatively associated with 2FA binding in each region of interest (rs = - .33 to - .59, p < .05 for each, uncorrected). Attention, immediate recall, and delayed recall scores were inversely associated with 2FA binding in most regions across the full sample. In the combined group of CU and MCI participants, attention was inversely associated with 2FA binding in most regions, beyond the effect of hippocampal volume. CONCLUSIONS: Nicotinic cholinergic receptor binding in specific limbic and subcortical regions is lower in MCI and further reduced in AD dementia, compared to CU older adults, and is related to cognitive deficits. Cognitive decline with age may be a consequence of reduced cholinergic receptor density or binding affinity that may also promote vulnerability to other Alzheimer's processes. Contemporary modification of the "cholinergic deficit" of aging and AD may reveal opportunities to prevent or improve clinical symptoms.

Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials.

Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs. This review focused on 4 key areas: 1) pre-dementia states; 2) assessment; 3) mechanisms/biomarkers and 4) treatment/intervention efficacy. Considerable progress has been made in understanding apathy as a treatment target and appreciating pharmacological and non-pharmacological apathy treatment interventions. Areas requiring greater investigation include: diagnostic procedures, symptom measurement, understanding the biological mechanisms/biomarkers of apathy, and a well-formed approach to the development of treatment strategies. A better understanding of the subdomains and biological mechanisms of apathy will advance apathy as a treatment target for clinical trials.

Trial of Pimavanserin in Dementia-Related Psychosis.

BACKGROUND: Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT2A inverse agonist and antagonist pimavanserin on psychosis related to various causes of dementia are not clear. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. The primary end point, assessed in a time-to-event analysis, was a relapse of psychosis as defined by any of the following: an increase of at least 30% in the SAPS-H+D score and a CGI-I score of 6 (much worse) or 7 (very much worse), hospitalization for dementia-related psychosis, stopping of the trial regimen or withdrawal from the trial for lack of efficacy, or use of antipsychotic agents for dementia-related psychosis. RESULTS: Of the 392 patients in the open-label phase, 41 were withdrawn for administrative reasons because the trial was stopped for efficacy; of the remaining 351 patients, 217 (61.8%) had a sustained response, of whom 105 were assigned to receive pimavanserin and 112 to receive placebo. A relapse occurred in 12 of 95 patients (13%) in the pimavanserin group and in 28 of 99 (28%) in the placebo group (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.73; P = 0.005). During the double-blind phase, adverse events occurred in 43 of 105 patients (41.0%) in the pimavanserin group and in 41 of 112 (36.6%) in the placebo group. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation occurred with pimavanserin. CONCLUSIONS: In a trial that was stopped early for efficacy, patients with dementia-related psychosis who had a response to pimavanserin had a lower risk of relapse with continuation of the drug than with discontinuation. Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis. (Funded by Acadia Pharmaceuticals; HARMONY ClinicalTrials.gov number, NCT03325556.).

Short-term Psychological Outcomes of Disclosing Amyloid Imaging Results to Research Participants Who Do Not Have Cognitive Impairment.

Importance: The goal of preclinical Alzheimer disease (AD) clinical trials is to move diagnosis and treatment to presymptomatic stages, which will require biomarker testing and disclosure. Objective: To assess the short-term psychological outcomes of disclosing amyloid positron emission tomography results to older adults who did not have cognitive impairment. Design, Setting, and Participants: This observational study included participants who were screening for a multisite randomized clinical trial that began on February 28, 2014, and is anticipated to be completed in 2022. Participants aged 65 to 85 years who had no known cognitive impairments underwent an amyloid positron emission tomography scan and learned their result from an investigator who used a protocol-specified process that included prescan education and psychological assessments. This report compares participants with elevated amyloid levels with at least 1 available outcome measure with participants who did not have elevated amyloid levels who enrolled in an observational cohort study and received further evaluations. Data were collected from April 2014 to December 2017 and analyzed from March 2019 to October 2019. Exposures: A personal biomarker result described as either an elevated or not elevated amyloid level. Main Outcomes and Measures: To assess the immediate and short-term psychological outcome of disclosure, the following validated measures were used: the Geriatric Depression Scale, the state items from the State-Trait Anxiety Inventory, and the Columbia Suicide Severity Rating Scale, as well as the Concerns About AD Scale and the Future Time Perspective Scale to assess changes in participants' perceived risk for AD and perceived remaining life span, respectively. Results: A total of 1167 participants with elevated amyloid levels and 538 participants with not elevated amyloid levels were included. Participants had a mean (SD) age of 71.5 (4.7) years, 1025 (60.1%) were women, and most were white (1611 [94.5%]) and non-Latino (1638 [96.1%]). Compared with participants who learned that they had a not elevated amyloid result, individuals who learned of an elevated amyloid result were no more likely to experience short-term increases in depression (mean [SD] change in the Geriatric Depression Scale score, 0.02 [1.3] vs 0.04 [1.3]; P = .90), anxiety (mean [SD] change in State-Trait Anxiety Inventory score, -0.02 [3.2] vs -0.15 [3.0]; P = .65), or suicidality (mean [SD] change in the Columbia Suicide Severity Rating Scale score, 0.0 [0.4] vs -0.01 [0.5]; P = .67). Participants with elevated amyloid levels had increased Concern About AD scores (raw change in scores: elevated amyloid group, 0.8 [3.9]; not elevated amyloid group, -0.4 [3.8]; P < .001). Participants with not elevated amyloid levels experienced a slight increase in Future Time Perspective score(mean [SD] score, 1.15 [7.4] points; P < .001); there was no change in time perspective among those receiving an elevated amyloid result (mean [SD] score, 0.33 [7.8] points). Conclusions and Relevance: In this observational preclinical AD study, participants who learned they had elevated amyloid levels did not experience short-term negative psychological sequelae compared with persons who learned they did not have elevated amyloid levels.

Emotional Awareness and Expression Therapy Achieves Greater Pain Reduction than Cognitive Behavioral Therapy in Older Adults with Chronic Musculoskeletal Pain: A Preliminary Randomized Comparison Trial.

OBJECTIVE: Emotional awareness and expression therapy (EAET) emphasizes the importance of the central nervous system and emotional processing in the etiology and treatment of chronic pain. Prior trials suggest EAET can substantially reduce pain; however, only one has compared EAET with an established alternative, demonstrating some small advantages over cognitive behavioral therapy (CBT) for fibromyalgia. The current trial compared EAET with CBT in older, predominately male, ethnically diverse veterans with chronic musculoskeletal pain. DESIGN: Randomized comparison trial. SETTING: Outpatient clinics at the West Los Angeles VA Medical Center. SUBJECTS: Fifty-three veterans (mean age = 73.5 years, 92.4% male) with chronic musculoskeletal pain. METHODS: Patients were randomized to EAET or CBT, each delivered as one 90-minute individual session and eight 90-minute group sessions. Pain severity (primary outcome), pain interference, anxiety, and other secondary outcomes were assessed at baseline, post-treatment, and three-month follow-up. RESULTS: EAET produced significantly lower pain severity than CBT at post-treatment and follow-up; differences were large (partial η2 = 0.129 and 0.157, respectively). At post-treatment, 41.7% of EAET patients had >30% pain reduction, one-third had >50%, and 12.5% had >70%. Only one CBT patient achieved at least 30% pain reduction. Secondary outcomes demonstrated small to medium effect size advantages of EAET over CBT, although only post-treatment anxiety reached statistical significance. CONCLUSIONS: This trial, although preliminary, supports prior research suggesting that EAET may be a treatment of choice for many patients with chronic musculoskeletal pain. Psychotherapy may achieve substantial pain reduction if pain neuroscience principles are emphasized and avoided emotions are processed.

Prefrontal working memory activity predicts episodic memory performance: A neuroimaging study.

Working memory (WM) and long term memory (LTM) are different neuropsychological processes, although distinction between these domains is an area of debate. LTM is thought to rely on hippocampal circuitry. Cognitive neuroscience models imply that WM processing may at least partially support LTM within regions of the prefrontal cortex (PFC). We sought to determine the association between PFC based WM processing and LTM in the visuospatial domain. In contrast to prior work, we aimed to query if WM was involved in learning and free recall trials as measured by standard neuropsychological tests of LTM. Forty-three older adults (24 with a diagnosis of amnestic Mild Cognitive Impairment and 19 elderly controls) were included in the analysis. Patients completed a fMRI task of visuospatial maintenance WM in which they were required to match a previously studied complex shape with one of two probes. Extent of activity in the right PFC during the WM task was tabulated for each patient. Hippocampal volume was quantified from T1 scans. On a separate day patients completed neuropsychological testing, including the Brief Visuospatial Memory Test- Revised (BVMT-R), which includes learning trials (total recall), delayed free recall, and recognition. Right PFC activity was associated with performance on BVMT-R total recall and delayed recall. Results from multiple regression showed that PFC activity explained an additional 9 % of the variance in memory performance above right hippocampal volume. These findings suggest that PFC processing that supports WM (including stimuli maintenance, retrieval, and selection) are also involved in LTM learning and recall.

Alterations to task positive and task negative networks during executive functioning in Mild Cognitive Impairment.

Poor executive functioning increases risk of decline in Mild Cognitive Impairment (MCI). Executive functioning can be conceptualized within the framework of working memory. While some components are responsible for maintaining representations in working memory, the central executive is involved in the manipulation of information and creation of new representations. We aimed to examine the neural correlates of these components of working memory using a maintenance working memory and visuospatial reasoning task. Twenty-five patients with amnestic MCI and 19 elderly controls (EC) completed functional MRI during reasoning and maintenance working memory tasks. In MCI, maintenance working memory was associated with hypoactivation of right frontoparietal regions and hyperactivation of left prefrontal cortex, coupled with attenuation of default mode network (DMN) relative to EC. During reasoning, MCI showed hypoactivation of parietal regions, coupled with attenuation of anterior DMN and increased deactivation of posterior DMN relative to EC. Comparing the reasoning task to the maintenance working memory task yields the central executive. In MCI, the central executive showed hypoactivation of right parietal lobe and increased deactivation of posterior DMN compared to EC. Consistent with prior work on executive functioning, MCI show different neural circuitry during visuospatial reasoning, including changes to both task positive frontoparietal regions, as well as to deactivation patterns within the DMN. Both hyperactivation of task positive networks and increased deactivation of DMN may be compensatory.

The National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease: Perspectives from the Research Roundtable.

The Alzheimer's Association's Research Roundtable met in November 2017 to explore the new National Institute on Aging and the Alzheimer's Association Research Framework for Alzheimer's disease. The meeting allowed experts in the field from academia, industry, and government to provide perspectives on the new National Institute on Aging and the Alzheimer's Association Research Framework. This review will summarize the "A, T, N System" (Amyloid, Tau, and Neurodegeneration) using biomarkers and how this may be applied to clinical research and drug development. In addition, challenges and barriers to the potential adoption of this new framework will be discussed. Finally, future directions for research will be proposed.

Cerebral metabolic correlates of attention networks in Alzheimer's Disease: A study of the Stroop.

Patients with Alzheimer's Disease (AD) show difficulties with attention. Cognitive neuroscience models posit that attention can be broken down into alerting, orienting, and executive networks. We used the Stroop Color-Word test to interrogate the neural correlates of attention deficits in AD. We hypothesized that the Word, Color, and Color-Word conditions of the Stroop would all tap into the alerting and orienting networks. The Color-Word condition would additionally tap into the executive network. A ratio of Color-Word to Color naming performance would isolate the executive network from the others. To identify the neural underpinnings of attention in AD we correlated performance on the Stroop with brain metabolic activity. Sixty-six patients with probable AD completed [18F] fluorodeoxyglucose PET scanning and neuropsychological testing. Analysis was conducted with SPM12 (p<0.001 uncorrected, extent threshold 50 voxels). Performance on the Word, Color, and Color-Word conditions directly correlated with metabolic rate in right inferior parietal lobules/intraparietal sulci. The Color-Word/Color ratio revealed associations with metabolic rate in right medial prefrontal cortex and insula/operculum. Overall findings were largely consistent with the hypothesized neuroanatomical substrates of the alerting, orienting, and executive networks. As such, attention deficits in AD reflect compromise to multiple large-scale networks.

Cortical Metabolic and Cognitive Correlates of Disorientation in Alzheimer's Disease.

Orientation to time, date, and place is commonly utilized in clinical settings to aid in diagnosis, staging, and monitoring of Alzheimer's disease (AD). This study aimed to identify the cerebral metabolic correlates of orientation in patients with AD, and the degree to which regions associated with orientation overlap with memory-related structures. Eighty-five patients with a diagnosis of probable AD underwent fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological testing. Orientation items from the Dementia Rating Scale and recognition performance from the Consortium to Establish a Registry for AD (CERAD) Word List Learning test were correlated with cerebral glucose metabolism. Post-hoc analyses examined neuropsychological predictors of orientation. Better orientation performance related to greater cerebral metabolism in the bilateral middle-inferior temporal lobes, bilateral middle-posterior cingulate, left angular gyrus, and left middle occipital gyrus. In comparison, higher CERAD recognition discriminability score was associated with greater metabolic activity in left medial temporal lobe regions including the hippocampal and parahippocampal gyri, and the left fusiform gyrus. Post-hoc behavioral analyses revealed multiple cognitive functions to be related to orientation, including list learning, recognition memory, visuospatial functioning, attention, and language. Findings from the present study suggest that disorientation in AD results from dysfunction of a network of structures and cognitive abilities commonly found to be implicated in AD. The study supports the notion that memory is necessary but not sufficient for successful orientation.

Cholinergic Receptor Binding in Alzheimer Disease and Healthy Aging: Assessment In Vivo with Positron Emission Tomography Imaging.

OBJECTIVE: To compare regional nicotinic cholinergic receptor binding in older adults with Alzheimer disease (AD) and healthy older adults in vivo and to assess relationships between receptor binding and clinical symptoms. METHODS: Using cross-sectional positron emission tomography (PET) neuroimaging and structured clinical assessment, outpatients with mild to moderate AD (N = 24) and healthy older adults without cognitive complaints (C group; N = 22) were studied. PET imaging of α4ß2* nicotinic cholinergic receptor binding using 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and clinical measures of global cognition, attention/processing speed, verbal memory, visuospatial memory, and neuropsychiatric symptoms were used. RESULTS: 2FA binding was lower in the AD group compared with the C group in the medial thalamus, medial temporal cortex, anterior cingulate, insula/opercula, inferior caudate, and brainstem (p < 0.05, corrected cluster), but binding was not associated with cognition. The C group had significant inverse correlations between 2FA binding in the thalamus (left: rs = -0.55, p = 0.008; right: rs = -0.50, p = 0.02; N = 22) and hippocampus (left: rs = -0.65, p = 0.001; right: rs = -0.55, p = 0.009; N = 22) and the Trails A score. The AD group had inverse correlation between 2FA binding in anterior cingulate (left: rs = -0.50, p = 0.01; right: rs = -0.50, p = 0.01; N = 24) and Neurobehavioral Rating Scale agitation/disinhibition factor score. CONCLUSION: Cholinergic receptor binding is reduced in specific brain regions in mild to moderate AD and is related to neuropsychiatric symptoms. Among healthy older adults, lower receptor binding may be associated with slower processing speed. Cholinergic receptor binding in vivo may reveal links to other key brain changes associated with aging and AD and may provide a potential molecular treatment target.

18F-Fluorodeoxyglucose Positron Emission Tomography Cortical Metabolic Activity Associated with Distinct Agitation Behaviors in Alzheimer Disease.

OBJECTIVE: This study aimed to investigate the neurobiologic correlates of two distinct clusters of agitation symptoms to identify the unique biologic substrates underlying agitated behaviors. METHODS: Eighty-eight outpatients with mild to moderate Alzheimer disease (AD) were recruited from the VA Greater Los Angeles Healthcare System Geropsychiatry Outpatient Program. A cross-sectional investigation was conducted of the relationship between cerebral glucose metabolism measured via 18F-fluorodeoxyglucose positron emission tomography and agitated symptoms from the Neuropsychiatric Inventory (NPI) in patients with AD. Two empirically derived clusters of agitation symptoms were investigated: an Agitation factor comprising agitation/aggression and irritability/lability items of the NPI, and a Behavioral Dyscontrol factor comprising elation/euphoria, disinhibition, aberrant motor behavior, sleep, and appetite items of the NPI. Mean cerebral metabolism for patients who scored positively on each of the two factors was compared with mean cerebral metabolism for those who did not. RESULTS: Patients with AD who scored positively on the Agitation factor showed reduced glucose metabolism of the right temporal, right frontal, and bilateral cingulate cortex. In contrast, the Behavioral Dyscontrol factor did not show specific neurobiologic correlates. CONCLUSION: Symptoms encompassed within the Agitation factor have distinct neurobiologic underpinnings. The precipitants, course, and outcomes related to these symptoms may be unique from other neuropsychiatric symptoms characteristic of AD. Special attention to treatment of agitated behaviors involving anger, aggressiveness, hostility, and irritability/emotional lability is warranted, because they appear to reflect a clinically relevant symptom cluster with unique underlying neurobiologic correlates.