Neuropsychiatric Symptom Burden Research Articles

Neuropsychiatric symptoms and neuroimaging-based brain age in mild cognitive impairment and early dementia: A multicenter study.

Despite the clinical importance and significant social burden of neuropsychiatric symptoms (NPS) in dementia, the underlying neurobiological mechanism remains poorly understood. Recently, neuroimaging-derived brain-age estimation by machine-learning analysis has shown promise as an individual-level biomarker. We investigated the relationship between NPS and brain-age in amnestic mild cognitive impairment (MCI) and early dementia. In this cross-sectional study, clinical data, including neuropsychiatric inventory (NPI), and structural brain MRI of 499 individuals with clinical diagnoses of amnestic MCI (n = 185), early Alzheimer's disease (AD) (n = 258) or dementia with Lewy bodies (DLB) (n = 56) were analyzed. We established a brain-age prediction model using 694 healthy brain MRIs and a support vector regression model and applied it to the participants' data. Finally, the brain-predicted age difference (brain-PAD: predicted age minus chronological age) was calculated. All groups showed significantly increased brain-PAD, and the median (IQR) brain-PAD was 4.3 (5.4) years in MCI, 6.3 (6.2) years in AD, and 5.0 (6.5) years in DLB. The NPI scores were subdivided into the following four categories: (i) Agitation and Irritability, (ii) Depression and Apathy, (iii) Delusions and Hallucinations, and (iv) Euphoria and Disinhibition. We found a significantly positive correlation between brain-PAD and the depression/apathy factor (Spearman's rs = 0.156, FDR-corrected P = 0.002), whereas no significance was shown for the other NPS factors. Higher brain-age may be associated with depression and apathy symptoms presented in MCI to early dementia stages, and brain-age analysis may be useful as a novel biomarker for the assessment or monitoring of NPS.

Depression, Anxiety, and Neuropsychiatric Symptom Burden in a Longitudinal Cohort with Persistent Psychophysical Post-COVID Olfactory Dysfunction.

Olfactory dysfunction (OD) is associated with a variety of neurologic deficits and impacts socialization decisions, mood, and overall quality of life. As a common symptom comprising the long COVID condition, persistent COVID-19-associated olfactory dysfunction (C19OD) may further impact the presentations of neuropsychiatric sequelae. Our study aims to characterize the longitudinal burden of depression, anxiety, and neuropsychiatric symptoms in a population with C19OD. Individuals with perceived C19OD completed a psychophysical screening evaluation of their sense of smell using the comprehensive Sniffin' Sticks olfactory assessment. Only those with validated psychophysical OD were included in this prospective longitudinal study for baseline and one-year follow-up. Participants also completed PHQ-9, Beck Anxiety Inventory (BAI), and neuropsychiatric symptom questionnaires at each time point. Anxiety, depression, and neuropsychiatric symptom prevalence was calculated and compared between time points with Pearson's chi-squared, Fisher's exact, and Wilcoxon rank sum tests. Each neuropsychiatric symptom evaluated in this study was reported by 13-49% of longitudinal cohort participants at both baseline and follow-up, except for seizure (0% at baseline and follow-up) and word-finding difficulty (61-68% at baseline and follow-up). Word-finding and focus difficulties were the most commonly reported symptoms. In total, 41% of participants reported some level of depression at baseline and 38% of participants reported depression at one-year follow-up, while 29% and 27% of participants reported some level of anxiety at respective time points. Individuals with C19OD are at risk for developing persistent neuropsychiatric conditions. These neurologic and psychiatric sequelae are persistent with repeated longitudinal assessment, even at nearly 2.5 years following initial COVID-19 diagnosis.

Sex Differences in Cortical Thickness and Neuropsychiatric Symptom Burden Based on APOE4 Homozygosity in Alzheimer's Disease.

Sex differences in patterns of cortical thickness and neuropsychiatric symptom (NPS) burden were examined among individuals with Alzheimer's disease (AD) and two copies (homozygote carriers) of the e4 allele of the apolipoprotein gene (APOE). A total of 752 participants with a clinical etiologic diagnosis of AD were selected from the National Alzheimer's Coordinating Center (NACC) database. Bayesian multilevel regression was used to examine both the within- and between-sex differences in gray-matter cortical thickness and total NPS burden associated with APOE homozygosity. Female homozygote carriers displayed a high probability of having reduced cortical thickness primarily in medial-lateral temporal regions and a greater burden of NPS, relative to both non-homozygous females and homozygous males. These findings support the notion that APOE4 status affects cortical thickness and symptom burden in men and women with AD differentially, with females showing more pronounced effects in brain areas known to be vulnerable in early AD. Future investigations should attempt to elucidate the proposed pattern of decline longitudinally.

Locus coeruleus integrity and neuropsychiatric symptoms in a cohort of early- and late-onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) shows a higher burden of neuropsychiatric symptoms than late-onset Alzheimer's disease (LOAD). We aim to determine the differences in the severity of neuropsychiatric symptoms and locus coeruleus (LC) integrity between EOAD and LOAD accounting for disease stage. One hundred four subjects with AD diagnosis and 32 healthy controls were included. Participants underwent magnetic resonance imaging (MRI) to measure LC integrity, measures of noradrenaline levels in cerebrospinal fluid (CSF) and Neuropsychiatric Inventory (NPI). We analyzed LC-noradrenaline measurements and clinical and Alzheimer's disease (AD) biomarker associations. EOAD showed higher NPI scores, lower LC integrity, and similar levels of CSF noradrenaline compared to LOAD. Notably, EOAD exhibited lower LC integrity independently of disease stage. LC integrity negatively correlated with neuropsychiatric symptoms. Noradrenaline levels were increased in AD correlating with AD biomarkers. Decreased LC integrity negatively contributes to neuropsychiatric symptoms. The higher LC degeneration in EOAD compared to LOAD could explain the more severe neuropsychiatric symptoms in EOAD. LC degeneration is greater in early-onset AD (EOAD) compared to late-onset AD. Tau-derived LC degeneration drives a higher severity of neuropsychiatric symptoms. EOAD harbors a more profound selective vulnerability of the LC system. LC degeneration is associated with an increase of cerebrospinal fluid noradrenaline levels in AD.

Neuropsychiatric symptom burden in early-onset and late-onset Alzheimer's disease as a function of age.

We examined the burden of neuropsychiatric symptoms (NPSs) in early-onset (EO) and late-onset (LO) Alzheimer's disease (AD) and adjusted for age effects via the inclusion of cognitively unimpaired (CU) individuals. Cross-sectional data from 2940 EOAD, 8665 LOAD, and 8775 age-stratified CU individuals (early-CU, n=2433; late-CU, n=6342) from the National Alzheimer's Coordinating Center database were included. Fisher's exact tests compared EOAD and LOAD on the presence and severity of NPSs. Multiple logistic regression models included an age*diagnosis interaction to examine age effects. Presence (ps<0.0001) and severity (ps<0.05) of NPS were greater in EOAD than in LOAD. However, after adjusting for base rates in NPS in CU individuals (age effects), only elation and eating behaviors were more frequent in EOAD (ps<0.05) and nighttime behaviors more frequent and severe in LOAD (ps<0.05). Few NPSs were specific to the EOAD versus LOAD. Previous findings of greater NPS burden in EOAD may partially reflect age effects. Adjusting for age effect, elation and eating problems are more frequent in EOAD. Adjusting for age effect, sleep disturbances are more frequent and severe in LOAD. Age effects underlie higher neuropsychiatric symptom presentation in EOAD than in LOAD.

Regional Burden of Enlarged Perivascular Spaces and Cognition and Neuropsychiatric Symptoms in Drug-Naive Patients With Parkinson Disease.

Although the potential role of enlarged perivascular spaces (EPVSs) in Parkinson disease (PD) is increasingly recognized, whether EPVSs located in different anatomical regions exert differential effects on clinical manifestation remains uncertain. We investigated the regional EPVS burden and its association with cognition and neuropsychiatric symptoms (NPSs) in newly diagnosed PD population. In this retrospective, cross-sectional study, EPVS in the temporal lobe (T-EPVS), centrum semiovale (CS-EPVS), and basal ganglia (BG-EPVS) were visually rated in drug-naive patients with PD who underwent magnetic resonance imaging, dopamine transporter (DAT) scans, neuropsychological assessments, and Neuropsychiatric Inventory Questionnaire at baseline. Cognitive performance, NPS burden, vascular risk factors, small vessel disease (SVD) imaging markers, and DAT availability were compared across groups dichotomized by their regional EPVS burden (cutoff for high-degree vs low-degree: >10 for T-EPVS/BG-EPVS and >20 for CS-EPVS). A total of 480 patients with PD (123 without cognitive impairment, 291 with mild cognitive impairment, and 66 with dementia) were included. The proportion of high-degree T-EPVS (p for trend <0.001) and BG-EPVS (p for trend = 0.001) exhibited an increasing trend across the cognitive spectrum, corresponding to worsening cognition. Compared with the low-degree group, the high-degree BG-EPVS group showed higher SVD burden (moderate-to-severe white matter hyperintensity [14.8% vs 40.5%, p < 0.001], lacune [10.3% vs 30.7%, p < 0.001], and cerebral microbleeds [8.1% vs 22.2%, p < 0.001]), greater atrophy in cortical gray matter (40.73% ± 1.09% vs 39.96% ± 1.20% of intracranial volume, p < 0.001), and lower cognitive performance (in language [-0.22 ± 1.18 vs -0.53 ± 1.29, p = 0.013], and visual memory domains [-0.24 ± 0.97 vs -0.61 ± 0.96, p = 0.009]). The high-degree T-EPVS group presented with greater NPS burden in decreased motivation (0.61 ± 1.78 vs 1.35 ± 2.36, p = 0.007), affective dysregulation (0.88 ± 2.13 vs 2.36 ± 3.53, p < 0.001), and impulse dyscontrol (0.43 ± 1.67 vs 1.74 ± 4.29, p < 0.001), compared with the low-degree T-EPVS group. Meanwhile, the burden of CS-EPVS did not reveal any differences in cognition or NPS. BG-EPVS and T-EPVS seem to exert differential effects on cognition and NPS in patients with PD. Investigating the EPVS profile in distinct anatomical regions may be useful in disentangling the heterogeneity within PD.

Sex‐specific neuropsychiatric burden distinguished by APOE4 status and cortical thickness

AbstractBackgroundThe APOE ε4 (APOE4) allele is a genetic risk factor for Alzheimer’s disease (AD). Prior work by our group found a significant association between the APOE4 allele and presence of psychosis as well as overall increased neuropsychiatric symptom (NPS) burden in female APOE4 homozygote AD patients, with no effect present in males. In this study, we sought to examine the relationship between APOE4 carrier status and sex on NPS burden from a neuroimaging perspective, with the aim to determine what brain regions may be driving this effect.MethodA cohort of 752 AD patients were selected from the National Alzheimer’s Coordinating Center (NACC) database: 104 APOE4 homozygotes (40F|64M), 304 APOE4 heterozygotes (160F|144M) and 310 APOE4 non‐carriers (131F|179M). Presence of NPS was identified using the Neuropsychiatric Inventory (NPI). Structural T1‐weighted images were downloaded from the NACC imaging dataset and cortical thickness measures corresponding to frontal, cingulate, temporal and parietal regions were assessed. Statistical analysis included a Bayesian multilevel regression where cortical thickness was modeled as an outcome variable against an interaction between sex and APOE4 homozygote status (0|1), while controlling for heterozygote status, APOE4 non‐carrier status, age, sex and MMSE as predictor variables. Within‐ and between‐groups mean differences in thickness were measured as a probability density estimate (Highest Density interval), and partial correlation was used to examine NPI correlates to thickness.ResultFemale APOE4 homozygotes displayed a high probability (&gt;90%HDI) of greater cortical thickness in the posterior cingulate and isthmus cingulate regions bilaterally and reduced cortical thickness in temporal regions (Figure 1). Cortical thickness in the fusiform cortex was positively correlated to greater NPI burden (p&lt;0.05) among female homozygotes, and negatively correlated to NPI burden among female heterozygotes. Cortical thickness in males, regardless of carrier status, did not correlate to NPI burden in any region.ConclusionThis study highlights an important relationship between the fusiform cortex and NPI burden in female APOE4 carriers, marking a female‐specific effect. Future work should further disentangle sex differences in APOE4 status and psychosis with a focus on the fusiform cortex as a potential region of interest.

Clinical Manifestations.

Early and reliable detection of Alzheimer's disease (AD) is fundamental in an era with novel disease modifying treatments on the market. Late in life emerging neuropsychiatric symptoms (NPS) (e.g., apathy, anxiety, depression) have been reported prevalent among cognitively unimpaired (CU) older adults, as well as among patients with Mild Cognitive Impairment (MCI). Findings have indicated that NPS can emerge prior to MCI in ∼50% of cases that subsequently develop a neurocognitive disorder (NCD). Additionally, ∼30% of AD patients have been reported to have received a primary psychiatric diagnosis before their final NCD diagnosis. Combined, these studies point to NPS as important early clinical manifestations of AD. NPS have furthermore been related to several clinically negative outcomes, such as reduced quality of life, increased caregiver burden and earlier institutionalization. Some reports even indicate that NPS can be stronger related to these outcomes than cognition. Importantly, several studies have demonstrated NPS to be predictive of future cognitive decline, dementia, or AD. For example, anxiety in non-demented subjects has consistently been shown to interact with beta-amyloid yielding accelerated cognitive decline. NPS are further demonstrated related to AD neuropathological changes including beta-amyloid, tau, and neurodegeneration. For instance, beta-amyloid in initially CU elderly has been demonstrated associated with steeper development of NPS over time. Intriguingly, an earlier study has reported the overall burden of NPS to precede memory deficits in its association with early tau deposition in amyloid-beta positive CU subjects, results supportive of NPS as early markers of dementing biochemical processes. Despite this growing evidence of being both prevalent and early prognostic markers, as well as associated with AD pathology, NPS are only given diminutive consideration in contemporary clinical AD diagnostic criteria. Perhaps so since the added value of NPS in such criteria has rarely been investigated. Consequently, CU subjects with a positive NPS and biomarker status face the risk of not being eligible for a disease modifying treatment since they formally do not fulfill diagnostic criteria for AD. Hence, studies exploring the added value of NPS in clinical diagnostic criteria for AD are prompted.

Specific neuropsychiatric symptoms are associated with functional decline trajectories in Alzheimer's disease and Lewy body dementia: a five-year follow-up study.

Neuropsychiatric symptoms (NPS) are often overlooked and under-identified symptoms associated with dementia, despite their significant impact on the prognosis of individuals living with the disease. The specific role of certain NPS in functional prognosis remains unclear. To determine the association of different NPS with functional decline in people living with Alzheimer's disease (AD) or Lewy body dementia (LBD). This is an analysis of data from the Dementia Study of Western Norway (DemVest) with 196 patients included of which 111 had AD and 85 LBD. The Neuropsychiatric Inventory (NPI) and the Rapid Disability Rating Scale (RDRS-2) for activities of daily living were administered annually for 5 years. NPI total score and individual items with RDRS-2 trajectories were analyzed with linear mixed models. The LBD group exhibited higher levels of functional impairment and a greater burden of NPS at baseline. Over the 5-year follow-up, hallucinations, aggression, depression, anxiety, apathy, disinhibition, aberrant motor behavior, nighttime behavior disturbances, and abnormal eating patterns were significantly associated with the decline in functional abilities in individuals with AD, as well as irritability and aberrant motor behavior in those with LBD. These results highlight the relevance of early detection and intervention of these particularly relevant NPS, due to its potential of also impacting physical function. Better detection and management of these NPS could improve functional prognosis in people living with dementia. Specific NPS demonstrate relevant distinct associations with Longitudinal trajectories of functional decline in AD and LBD.

Neuropsychiatric features in a multi-ethnic population with Alzheimer disease and mild cognitive impairment.

Alzheimer disease (AD) is more prevalent in African American (AA) and Hispanic White (HIW) compared to Non-Hispanic White (NHW) individuals. Similarly, neuropsychiatric symptoms (NPS) vary by population in AD. This is likely the result of both sociocultural and genetic ancestral differences. However, the impact of these NPS on AD in different groups is not well understood. Self-declared AA, HIW, and NHW individuals were ascertained as part of ongoing AD genetics studies. Participants who scored higher than 0.5 on the Clinical Dementia Rating (CDR) Scale (CDR) were included. Group similarities and differences on Neuropsychiatric Inventory Questionnaire (NPI-Q) outcomes (NPI-Q total score, NPI-Q items) were evaluated using univariate ANOVAs and post hoc comparisons after controlling for sex and CDR stage. Our sample consisted of 498 participants (26% AA; 30% HIW; 44% NHW). Overall, NPI-Q total scores differed significantly between our groups, with HIW having the highest NPI-Q total scores, and by AD stage as measured by CDR. We found no significant difference in NPI-Q total score by sex. There were six NPI-Q items with comparable prevalence in all groups and six items that significantly differed between the groups (Anxiety, Apathy, Depression, Disinhibition, Elation, and Irritability). Further, within the HIW group, differences were found between Puerto Rican and Cuban American Hispanics across several NPI-Q items. Finally, Six NPI-Q items were more prevalent in the later stages of AD including Agitation, Appetite, Hallucinations, Irritability, Motor Disturbance, and Nighttime Behavior. We identified differences in NPS among HIW, AA, and NHW individuals. Most striking was the high burden of NPS in HIW, particularly for mood and anxiety symptoms. We suggest that NPS differences may represent the impact of sociocultural influences on symptom presentation as well as potential genetic factors rooted in ancestral background. Given the complex relationship between AD and NPS it is crucial to discern the presence of NPS to ensure appropriate interventions.

Examining the sex-specific association between APOE ε4 status and increased neuropsychiatric symptom burden in populations at risk for Alzheimer's disease

Examining the sex-specific association between APOE ε4 status and increased neuropsychiatric symptom burden in populations at risk for Alzheimer's disease

Association of Neuropsychiatric Symptom Profiles With Cognitive Decline in Patients With Parkinson Disease and Mild Cognitive Impairment.

Neuropsychiatric symptoms (NPS) are closely associated with cognitive decline in patients with Parkinson's disease (PD). We investigated which profiles of NPS are associated with the risk of dementia in PD with mild cognitive impairment (PD-MCI). We retrospectively assessed 338 patients with PD-MCI from a single tertiary hospital, who underwent neuropsychological tests and a neuropsychiatric inventory (NPI) questionnaire. We conducted a factor analysis of the dichotomized presence of 12 NPI symptoms, yielding three NPI factors: factor 1, mood symptoms; factor 2, hyperactivity-related symptoms; and factor 3, psychotic symptoms. Factor analysis of the severity of NPI symptoms also identified similar NPI factors. The neuropsychiatric correlates of NPI factors were evaluated using general linear models for cognitive tests. Subsequently, we evaluated the hazard ratio (HR) of NPI factors on conversion to dementia. A higher prevalence factor 1 score was associated with lower scores in the verbal memory (β = -0.15; 95% confidence interval [CI] = -0.24 - -0.06; p = 0.001) and executive domains (β = -0.16; 95% CI = -0.28 - -0.04; p = 0.007), whereas higher severity factor 2 scores were associated with lower scores in the naming (β = -0.16; 95% CI = -0.28 - -0.03; p = 0.012), visuospatial (β = -0.24; 95% CI = -0.41 - -0.07; p = 0.005), and verbal memory domains (β = -0.15; 95% CI = -0.24 - -0.05; p = 0.005). A higher severity factor 3 score was associated with lower scores in the visuospatial domain (β = -0.25; 95% CI = -0.46 - -0.07; p = 0.007). Cox regression models demonstrated that the risk of dementia was increased in those with higher prevalence factor 1 (HR = 1.48, 95% CI = 1.17 - 1.88, p = 0.001) and factor 2 scores (HR = 1.27, 95% CI = 1.07 - 1.51, p = 0.007) and severity factor 3 score (HR = 1.52, 95% CI = 1.29 - 1.80, p < 0.001) after adjusting for age, sex, education, disease duration, scores for cognition and parkinsonism, and levodopa equivalent dose. This study demonstrated that a higher burden of NPS is associated with dementia conversion in patients with PD-MCI.

Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort.

We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n=212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n=70). Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.

Associations between neuropsychiatric symptoms, pathology, and survival in an autopsy-confirmed cohorts of Alzheimer’s disease, Alzheimer’s disease with Lewy bodies and Dementia with Lewy bodies (S39.008)

Associations between neuropsychiatric symptoms, pathology, and survival in an autopsy-confirmed cohorts of Alzheimer’s disease, Alzheimer’s disease with Lewy bodies and Dementia with Lewy bodies (S39.008)

ADVANCE-TBI study protocol: traumatic brain injury outcomes in UK military personnel serving in Afghanistan between 2003 and 2014 – a longitudinal cohort study

IntroductionOutcomes of traumatic brain injury (TBI) are highly variable, with cognitive and psychiatric problems often present in survivors, including an increased dementia risk in the long term. Military personnel are...

Neuropsychiatric Symptom Burden across Neurodegenerative Disorders and its Association with Function.

Neuropsychiatric symptoms (NPS) are prevalent in neurodegenerative disorders, however, their frequency and impact on function across different disorders is not well understood. We compared the frequency and severity of NPS across Alzheimer's disease (AD) (either with mild cognitive impairment or dementia), Cerebrovascular disease (CVD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), and explored the association between NPS burden and function. We obtained data from Ontario Neurodegenerative Disease Research Initiative (ONDRI) that included following cohorts: AD (N = 111), CVD (N = 148), PD (N = 136), FTD (N = 50) and ALS (N = 36). We compared the frequency and severity of individual NPS (assessed by the neuropsychiatric inventory questionnaire) across cohorts using generalized estimating equations and analysis of variance. Second, we assessed the relationship of NPS burden with instrumental (iADLs) and basic (ADLs) activities of living across cohorts using multivariate linear regression while adjusting for relevant demographic and clinical covariates. Frequency of NPS varied across cohorts (χ2(4) = 34.4, p < .001), with post-hoc tests showing that FTD had the greatest frequency as compared to all other cohorts. The FTD cohort also had the greatest severity of NPS (H(4) = 34.5, p < .001). Further, there were differences among cohorts in terms of the association between NPS burden and ADLs (F(4,461) = 3.1, p = 0.02). Post-hoc comparisons suggested that this finding was driven by the FTD group, however, the differences did not remain significant following Bonferroni correction. There were no differences among cohorts in terms of the association between NPS burden and IADLs. NPS frequency and severity are markedly greater in FTD as compared to other neurodegenerative diseases. Further, NPS burden appears to be associated differently with function across neurodegenerative disorders, highlighting the need for individualized clinical interventions.

Sex Modifies the Associations of APOEɛ4 with Neuropsychiatric Symptom Burden in Both At-Risk and Clinical Cohorts of Alzheimer's Disease.

Recent work suggests that APOEɛ4/4 females with Alzheimer's disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS). To examine the interaction of sex and APOEɛ4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n = 252) and 2) patients with probable AD (n = 7,261). Regression models examined the interactive effects of sex and APOEɛ4 on the number of NPS experienced and NPS Severity. APOEɛ3/4 and APOEɛ4/4 were pooled in the at-risk cohort due to the sample size. In the at-risk cohort, there was a significant sex*APOEɛ4 interaction (p = 0.007) such that the association of APOEɛ4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOEɛ4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOEɛ4/4 females had significantly more NPS (IRR = 1.1, p = 0.001, mean = 3.1) and higher severity scores (b = 0.31, p = 0.015, mean = 3.7) than APOEɛ3/3 females (meanNPS = 2.9, meanSeverity = 3.3). No association was found in males. Our study suggests that sex modifies the association of APOEɛ4 on NPS burden. APOEɛ4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed.

Projection in Proxy Assessments of Everyday Preferences for Persons with Cognitive Impairment

AbstractBackgroundA source of bias in surrogate decision‐making has been articulated alternatively as the false consensus effect, assumed similarity, and attributive/social projection by which proxies overestimate the degree that their values and preferences are shared by others, resulting in a projection of their own beliefs onto others in the process of surrogate decision‐making. The aims of this study are to assess for projection of proxies’ preferences onto surrogate assessments of everyday preferences for persons with cognitive impairment (CI) and to address cognitive and neuropsychiatric symptom burden as predictors of projection.MethodThe sample included 116 dyads of persons with CI (Clinical Dementia Rating Scale score ≥ 0.5) and their care partners. The Preferences for Everyday Living Inventory (PELI) was used to assess importance of preferences among persons with CI. Care partners completed two separate PELI assessments: one from the perspective of the persons with CI (i.e., acting as a surrogate decision‐maker) and one from their own perspective. To assess for projection of care partners’ preferences onto surrogate assessments of preferences for persons with CI, two‐step regression with multivariable‐adjusted general linear models was used.ResultSignificant projection effects were noted within the PELI domains of autonomous choice, personal growth, and keeping a routine (p &lt; 0.0005). More significant cognitive impairment was associated with increased projection effects within the PELI domains of autonomous choice and personal growth (p &lt; 0.01)ConclusionThe results of this study suggest that projection effects of care partners own preferences may be a significant source of bias in everyday proxy decision‐making for persons with CI, particularly for those with more significant CI.

Posterior Cortical Atrophy: Primary Occipital Variant

AbstractBackgroundPosterior Cortical Atrophy (PCA) is one of the atypical Alzheimer’s Disease (AD) variants, characterized by predominant visuospatial and visuoperceptual deficits, with dorsal and ventral subtypes recognized clinically and radiographically. A third primary occipital (caudal) variant has been suggested. The objective of this study was to determine its demographics, clinical manifestations, and biomarker findings.MethodFifty‐two PCA patients with positive amyloid PET scans were investigated. Patients underwent neuropsychological assessment, 3T MRI imaging and FDG‐, amyloid‐ and tau‐PET scans. Regional FDG‐PET values were normalized to the pons and represented as z‐scores relative to a control population. Patients were divided into “primary occipital” and “other PCA” subgroups according to FDG‐PET defined criteria, with primary occipital defined as patients in which the z‐scores for occipital subregions were at least one standard deviation lower (i.e., more abnormal) than the z scores in all other brain regions. Global amyloid‐PET, temporoparietal FDG‐PET and temporal tau‐PET regions‐of‐interest (ROI) were calculated. Student’s T test and Fisher’s exact analyses were used to investigate differences in demographics, clinical findings, and imaging biomarkers across the two groups.ResultNine patients were classified as primary occipital; primary occipital patients were older (64.8±6.9 versus 59.3±6.8, p=0.034) and had more years of education (17.7±1.7 versus 15.1±2.6, p=0.007) compared to the other PCA patients. Clinical evaluation revealed worse performance for the primary occipital group on the Ishihara test for color perception (p&lt;0.001), while the other PCA patients performed worse on the Western Aphasia Battery (WAB) praxis scale (p=0.005). Overall neuropsychiatric symptom burden as defined by the NPI‐Q was lower in the primary occipital group (p&lt;0.001). The FDG‐PET meta‐ROI (weighted median uptake in angular gyrus, posterior cingulate, and inferior temporal ROIs, normalized to the pons and vermis) was higher in the primary occipital subtype (p=0.006), but no differences were observed in amyloid and tau‐PET.ConclusionClinical and biomarker findings suggest primary occipital PCA is characterized by an older age at onset, more color perception dysfunction, less severe ideomotor apraxia and less hypometabolism in temporal‐parietal meta‐ROI compared to more established phenotypes.

Mild behavioral impairment is associated with plasma p‐tau181 in a dementia‐free population

AbstractBackgroundMild behavioral impairment (MBI) is a validated neurobehavioral syndrome describing emergent and persistent neuropsychiatric symptoms (NPS) as an at‐risk state for incident cognitive decline and dementia. In cognitively normal older adults MBI is associated with positron emission tomography and cerebrospinal fluid measured amyloid‐β and tau, the characteristic hallmarks of Alzheimer’s disease (AD). Plasma p‐tau181 is a blood‐based biomarker recently identified as an accessible alternative for in‐vivo detection of AD pathologies. So far, no study has explored plasma p‐tau181 in MBI. Here, we investigated the cross‐sectional and longitudinal associations of MBI with plasma p‐tau181 in dementia‐free older adults, and the associations of MBI with risk of AD.MethodThe sample included Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants who were cognitively unimpaired (CU) or had mild cognitive impairment (MCI). MBI status was determined using NPS total score at baseline and year‐one. NPS scores were derived from the Neuropsychiatric Inventory and categorized as persistent NPS (i.e., MBI, score&gt;0 at both visits); transient/impersistent NPS (score&gt;0 at only one visit); and no NPS (score = 0 at both visits). Cross‐sectionally, linear regression models were fitted with p‐tau181 as dependent variable and NPS profile as independent variable. Longitudinally, Cox proportional hazards models examined associations between NPS profile and incident dementia. Multilevel linear mixed effect (MLME) models assessed the associations between NPS status, categorized as within‐person NPS variability (impersistent NPS, not consistent with MBI) and between‐person NPS burden (persistent NPS, consistent with MBI), and p‐tau181 across four years.ResultThe final sample consisted of 571 dementia‐free participants (age 72.2, 46.8% females). Compared to no NPS, participants with persistent NPS but not transient NPS had higher baseline plasma ptau‐181 levels. Longitudinally, persistent NPS were associated with 3.42 times greater risk for dementia compared to no NPS. MLME analyses on annual measures of NPS and p‐tau181 over four years demonstrated that only the between‐person NPS measure was associated with higher p‐tau181 levels.ConclusionThese findings extend the evidence base that MBI is a clinically relevant syndrome associated with the AD pathophysiological process. Incorporating MBI into clinical screening may help to identify those with preclinical or prodromal AD.