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.

Translating clinical notes into quantitative measures-a real-world observation on the response to cholinesterase inhibitors or selective serotonin reuptake inhibitors prescribed to outpatients with dementia using electronic medical records.

Objective: Cholinesterase inhibitors (CEIs) are prescribed for dementia to maintain or improve memory. Selective serotonin reuptake inhibitors (SSRIs) are also prescribed to manage psychiatric symptoms seen in dementia. What proportion of outpatients actually responds to these drugs is still unclear. Our objective was to investigate the responder rates of these medications in an outpatient setting using the electronic medical record (EMR). Methods: We used the Johns Hopkins EMR system to identify patients with dementia who were prescribed a CEI or SSRI for the first time between 2010 and 2021. Treatment effects were assessed through routinely documented clinical notes and free-text entries in which healthcare providers record clinical findings and impressions of patients. Responses were scored using a three-point Likert scale named the NOte-based evaluation method for Treatment Efficacy (NOTE) in addition to the Clinician's Interview-Based Impression of Change Plus caregiver input (CIBIC-plus), a seven-point Likert scale used in clinical trials. To validate NOTE, the relationships between NOTE and CIBIC-plus and between NOTE and change in MMSE (Mini-Mental State Examination) before and after medication were examined. Inter-rater reliability was evaluated using Krippendorff's alpha. The responder rates were calculated. Results: NOTE showed excellent inter-rater reliability and correlated well with CIBIC-plus and changes in MMSEs. Out of 115 CEI cases, 27.0% reported improvement and 34.8% reported stable symptoms in cognition; out of 225 SSRI cases, 69.3% reported an improvement in neuropsychiatric symptoms. Conclusion: NOTE showed high validity in measuring the pharmacotherapy effects based on unstructured clinical entries. Although our real-world observation included various types of dementia, the results were remarkably similar to what was reported in controlled clinical trials of Alzheimer's disease and its related neuropsychiatric symptoms.

Preclinical Alzheimer Disease and the Electronic Health Record: Balancing Confidentiality and Care.

Because information technologies are increasingly used to improve clinical research and care, personal health information (PHI) has wider dissemination than ever before. The 21st Century Cures Act in the United States now requires patient access to many components of the electronic health record (EHR). Although these changes promise to enhance communication and information sharing, they also bring higher risks of unwanted disclosure, both within and outside of health systems. Having preclinical Alzheimer disease (AD), where biological markers of AD are identified before the onset of any symptoms, is sensitive PHI. Because of the melding of ideas between preclinical and "clinical" (symptomatic) AD, unwanted disclosure of preclinical AD status can lead to personal harms of stigma, discrimination, and changes to insurability. At present, preclinical AD is identified mainly in research settings, although the consensus criteria for a clinical diagnosis may soon be established. There is not yet adequate legal protection for the growing number of individuals with preclinical AD. Some PHI generated in preclinical AD trials has clinical significance, necessitating urgent evaluations and longitudinal monitoring in care settings. AD researchers are obligated to both respect the confidentiality of participants' sensitive PHI and facilitate providers' access to necessary information, often requiring disclosure of preclinical AD status. The AD research community must continue to develop ethical, participant-centered practices related to confidentiality and disclosure, with attention to sensitive information in the EHR. These practices will be essential for translation into the clinic and across health systems and society at large.

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.

Crossword Puzzles for Brain Training in Mild Cognitive Impairment.

Given the increasing prevalence and public health impact of dementia, it is imperative that we identify prevention strategies. One approach, broadly termed brain training, can be defined as guided drill-and-practice mental exercises targeting cognitive domains. We have evidence suggesting that brain training may prevent dementia in cognitively intact adults, including the well-validated protective effect of education early in life and the results of the ACTIVE (Advanced Cognitive Training for Independent and Vital Elderly) trial,1 which showed not only a long-term cognitive benefit of training in processing speed, but also a possible decrease in dementia incidence and transfer of cognitive benefits to performance in everyday functioning (as measured by performance on instrumental activities of daily living).

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.

The association of neuropsychiatric symptoms with regional brain volumes from patients in a tertiary multi-disciplinary memory clinic.

BACKGROUND: To examine the interaction between structural brain volume measures derived from a clinical magnetic resonance imaging (MRI) and occurrence of neuropsychiatric symptoms (NPS) in outpatient memory clinic patients. METHODS: Clinical and neuroimaging data were collected from the medical records of outpatient memory clinic patients who were seen by neurologists, geriatric neuropsychiatrists, and geriatricians. MRI scan acquisition was carried out on a 3 T Siemens Verio scanner at Johns Hopkins Bayview Medical Center. Image analyses used an automated multi-label atlas fusion method with a geriatric atlas inventory to generate 193 anatomical regions from which volumes were measured. Regions of interest were generated a priori based on previous literature review of NPS in dementia. Regional volumes for agitation, apathy, and delusions were carried forward in a linear regression analysis. RESULTS: Seventy-two patients had clinical and usable neuroimaging data that were analyzed and grouped by Mini-Mental State Exam (MMSE). Neuropsychiatric Inventory Questionnaire (NPI-Q) agitation was inversely associated with rostral anterior cingulate cortex (ACC) bilaterally and left subcallosal ACC volumes in the moderate severity group. Delusions were positively associated with left ACC volumes in both severe and mild groups but inversely associated with the right dorsolateral prefrontal cortex (DLPFC) in the moderate subgroup. CONCLUSIONS: Agitation, apathy, and delusions are associated with volumes of a priori selected brain regions using clinical data and clinically acquired MRI scans. The ACC is an anatomic region common to these symptoms, particularly agitation and delusions, which closely mirror the findings of research-quality studies and suggest its importance as a behavioral hub.

Developing Treatments for Alzheimer's and Related Disorders with Precision Medicine: A Vision.

Precision medicine, also known as personalized medicine, is concerned with finding the right treatment for the right patient at the right time. It is a way of thinking focused on parsing heterogeneity ultimately down to the level of the individual. Its main mission is to identify characteristics of heterogeneous clinical conditions so as to target tailored therapies to individuals. Precision Medicine however is not an agnostic collection of all manner of clinical, genetic and other biologic data in select cohorts. This is an important point. Simply collecting as much information as possible on individuals without applying this way of thinking should not be considered Precision Medicine.

Association of Hearing Loss With Neuropsychiatric Symptoms in Older Adults With Cognitive Impairment.

Neuropsychiatric symptoms (NPS) in persons with dementia (PWD) are common and can lead to poor outcomes, such as institutionalization and mortality, and may be exacerbated by sensory loss. Hearing loss is also highly prevalent among older adults, including PWD. OBJECTIVE: This study investigated the association between hearing loss and NPS among community- dwelling patients from a tertiary memory care center. DESIGN, SETTING, AND PARTICIPANTS: Participants of this cross-sectional study were patients followed at the Johns Hopkins Memory and Alzheimer's Treatment Center who underwent audiometric testing during routine clinical practice between October 2014 and January 2017. OUTCOME MEASUREMENTS: Included measures were scores on the Neuropsychiatric Inventory-Questionnaire and the Cornell Scale for Depression in Dementia. RESULTS: Participants (n = 101) were on average 76 years old, mostly female and white, and had a mean Mini-Mental State Examination score of 23. We observed a positive association between audiometric hearing loss and the number of NPS (b = 0.7 per 10 dB; 95% confidence interval [CI]: 0.2, 1.1; t = 2.86; p = 0.01; df = 85), NPS severity (b = 1.3 per 10 dB; 95% CI: 0.4, 2.5; t = 2.13; p = 0.04; df = 80), and depressive symptom severity (b = 1.5 per 10 dB; 95% CI: 0.4, 2.5; t = 2.83; p = 0.01; df = 89) after adjustment for demographic and clinical characteristics. Additionally, the use of hearing aids was inversely associated with the number of NPS (b = -2.09; 95% CI -3.44, -0.75; t = -3.10; p = 0.003; df = 85), NPS severity (b = -3.82; 95% CI -7.19, -0.45; t = -2.26; p = 0.03; df = 80), and depressive symptom severity (b = -2.94; 95% CI: -5.93, 0.06; t = 1.70; p = 0.05; df = 89). CONCLUSION: Among patients at a memory clinic, increasing severity of hearing loss was associated with a greater number of NPS, more severe NPS, and more severe depressive symptoms, while hearing aid use was associated with fewer NPS, lower severity, and less severe depressive symptoms. Identifying and addressing hearing loss may be a promising, low-risk, non-pharmacological intervention in preventing and treating NPS.

Treatment of Depression After Traumatic Brain Injury: A Systematic Review Focused on Pharmacological and Neuromodulatory Interventions.

BACKGROUND: Depression is the most common psychiatric sequela after traumatic brain injury (TBI) and poses a variety of treatment challenges. There is a lack of clinical trials focused on biological interventions used to manage TBI depression. OBJECTIVE: The aim of this systematic review is to summarize the current evidence of psychotropic and neuromodulatory interventions used to treat TBI depression and to provide directions for future research. METHODS: Key words were used to describe the following search terms: "traumatic brain injury", "depression", "pharmacological/drug therapy", and "neuromodulation". Studies focused on pharmacotherapy or neuromodulation in TBI depression were identified in 5 databases: Medline (PubMed), EMBASE (Embase.com), the Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), PsycINFO (EbscoHost), and Web of Science. Article inclusion/exclusion using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-based systematic protocol of extraction and evaluation was applied. Level of evidence for each study was determined using the American Academy of Neurology criteria. RESULTS: The initial search provided 1473 citations. Twenty-two studies met inclusion criteria. Sixteen studies explored pharmacological interventions with emphasis on serotonergic agents. Results between studies were conflicting, and interventions did not always outperform placebos, although sertraline provided the highest level of evidence for treatment of TBI depression. Six studies examining neuromodulatory interventions show preliminary evidence of efficacy with a range of interventions and modes of delivery used. CONCLUSIONS: Additional research including large-sample randomized-controlled trials using pharmacological, neuromodulation, or combination treatment is needed. These studies should incorporate premorbid psychosocial functioning, preinjury psychiatric disease, cognitive deficits, and functional recovery when examining outcomes.

Neuropsychiatric Aspects of Alzheimer Dementia: From Mechanism to Treatment.

Developing disease-modifying treatments for Alzheimer dementia requires innovative approaches to identify novel biological targets during the course of the disease. Treatment development for the neuropsychiatric symptoms of Alzheimer may benefit from a mechanistic approach to treatment. There has been progress in identifying mild forms of behavioral impairment along the Alzheimer spectrum that may lead to additional insights into progression to dementia as well as the fundamental mechanisms of the symptoms. Developing therapies for complex neurobehavioral syndromes may require the translation of mechanistic insights into therapy, which may both improve the symptoms and delay progression to dementia in certain patients.

Neuropsychiatric Symptoms as Risk Factors for Cognitive Decline in Clinically Normal Older Adults: The Cache County Study.

INTRODUCTION: There has been considerable progress in identifying early cognitive and biomarker predictors of Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are common in AD and appear to predict progression after the onset of mild cognitive impairment or dementia. OBJECTIVES: The objective of the study is to examine the relationship between NPS in clinically normal older adults and subsequent cognitive decline in a population-based sample. METHODS: The Cache County Study on Memory in Aging consists of a population-based sample of 5,092 older adults. We identified 470 clinically normal adults who were followed for an average period of 5.73 years. NPS were evaluated at the baseline clinical assessment using the Neuropsychiatric Inventory (NPI). NPI domain scores were quantified as the product of frequency X severity in individual NPI domains, and then summed for the NPI-Total. Neuropsychological measures were collected at baseline and at each subsequent follow-up wave. Linear mixed-effects models assessed the association of NPI-Total, NPI-Depression, and NPI-Anxiety scores (obtained at baseline) on longitudinal change in neuropsychological performance, controlling for age, sex, and education. RESULTS: Baseline NPI-Total score was associated with a more rapid rate of decline in word list memory, praxis recall, and animal fluency. Baseline NPI-Depression was not associated with later decline on any of the cognitive tests, while baseline NPI-Anxiety was associated with decline in Symbol Digit Modality. CONCLUSION: In conclusion, among clinically normal older adults derived from this population-based study, total burden of NPS was associated with longitudinal cognitive decline. These results add to the evidence that NPS are risk factors for or clinical indicators of preclinical dementia syndrome. Our study was an exploratory study and we did not control for multiple comparisons.

Synthetic review of financial capacity in cognitive disorders: Foundations, interventions, and innovations.

PURPOSE OF REVIEW: Financial capacity (FC) is a complex, multi-dimensional construct that changes over the lifespan and commonly becomes impaired as individuals age and develop dementia. Impaired FC results in several important negative outcomes including loss of independence and increased victimization and abuse. The goal of this review is to synthesize current knowledge of the assessment and intervention of impaired financial capacity in order to propose its further development in the context of technological advancements. RECENT FINDINGS: Current methods of assessing FC are based on conceptual foundations that include judgment, procedural, and other pragmatic skills. The neurocognitive correlates of FC include basic arithmetic skills, attention, and visual memory. These cognitive domains are presently assessed through clinical and neuropsychological evaluation as well as instruments specifically designed to assess financial capacity. Despite having a firm conceptual and neurocognitive foundation, current assessment methods of FC are limited by their ability to be flexible, individualizable, or scalable. SUMMARY: Computer and software technologies such as artificial intelligence, virtual reality, and the internet of things are exciting tools to achieve the ultimate goal of developing measures that allow patients to maintain or support maximal independence in financial functioning. These tools will allow for contemporaneous and ecologically valid assessment and would be useful to legal professionals and clinicians in determinations of financial competency and capacity. Moreover, interventions that provide safety and monitoring while allowing patients maximal autonomy of preserved financial abilities are needed.

Age-related hearing loss in older adults with cognitive impairment.

BACKGROUND: Hearing loss can impair effective communication between caregivers and individuals with cognitive impairment. However, hearing loss is not often measured or addressed in care plans for these individuals. The aim of this study is to measure the prevalence of hearing loss and the utilization of hearing aids in a sample of individuals with cognitive impairment in a tertiary care memory clinic. METHODS: A retrospective review of 133 charts of individuals >50 years who underwent hearing assessment at a tertiary care memory clinic over a 12-month period (June 2014-June 2015) was undertaken. Using descriptive statistics, the prevalence of hearing loss was determined and associations with demographic variables, relevant medical history, cognitive status, and hearing aid utilization were investigated. RESULTS: Results indicate that hearing loss is highly prevalent among this sample of cognitively impaired older adults. Sixty percent of the sample had at least a mild hearing loss in the better hearing ear. Among variables examined, age, MMSE, and medical history of diabetes were strongly associated with hearing impairment. Hearing aid utilization increased in concordance with severity of hearing loss, from 9% to 54% of individuals with a mild or moderate/severe hearing loss, respectively. CONCLUSIONS: Hearing loss is highly prevalent among older adults with cognitive impairment. Despite high prevalence of hearing loss, hearing aid utilization remains low. Our study highlights the importance of hearing evaluation and rehabilitation as part of the cognitive assessment and care management plan in this vulnerable population.

Subtle changes in daily functioning predict conversion from normal to mild cognitive impairment or dementia: an analysis of the NACC database.

BACKGROUND: There are relatively small but observable changes in functional ability in those without Mild cognitive impairment (MCI) or dementia. The present study seeks to understand whether these individuals go on to develop MCI or dementia by assessing the association between baseline Functional Activities Questionnaire (FAQ) and conversion independent and after adjustment for cognitive tests. METHODS: The NACC database was used to conduct the analysis of which 7,625 participants were initially identified as having more than one visit and who were cognitively normal at their first visit. Cox proportional hazards were used to fit three models that controlled for executive and non-executive cognitive domains. A similar model was used to assess the effect of FAQ subcategories on conversion. RESULTS: Of these individuals, 1,328 converted to either MCI or dementia by visit 10. Converters had a total visit 1 FAQ score significantly higher than non-converters indicating more functional impairment at baseline. After adjustment for cognitive tests, the association between visit 1 FAQ and subsequent conversion was not attenuated. Doing taxes, remembering dates, and traveling were individually identified as significant predictors of conversion. CONCLUSIONS: The FAQ can be used as an indirect measure of functional ability and is associated with conversion to MCI or dementia. There is a selective and significant association between changes in financial ability and conversion that is in accordance with other research of financial capacity.

Neuropsychiatric symptoms in Alzheimer's disease: What might be associated brain circuits?

Neuropsychiatric symptoms (NPS) are very common in Alzheimer's disease (AD), particularly agitation, apathy, depression, and delusions. Brain networks or circuits underlying these symptoms are just starting to be understood, and there is a growing imaging and neurochemical evidence base for understanding potential mechanisms for NPS. We offer a synthetic review of the recent literature and offer hypotheses for potential networks/circuits underlying these NPS, particularly agitation, apathy, and delusions. Agitation in AD appears to be associated with deficits in structure and function of frontal cortex, anterior cingulate cortex, posterior cingulate cortex, amygdala, and hippocampus, and may be associated with mechanisms underlying misinterpretation of threats and affective regulation. Apathy in AD is associated with frontal cortex, anterior cingulate cortex, posterior cingulate cortex, as well as orbitofrontal cortex, and inferior temporal cortex, and may be associated with mechanisms underlying avoidance behaviors.

The fornix in mild cognitive impairment and Alzheimer's disease.

The fornix is an integral white matter bundle located in the medial diencephalon and is part of the limbic structures. It serves a vital role in memory functions and as such has become the subject of recent research emphasis in Alzheimer's disease (AD) and mild cognitive impairment (MCI). As the characteristic pathological processes of AD progress, structural and functional changes to the medial temporal lobes and other regions become evident years before clinical symptoms are present. Though gray matter atrophy has been the most studied, degradation of white matter structures especially the fornix may precede these and has become detectable with use of diffusion tensor imaging (DTI) and other complimentary imaging techniques. Recent research utilizing DTI measurement of the fornix has shown good discriminability of diagnostic groups, particularly early and preclinical, as well as predictive power for incident MCI and AD. Stimulating and modulating fornix function by the way of DBS has been an exciting new area as pharmacological therapeutics has been slow to develop.

Principles and management of neuropsychiatric symptoms in Alzheimer's dementia.

Neuropsychiatric symptoms of Alzheimer's disease (NPS-AD) are highly prevalent and lead to poor medical and functional outcomes. In spite of the burdensome nature of NPS-AD, we are continuing to refine the nosology and only beginning to understand the underlying pathophysiology. Cluster analyses have frequently identified three to five subsyndromes of NPS-AD: behavioral dysfunction (for example, agitation/aggressiveness), psychosis (for example, delusions and hallucinations), and mood disturbance (for example, depression or apathy). Recent neurobiological studies have used new neuroimaging techniques to elucidate behaviorally relevant circuits and networks associated with these subsyndromes. Several fronto-subcortical circuits, cortico-cortical networks, and neurotransmitter systems have been proposed as regions and mechanisms underlying NPS-AD. Common to most of these subsyndromes is the broad overlap of regions associated with the salience network (anterior cingulate and insula), mood regulation (amygdala), and motivated behavior (frontal cortex). Treatment strategies for dysregulated mood syndromes (depression and apathy) have primarily targeted serotonergic mechanisms with antidepressants or dopaminergic mechanisms with psychostimulants. Psychotic symptoms have largely been targeted with anti-psychotic medications despite controversial risk/benefit tradeoffs. Management of behavioral dyscontrol, including agitation and aggression in AD, has encompassed a wide range of psychoactive medications as well as non-pharmacological approaches. Developing rational therapeutic approaches for NPS-AD will require a firmer understanding of the underlying etiology in order to improve nosology as well as provide the empirical evidence necessary to overcome regulatory and funding challenges to further study these debilitating symptoms.

Atlas-based diffusion tensor imaging correlates of executive function.

Impairment in executive function (EF) is commonly found in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Atlas-based diffusion tensor imaging (DTI) methods may be useful in relating regional integrity to EF measures in MCI and AD. Sixty-six participants (25 normal controls, 22 MCI, and 19 AD) received DTI scans and clinical evaluation. DTI scans were applied to a pre-segmented atlas and fractional anisotropy (FA) and mean diffusivity (MD) were calculated. ANOVA was used to assess group differences in frontal, parietal, and cerebellar regions. For regions differing between groups (p < 0.01), linear regression examined the relationship between EF scores and regional FA and MD. Anisotropy and diffusivity in frontal and parietal lobe white matter structures were associated with EF scores in MCI and only frontal lobe structures in AD. EF was more strongly associated with FA than MD. The relationship between EF and anisotropy and diffusivity was strongest in MCI. These results suggest that regional white matter integrity is compromised in MCI and AD and that FA may be a better correlate of EF than MD.