Neuropsychiatric Symptom Clusters and their Association with Function and Brain Structure

BackgroundNeuropsychiatric Symptoms (NPS) in Alzheimer's Disease (AD) can exacerbate symptom burden and impair quality of life in patients. It is imperative to gain a better understanding of factors that contribute to NPS manifestation. This study explores the association between NPS scores and blood‐based biomarkers implicated in AD including Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light Chain (NFL), Amyloid Beta 40 (AB40), Amyloid Beta 42 (AB42), and Phosphorylated Tau at Threonine 181 (pTAU181).MethodsIndividuals with a diagnosis of Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI) were included based on data from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) database. From 126 participants, 107 had completed the Neuropsychiatric Inventory Questionnaire (NPI‐Q) and provided blood samples for measurement of GFAP, NFL, AB40, AB42, and pTAU181 plasma levels. To assess the association between NPS severity scores and blood‐based biomarkers, a partial Spearman correlation was conducted; adjusting for age, sex, and education level. A False Discovery Rate (FDR) threshold of 0.05 was applied to all p‐values to control for multiple comparisons.ResultsWe found significant correlations between several NPS domains and blood‐based biomarkers. Apathy scores had a significant positive correlation with pTAU181 (Rs = 0.27, p = 0.04) and NFL plasma levels (Rs =0.30, p = 0.02); Anxiety scores showed a significant positive correlation with GFAP (Rs = 0.28, p = 0.03) and NFL plasma levels (Rs = 0.33, p = 0.006); Euphoria scores were positively correlated with NFL plasma levels (Rs = 0.27, p = 0.05); Appetite, Motor function, and Total NPI severity scores had a significant positive correlation with GFAP plasma levels (Rs = 0.31, p = 0.01; Rs = 0.31, p = 0.01; Rs = 0.29, p = 0.03). No significant findings were observed for AB40 and 42 with any NPS domain.ConclusionOur findings suggest that certain blood‐based biomarkers—pTAU181, NFL, and GFAP— are associated with the development of NPS in Alzheimer's Disease. These biomarkers may help shed light on underlying mechanisms and monitor NPS severity. However, further research in larger cohorts and longitudinal studies is needed to confirm these findings and explore causal relationships.

We examined the association between cerebrospinal fluid (CSF)-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms (NPS) in older non-demented adults. We included 784 persons (699 cognitively unimpaired, 85 with mild cognitive impairment) aged ≥ 50 years who underwent CSF amyloid beta (Aβ42), hyperphosphorylated tau 181 (p-tau), and total tau (t-tau) as well as NPS assessment using Beck Depression and Anxiety Inventories (BDI-II, BAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Lower CSF Aβ42, and higher t-tau/Aβ42 and p-tau/Aβ42 ratios were associated with BDI-II and BAI total scores, clinical depression (BDI-II ≥ 13), and clinical anxiety (BAI ≥ 10), as well as NPI-Q-assessed anxiety, apathy, and nighttime behavior. CSF Aβ42, t-tau/Aβ42, and p-tau/Aβ42 ratios were associated with NPS in community-dwelling individuals free of dementia. If confirmed by a longitudinal cohort study, the findings have clinical relevance of taking into account the NPS status of individuals with abnormal CSF biomarkers.

Functional connectome and neuropsychiatric symptom clusters of Alzheimer's disease

BackgroundNeuropsychiatric symptoms due to Alzheimer’s disease (AD) and mild cognitive impairment (MCI) can decrease quality of life for patients and increase caregiver burden. Better characterization of neuropsychiatric symptoms and methods of analysis are needed to identify effective treatment targets. The current investigation leveraged the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) to examine the network structure of neuropsychiatric symptoms among symptomatic older adults with cognitive impairment.MethodsThe network relationships of behavioral symptoms were estimated from Neuropsychiatric Inventory Questionnaire (NPI-Q) data acquired from 12,494 older adults with MCI and AD during their initial visit. Network analysis provides insight into the relationships among sets of symptoms and allows calculation of the strengths of the relationships. Nodes represented individual NPI-Q symptoms and edges represented the pairwise dependency between symptoms. Node centrality was calculated to determine the relative importance of each symptom in the network.ResultsThe analysis showed patterns of connectivity among the symptoms of the NPI-Q. The network (M = .28) consisted of mostly positive edges. The strongest edges connected nodes within symptom domain. Disinhibition and agitation/aggression were the most central symptoms in the network. Depression/dysphoria was the most frequently endorsed symptom, but it was not central in the network.ConclusionsNeuropsychiatric symptoms in MCI and AD are highly comorbid and mutually reinforcing. The presence of disinhibition and agitation/aggression yielded a higher probability of additional neuropsychiatric symptoms. Interventions targeting these symptoms may lead to greater neuropsychiatric symptom improvement overall. Future work will compare neuropsychiatric symptom networks across dementia etiologies, informant relationships, and ethnic/racial groups, and will explore the utility of network analysis as a means of interrogating treatment effects.

Intracellular alpha-synuclein aggregates, known as Lewy bodies (LB), are commonly observed in Alzheimer's disease (AD) dementia. Post-mortem studies have shown a higher frequency of neuropsychiatric symptoms among individuals with AD and LB co-pathology. However, the effects of in vivo-measured LB pathology on neuropsychiatric symptoms in AD remain underexplored. This study aimed to evaluate cross-sectional and longitudinal effects of in vivo-measured LB pathology on neuropsychiatric symptoms across the AD continuum. We analyzed data from 1169 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants had in vivo measures of LB pathology (assessed using an alpha-synuclein seed amplification assay), amyloid-beta (Aβ) and phosphorylated tau (p-tau) levels in cerebrospinal fluid, and neuropsychiatric symptoms evaluated using the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Logistic and Cox proportional hazards regression models were used to assess cross-sectional and longitudinal effects, respectively, adjusting for age, sex, and cognitive status. Participants had a mean baseline age of 73.05 (SD 7.22) years, 47.13% were women, 426 (36.44%) cognitively unimpaired, and 743 (63.56%) cognitively impaired. In cross-sectional analyses, LB pathology was associated with higher rates of anxiety, apathy, motor disturbances, and appetite disturbances. In longitudinal analyses, LB pathology increased the risk of developing psychosis and anxiety. These effects were independent of Aβ and p-tau. Our results suggest that in vivo-measured LB pathology is closely associated with neuropsychiatric symptoms across the AD continuum. These findings underscore the potential of in vivo LB detection as a marker for identifying individuals at increased risk of neuropsychiatric symptoms, both in clinical trials and in clinical practice.

Association between clinical dementia rating and clinical outcomes in Alzheimer's disease

An Exploration of Subgroups of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Their Risks of Conversion to Dementia or Death

BackgroundAnxiety is associated with faster progression of Alzheimer’s disease (AD) and related imaging biomarkers. However, the association of anxiety with plasma biomarkers of AD is unclear. We investigated the relationship between various plasma AD biomarkers and anxiety at different AD stages.MethodThe study included 192 older adults evaluated at the NYU Alzheimer’s Disease Research Center with a consensus diagnosis of cognitively normal (CN, n = 99), mild cognitive impairment (MCI, n = 52), and mild AD dementia (AD, n = 41). Anxiety and depression were measured by study partner report via the Neuropsychiatric Inventory Questionnaire (NPI‐Q). Plasma levels of Aβ40, Aβ42, neurofilament light (NfL) and total tau were measured using ultra‐sensitive, single‐molecule array (SIMOA) technology. Secondarily‐calculated measures included Aβ42/Aβ40 and tau/Aβ42 ratios.ResultAnxiety had a prevalence of 14%, 48%, and 24% at CN, MCI, and AD, respectively. Comparing plasma biomarkers from participants with and without anxiety within each stage, anxiety associated with a significantly higher plasma tau/Aβ42 ratio in AD (p = 0.0127). In contrast, while depression had a higher prevalence of 37% at the AD stage, it was not associated with a significant difference in tau/Aβ42 ratio (p = 0.6459). Comparing stages, plasma tau/Aβ42 was significantly elevated in AD versus CN only among participants with anxiety (p = 0.034). In contrast, plasma NfL was significantly elevated in AD versus CN among participants with (p = 0.0475) and without (p < 0.0001) anxiety.ConclusionThe presence of anxiety uniquely modulates the levels of specific plasma biomarkers depending on stage, as well as the ability of specific biomarkers to distinguish AD stages. These results highlight a complex relationship between neuropsychiatric symptoms and plasma biomarkers that warrants further study.

One of the key research agenda of the field of aging is investigation of presymptomatic Alzheimer’s disease (AD). Furthermore, abnormalities in brain glucose metabolism (as measured by FDG-PET) have been reported among cognitively normal elderly persons. However, little is known about the association of FDG-PET abnormalities with neuropsychiatric symptoms (NPS) in a population-based setting. Thus, we conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging in order to examine the association between brain glucose metabolism and NPS among cognitively normal (CN) persons aged > 70 years. Participants underwent FDG-PET and completed the Neuropsychiatric Inventory Questionnaire (NPI-Q), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). Cognitive classification was made by an expert consensus panel. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals after adjusting for age, sex, and education. For continuous variables, we used linear regression and Spearman rank-order correlations. Of 668 CN participants (median 78.1 years, 55.4% males), 205 had an abnormal FDG-PET (i.e., standardized uptake value ratio < 1.32 in AD-related regions). Abnormal FDG-PET was associated with depression as measured by NPI-Q (OR = 2.12; 1.23–3.64); the point estimate was further elevated for APOE ɛ4 carriers (OR = 2.59; 1.00–6.69), though marginally significant. Additionally, we observed a significant association between abnormal FDG-PET and depressive and anxiety symptoms when treated as continuous measures. These findings indicate that NPS, even in community-based samples, can be an important additional tool to the biomarker-based investigation of presymptomatic AD.

Young-onset and late-onset Alzheimer's disease has different clinical presentations with late-onset presenting most often with memory deficits while young-onset often presents with a non-amnestic syndrome. However, it is unknown whether there are differences in presentation and progression of neuropsychiatric symptoms in young- versus late-onset Alzheimer's disease. We aimed to investigate differences in the prevalence and severity of neuropsychiatric symptoms in patients with young- and late-onset Alzheimer's disease longitudinally with and without accounting for the effect of medication usage. Sex differences were also considered in these patient groups. We included 126 young-onset and 505 late-onset Alzheimer's disease patients from National Alzheimer's Coordinating Center-Uniform Data Set (NACC-UDS) and Alzheimer's Disease Neuroimaging Initiative (ADNI). We investigated the prevalence and severity of neuropsychiatric symptoms using the Neuropsychiatric Inventory-Questionnaire over 4 visits with 1-year intervals, using a linear mixed-effects model. The prevalence of depression was significantly higher in young-onset than late-onset Alzheimer's disease over a 4-year interval when antidepressant usage was included in our analyses. Our findings suggest that neuropsychiatric symptom profiles of young- and late-onset Alzheimer's disease differ cross-sectionally but also display significant differences in progression.

BackgroundThe prodrome of cognitive declines and/or dementia may include late‐life neuropsychiatric symptoms such as apathy. In primarily non‐Hispanic White samples, apathy associates with both cognition and amyloid deposition in cognitively intact patients and those with Alzheimer’s disease (AD). However, little is known about these relationships in African Americans, who are both disproportionately affected by AD and under‐represented in AD research. Apathy could reflect higher levels of proteinopathy or occur co‐morbidly, exacerbating its deleterious effects. We examined associations between apathy and cognition and their potential moderation by plasma beta amyloid in cognitively healthy African American participants.MethodStudy participants enrolled in African Americans Fighting Alzheimer’s In Mid‐Life(AA‐FAIM, a linked study to the WRAP and Wisconsin ADRC) were included in the analytic sample (N = 166; Table 1) if they had ≥1 cognitive visits, plasma amyloid biomarker data, and apathy ratings by study partners using the Neuropsychiatric Inventory Questionnaire (NPI‐Q) or the Apathy Evaluation Scale (AES). Cognitive outcomes included performance on measures of processing speed, mental flexibility and immediate and delayed memory. We used linear mixed models to examine association of baseline apathy with cognitive performance measures at multiple time points, and the moderation of apathy‐cognition relationships by plasma Aβ42/40 ratio (C2N, USA). Apathy‐cognitive outcome pairings were selected based on significant findings from a proof‐of‐concept linear mixed effects analysis of the full Wisconsin ADRC sample.ResultResults are shown in Table 2. Among AA‐FAIM participants, NPI‐Q apathy was associated with RAVLT immediate (estimate = ‐7.7, p = .001) and delayed recall (estimate = ‐3.2, p = .001). However, AES was unrelated to Trails A or B performance. There were no associations between plasma amyloid or the Aβ42/40*apathy interaction term with any cognitive outcomes.ConclusionPartner‐rated apathy, but not plasma Aβ42/40, was related to cognition in our African American participants, an important finding given limited data available on this population. It will be critical to address apathy and its antecedents to improve the cognitive and affective health of African American older adults. Future research needs to expand cohorts to African American and other diverse populations to investigate disease mechanisms in Alzheimer’s disease and related dementias more inclusively.

Background:Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) can be disruptive for patients and their families.Objective:We aimed to classify patients based on NPS and to explore the relationship of these classes with sex and with caregiver burden.Methods:The study cohort comprised individuals with AD dementia diagnosed at Ace Alzheimer Center in Barcelona, Spain, between 2011–2020. NPS were ascertained by using the Neuropsychiatric Inventory-Questionnaire. Latent class analysis was used to identify clusters of individuals sharing a similar NPS profile. We evaluated the caregiver burden using the Zarit Burden Interview. Multivariable regression models were used to obtain adjusted estimates of the association between sex, NPS classes, and caregiver burden.Results:A total of 1,065 patients with AD dementia and their primary caregivers were included. We classified patients into five different classes according to their NPS profile: “Affective”, “High-behavioral-disturbance”, “Negative-affect”, “Affective/deliriant”, and “Apathy”. We found that age, sex, and type of AD diagnosis differed greatly across classes. We found that patients from the “High-behavioral-disturbance” (OR = 2.56, 95% CI: 1.00–6.56), “Negative-affect” (OR = 2.72, 95% CI: 1.26–3.64), and “Affective/deliriant” (OR = 2.14, 95% CI: 1.26–3.64) classes were over two times more likely to have a female caregiver than those in “Apathy” class. These three classes were also the ones associated to the greatest caregiver burden in the adjusted analyses, which seems to explain the increased burden observed among female caregivers.Conclusion:Caregiver burden is highly dependent on the patient’s NPS profiles. Female caregivers provide care to patients that pose a greater burden, which makes them more susceptible to become overwhelmed.

Trajectories of Neuropsychiatric Symptoms and Cognitive Decline in Mild Cognitive Impairment.

Introduction We aimed to evaluate how the presence of individual neuropsychiatric symptoms in non-institutionalised patients with dementia is associated with caregiver burden of their informal caregivers, family members. Methods We performed a cross-sectional study on a total of 131 pairs of one informal caregiver family member and non-institutionalised patient with dementia in a family medicine practices in a city of Zagreb, Croatia. Caregiver measures included Zarit Burden Interview (ZBI) whereas patient measures included Mini mental state examination (MMSE), Barthel index and Neuropsychiatric Inventory Questionnaire (NPI-Q). Results Total NPI-Q score explained 21% of overall burden. In order of strength of the association, after adjustments for age, sex, MMSE and Barthel index, overall burden was significantly associated with higher NPI-Q scores for agitation/aggression, apathy/indifference, irritability/lability, disinhibition, motor disturbance, appetite/eating, depression/dysphoria, anxiety, elation/euphoria and nighttime behaviours. When evaluating mutually independent contribution of unique NPI-Q symptoms to caregiver burden, agitation/aggression and apathy/indifference remained only two mutually independently associated symptoms, each explaining 5% of overall burden in this context. Conclusions Informal caregivers who provide for family members with dementia suffering from agitation/aggression or apathy/indifference should be recognised as under special risk for the development of caregiver burden and considered as candidates for early targeted interventions.

The aim of the study was to investigate the factors that underpin neuropsychiatric symptoms and how they might evolve over time in people with Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD) dementia. Neuropsychiatric symptoms are psychiatric and behavioural manifestations that occur in people with AD. These are highly prevalent along the continuum of the disease, including at the stage of MCI, as well as before cognitive decline. Various small- and large-scale projects have investigated the underlying factors that underpin these symptoms; however, the identification of clear clusters is still a matter of debate; furthermore, no study has investigated how the clusters might change across the development of AD pathology by comparing different time points. Our objective was to investigate the factors that underpin neuropsychiatric symptoms in Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) and to assess how the loadings might differ based on considerations such as the disease stage of the samples. Data was obtained from the Alzheimer's Disease Neuroimaging Initiative database (adni. loni.usc.edu), using scores from the Neuropsychiatric Inventory, followed up yearly from baseline until month 72. Participant groups included those with MCI or AD dementia, or a mixture of both, with all participants presenting with at least one neuropsychiatric symptom. A series of exploratory Principal Component and Factor (Principal Axis) Analyses were performed using Direct Oblimin rotation. The best-fitting structure was interpreted for each time point. A consistent, unique structure could not be identified, as the factors were unstable over time, both within the MCI and AD groups. However, some symptoms showed a tendency to load on the same factors across most measurements (i.e., agitation with irritability, depression with anxiety, elation with disinhibition, delusions with hallucinations). Although the analyses revealed some degree of co-occurrence of neuropsychiatric symptoms across time points/samples, there was also considerable variation. In the AD group, more discrete syndromes were evident at the early time points, whereas a more complex picture of co-occurring symptoms, with differences likely reflecting disease staging, was seen at later time points. As a clear and distinctive factor structure was not consistently identified across time points/ samples, this highlights the potential importance of sample selection (e.g., disease stage and/or heterogeneity) when studying, for example, the neurobiological underpinnings of neuropsychiatric symptoms.