ABSTRACT
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 (nâ¯=â¯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 (bâ¯=â¯0.7 per 10 dB; 95% confidence interval [CI]: 0.2, 1.1; tâ¯=â¯2.86; pâ¯=â¯0.01; dfâ¯=â¯85), NPS severity (bâ¯=â¯1.3 per 10 dB; 95% CI: 0.4, 2.5; tâ¯=â¯2.13; pâ¯=â¯0.04; dfâ¯=â¯80), and depressive symptom severity (bâ¯=â¯1.5 per 10 dB; 95% CI: 0.4, 2.5; tâ¯=â¯2.83; pâ¯=â¯0.01; dfâ¯=â¯89) after adjustment for demographic and clinical characteristics. Additionally, the use of hearing aids was inversely associated with the number of NPS (bâ¯=â¯-2.09; 95% CI -3.44, -0.75; tâ¯=â¯-3.10; pâ¯=â¯0.003; dfâ¯=â¯85), NPS severity (bâ¯=â¯-3.82; 95% CI -7.19, -0.45; tâ¯=â¯-2.26; pâ¯=â¯0.03; dfâ¯=â¯80), and depressive symptom severity (bâ¯=â¯-2.94; 95% CI: -5.93, 0.06; tâ¯=â¯1.70; pâ¯=â¯0.05; dfâ¯=â¯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.
Subject(s)
Cognitive Dysfunction , Hearing Aids , Hearing Loss , Aged , Cognitive Dysfunction/complications , Cognitive Dysfunction/epidemiology , Cross-Sectional Studies , Female , Hearing Loss/complications , Hearing Loss/epidemiology , Humans , Male , Neuropsychological TestsABSTRACT
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.
Subject(s)
Alzheimer Disease/psychology , Apathy , Brain/diagnostic imaging , Neuroimaging , Neuropsychological Tests , Aged , Brain/pathology , Female , Humans , Magnetic Resonance Imaging , MaleABSTRACT
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.
ABSTRACT
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.
Subject(s)
Aging/physiology , Anxiety/physiopathology , Behavioral Symptoms/physiopathology , Cognitive Dysfunction/physiopathology , Dementia/physiopathology , Depression/physiopathology , Aged , Aged, 80 and over , Alzheimer Disease/epidemiology , Alzheimer Disease/physiopathology , Anxiety/epidemiology , Behavioral Symptoms/epidemiology , Case-Control Studies , Cognitive Dysfunction/epidemiology , Dementia/epidemiology , Depression/epidemiology , Female , Humans , Longitudinal Studies , Male , Neuropsychological Tests , Psychiatric Status Rating Scales , Risk Factors , Utah/epidemiologyABSTRACT
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.
Subject(s)
Aging/pathology , Cognitive Dysfunction/complications , Hearing Aids/statistics & numerical data , Hearing Loss/epidemiology , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Logistic Models , Male , Maryland , Middle Aged , Psychiatric Status Rating Scales , Retrospective Studies , Tertiary Care CentersABSTRACT
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.
Subject(s)
Activities of Daily Living/psychology , Cognition/physiology , Cognitive Dysfunction , Dementia , Mental Status and Dementia Tests , Aged , Aged, 80 and over , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/psychology , Dementia/diagnosis , Dementia/physiopathology , Dementia/psychology , Disease Progression , Female , Humans , Male , Neuropsychological Tests , Predictive Value of Tests , Prognosis , Proportional Hazards ModelsABSTRACT
Executive functioning (EF) is an important cognitive domain that is negatively affected in a number of neuropsychiatric conditions. Neuroimaging methods have led to insights into the anatomical and functional nature of EF. The authors conducted a systematic review of the recent cognitive and neuroimaging literature to investigate how the neuroimaging correlates of EF compare between different diagnostic groups. The authors found that the frontal, parietal, and cerebellar lobes were most frequently associated with EF when comparing results from different clinical populations; the occipital lobe was not correlated with EF in any group. These findings suggest that individual disease processes affect circuits within an identifiable distributed network rather than isolated regions.
Subject(s)
Brain/pathology , Cognition Disorders/diagnosis , Executive Function , Neuroimaging , Cognition Disorders/etiology , Cognition Disorders/pathology , Databases, Factual/statistics & numerical data , Humans , Neuropsychological TestsABSTRACT
BACKGROUND: Suicidal behavior after traumatic brain injury (TBI) is an increasingly recognized phenomenon. Both TBI and suicide are major public health problems and leading causes of death. The interaction between both of them is complex, and understanding it requires a multifaceted approach. Epidemiologic studies have shown a markedly higher incidence of suicide in individuals with TBI as compared with the general population, but imprecise definitions of suicide and suicidality as well as sample characteristics caution conclusive interpretation. Risk factors for suicide after TBI include male gender, presence of substance abuse or psychiatric disorders, and the severity of the injury. Evaluation of a suicidal patient with previous TBI currently relies on careful clinical examination. Established assessment tools can be useful but have not all been validated in this population. Intervention strategies should stress a multidimensional approach incorporating neurologic, behavioral, psychologic, pharmacotherapeutic, and psychosocial factors. OBJECTIVE: This article serves to review the currently available literature on suicidal behavioral after TBI. METHODS: It uses a case to illustrate how one might conceptualize this complex problem. CONCLUSION: It is hoped that this review stimulates further research in an area where there are still large gaps in our knowledge of this very important problem.
Subject(s)
Brain Injuries/psychology , Suicide Prevention , Suicide, Attempted/prevention & control , Suicide, Attempted/psychology , Suicide/psychology , Accidents, Traffic , Adult , Comorbidity , Humans , Male , Risk FactorsABSTRACT
BACKGROUND: Diffusion tensor imaging (DTI) is a promising method for identifying significant cross-sectional differences of white-matter tracts in normal controls (NC) and those with mild cognitive impairment (MCI) or Alzheimer's disease (AD). There have not been many studies establishing its longitudinal utility. METHODS: Seventy-five participants (25 NC, 25 amnestic MCI, and 25 AD) had 3-Tesla MRI scans and clinical evaluations at baseline and 3, 6, and 12 months. Fractional anisotropy (FA) and mean diffusivity (MD) were analyzed at each time-point and longitudinally in eight a priori-selected areas taken from four regions of interest (ROIs). RESULTS: Cross-sectionally, MD values were higher, and FA values lower in the fornix and splenium of the AD group compared with either MCI or NC (P < .01). Within-group change was more evident in MD than in FA over 12 months: MD increased in the inferior, anterior cingulum, and fornix in both the MCI and AD groups (P < .01). CONCLUSIONS: There were stable, cross-sectional, region-specific differences between the NC and AD groups in both FA and MD at each time-point over 12 months. Longitudinally, MD was a better indicator of change than FA. Significant increases of fornix MD in the MCI group suggest this is an early indicator of progression.
Subject(s)
Alzheimer Disease/pathology , Brain/pathology , Cognitive Dysfunction/pathology , Diffusion Magnetic Resonance Imaging , Nerve Fibers, Myelinated/pathology , Aged , Anisotropy , Female , Humans , Image Interpretation, Computer-Assisted , Longitudinal Studies , MaleABSTRACT
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.
Subject(s)
Alzheimer Disease , Psychotic Disorders , Humans , Alzheimer Disease/genetics , Alzheimer Disease/therapy , Alzheimer Disease/diagnosis , Caregivers , Anxiety , NeuroimagingABSTRACT
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.
ABSTRACT
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).
Subject(s)
Cognitive Dysfunction , Dementia , Adult , Humans , Aged , Cognitive Training , Activities of Daily Living , Cognitive Dysfunction/prevention & control , Dementia/prevention & controlABSTRACT
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 (Nâ=â17) and normal older adults (Nâ=â15). 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) (râ=â-0.455, pâ=â0.009). 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.
Subject(s)
Cognitive Dysfunction , Aged , Brain , Humans , Magnetic Resonance Imaging/methods , Neuropsychological Tests , Parietal Lobe/diagnostic imagingABSTRACT
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.
Subject(s)
Alzheimer Disease/therapy , Aggression , Apathy , Depression/therapy , Disease Progression , Humans , Neuropsychological Tests , Psychomotor Agitation/therapyABSTRACT
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.
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OBJECTIVE: The need to evaluate decisional capacity among patients in treatment settings as well as subjects in clinical research settings has increasingly gained attention. Decisional capacity is generally conceptualized to include not only an understanding of disclosed information but also an appreciation of its significance, the ability to use the information in reasoning, and the ability to express a clear choice. The authors critically reviewed existing measures of decisional capacity for research and treatment. METHOD: Electronic medical and legal databases were searched for articles published from 1980 to 2004 describing structured assessments of adults' capacity to consent to clinical treatment or research protocols. The authors identified 23 decisional capacity assessment instruments and evaluated each in terms of format, content, administration features, and psychometric properties. RESULTS: Six instruments focused solely on understanding of disclosed information, and 11 tested for understanding, appreciation, reasoning, and expression of a choice. The instruments varied substantially in format, degree of standardization of disclosures, flexibility of item content, and scoring procedures. Reliability and validity also varied widely. All instruments have limitations, ranging from lack of supporting psychometric data to lack of generalizability across contexts. CONCLUSIONS: Of the instruments reviewed, the MacArthur Competence Assessment Tools for Clinical Research and for Treatment have the most empirical support, although other instruments may be equally or better suited to certain situations. Contextual factors are important but understudied. Capacity assessment tools should undergo further empirically based development and refinement as well as testing with a variety of populations.
Subject(s)
Clinical Protocols/standards , Informed Consent/psychology , Mental Competency/psychology , Psychiatric Status Rating Scales , Research Subjects/psychology , Adult , Decision Making , Humans , Informed Consent/standards , Mental Competency/classification , Mental Disorders/classification , Mental Disorders/psychology , Middle Aged , Patients/classification , Patients/psychology , Psychometrics , Reproducibility of Results , Research Subjects/classificationABSTRACT
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.
ABSTRACT
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.
Subject(s)
Alzheimer Disease/physiopathology , Brain/physiopathology , Delusions/physiopathology , Depression/physiopathology , Alzheimer Disease/complications , Amygdala/physiopathology , Delusions/etiology , Depression/etiology , Gyrus Cinguli/physiopathology , Humans , NeuroimagingABSTRACT
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.