Neuropsychiatric symptoms in at-risk groups for AD dementia and their association with worry and AD biomarkers-results from the DELCODE study.
ABSTRACT: BACKGROUND:Early identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer's disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries. METHODS:We analyzed data of n?=?687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n?=?242), mild cognitive impairment (MCI, n?=?115), AD (n?=?77), CO (n?=?209), and first-degree relatives of AD patients (REL, n?=?44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries. RESULTS:The numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low Aß42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996-1.000, p?
Project description:BACKGROUND:Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer's disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers. METHODS:We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers. RESULTS:Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181. CONCLUSIONS:Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology.
Project description:OBJECTIVE:We investigated different dimensions of subjective cognitive decline (SCD) to determine which was the best prognostic risk factor for incident mild cognitive impairment (MCI) among cognitively unimpaired participants. METHODS:We included 1,167 cognitively unimpaired participants, aged 70 to 95 years, from the Mayo Clinic Study of Aging based on 2 concurrent SCD scales (part of the Blessed memory test and the 39-item Everyday Cognition [ECog] scale, which included a validated 12-item derivative) and a single question assessing worry about cognitive decline. We evaluated multiple ways to dichotomize scores. In continuous models, we compared average scores on 4 ECog domains and multidomain (39- and 12-item) ECog scores. Cox proportional hazards models were used to assess the association between each measure and risk of MCI in models adjusted for objective memory performance, depression, anxiety, sex, APOE ?4 carriership, and medical comorbidities. RESULTS:It was possible to select a substantial group of participants (14%) at increased risk of incident MCI based on combined baseline endorsement of any consistent SCD on the ECog (any item scored ?3; 12-item ECog hazard ratio [HR] 2.17 [95% confidence interval 1.51-3.13]) and worry (HR 1.79 [1.24-2.58]) in an adjusted model combining these dimensions. In continuous models, all ECog domains and the multidomain scores were associated with risk of MCI with a small advantage for multidomain SCD (12-item ECog HR 2.13 [1.36-3.35] per point increase in average score). Information provided by the informant performed comparable to self-perceived SCD. CONCLUSION:Prognostic value of SCD for incident MCI improves when both consistency of SCD and associated worry are evaluated.
Project description:BACKGROUND:Subjective cognitive decline (SCD) defines a heterogeneous population, part of which having Alzheimer's disease (AD). We aimed at characterizing SCD populations according to whether or not they referred to a memory clinic, by assessing the factors associated with increased AD risk. METHODS:Seventy-eight cognitively unimpaired older adults from the IMAP+ study (Caen) were included, amongst which 28 healthy controls (HC) and 50 SCD recruited from the community (SCD-community; n = 23) or from a memory clinic (SCD-clinic; n = 27). Participants underwent cognitive, psychoaffective, structural MRI, FDG-PET, and amyloid-PET assessments. They were followed up over a mean period of 2.4 ± 0.8 years. The groups were compared in terms of baseline and follow-up levels of SCD (self- and informant-reported), cognition, subclinical anxiety and depression, and atrophy progression over time. We also investigated SCD substrates within each SCD group through the correlations between self-reported SCD and other psychometric and brain measures. RESULTS:Compared to HC, both SCD groups showed similar cognitive performances but higher informant-reported SCD and anxiety. Compared to SCD-community, SCD-clinic showed higher informant-reported SCD, depression score, and atrophy progression over time but similar brain amyloid load. A significant increase over time was found for depression in the SCD-community and for self-reported praxis-domestic activities SCD factor in the SCD-clinic. Higher self-reported SCD correlated with (i) lower grey matter volume and higher anxiety in SCD-community, (ii) greater informant-reported SCD in SCD-clinic, and (iii) lower glucose metabolism in both SCD groups. CONCLUSIONS:Higher subclinical depression and informant-reported SCD specifically characterize the SCD group that refers to a memory clinic. The same group appears as a frailer population than SCD-community as they show greater atrophy progression over time. Yet, both the SCD groups were quite similar otherwise including for brain amyloid load and the SCD-community showed increased depression score over time. Altogether, our findings highlight the relevance of assessing psychoaffective factors and informant-reported SCD in SCD populations and point to both differences and similarities in SCD populations referring or not to a memory clinic.
Project description:Subjective cognitive decline (SCD) and biomarker-based "at-risk" concepts such as "preclinical" Alzheimer's disease (AD) have been developed to predict AD dementia before objective cognitive impairment is detectable. We longitudinally evaluated cognitive outcome when using these classifications.Memory clinic patients (n = 235) were classified as SCD (n = 122): subtle cognitive decline (n = 36) and mild cognitive impairment (n = 77) and subsequently subclassified into SCDplus and National Institute on Aging-Alzheimer's Association (NIA-AA) stages 0 to 3. Mean (standard deviation) follow-up time was 48 (35) months. Proportion declining cognitively and prognostic accuracy for cognitive decline was calculated for all classifications.Among SCDplus patients, 43% to 48% declined cognitively. Among NIA-AA stage 1 to 3 patients, 50% to 100% declined cognitively. The highest positive likelihood ratios (+LRs) for subsequent cognitive decline (+LR 6.3), dementia (+LR 3.4), and AD dementia (+LR 6.5) were found for NIA-AA stage 2.In a memory clinic setting, NIA-AA stage 2 seems to be the most successful classification in predicting objective cognitive decline, dementia, and AD dementia.
Project description:Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia. Its cleaved fragments, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF). Previous studies indicate higher CSF sTREM2 in symptomatic AD; however most of these studies have included biomarker positive AD cases and biomarker negative controls. The aim of the study was to explore potential differences in the CSF level of sTREM2 and factors associated with an increased sTREM2 level in patients diagnosed with mild cognitive impairment (MCI) or dementia due to AD compared with cognitively unimpaired controls as judged by clinical symptoms and biomarker category (AT). We included 299 memory clinic patients, 62 (20.7%) with AD-MCI and 237 (79.3%) with AD dementia, and 113 cognitively unimpaired controls. CSF measures of the core biomarkers were applied to determine AT status. CSF sTREM2 was analyzed by ELISA. Patients presented with comparable CSF sTREM2 levels as the cognitively unimpaired (9.6 ng/ml [SD 4.7] versus 8.8 ng/ml [SD 3.6], p?=?0.27). We found that CSF sTREM2 associated with age-related neuroinflammation and tauopathy irrespectively of amyloid ?, APOE ?4 status or gender. The findings were similar in both symptomatic and non-symptomatic individuals.
Project description:Importance:It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms. Objective:To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation. Design, Setting, and Participants:In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals' proximity to the expected onset of dementia. Cross-sectional measures of carbon 11-labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24 PSEN1 E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpaired and 3 of whom had mild cognitive impairment, and 12 cognitively unimpaired noncarriers. Main Outcomes and Measures:We compared carbon 11-labeled Pittsburgh Compound B PET cerebral with cerebellar distribution volume ratios as well as flortaucipir F 18 PET cerebral with cerebellar standardized uptake value ratios in mutation carriers and noncarriers. Spearman correlations characterized the associations between age and mean cortical Pittsburgh Compound B distribution volume ratio levels or regional flortaucipir standardized uptake value ratio levels in both groups. Results:Of the 24 individuals, the mean (SD) age was 38.0 (7.4) years, or approximately 6 years younger than the expected onset of clinical symptoms in carriers. Compared with noncarriers, cognitively unimpaired mutation carriers had elevated mean cortical Pittsburgh Compound B distribution volume ratio levels in their late 20s, and 7 of 9 carriers older than 30 years reached the threshold for amyloidosis (distribution volume ratio level > 1.2). Elevated levels of tau deposition were seen within medial temporal lobe regions in amyloid-positive mutation carriers 6 years before clinical onset of AD in this kindred. Substantial tau deposition in the neocortex was only observed in 1 unimpaired carrier and in those with mild cognitive impairment. β-Amyloid uptake levels were diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment. In carriers, higher levels of tau deposition were associated with worse performance on the Mini-Mental State Examination (entorhinal cortex: r = -0.60; P = .04; inferior temporal lobe: r = -0.54; P = .06) and the Consortium to Establish a Registry for Alzheimer Disease Word List Delayed Recall (entorhinal cortex: r = -0.86; P < .001; inferior temporal lobe: r = -0.70; P = .01). Conclusions and Relevance:The present findings add to the growing evidence that molecular markers can characterize biological changes associated with AD in individuals who are still cognitively unimpaired. The findings also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptoms of AD and to track disease progression.
Project description:Objective: Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer's Disease (AD). Early disease processes, such as amyloid-? aggregation measured with quantitative PET, may help to explain the phenotype of SCD. The aim of this study was to investigate whether quantitative amyloid-? load is associated with both self- and informant-reported cognitive complaints and memory deficit awareness in individuals with SCD. Methods: We included 106 SCD patients (mean ± SD age: 64 ± 8, 45%F) with 90 min dynamic [18F]florbetapir PET scans. We used the following questionnaires to assess SCD severity: cognitive change index (CCI, self and informant reports; 2 × 20 items), subjective cognitive functioning (SCF, four items), and five questions "Do you have complaints?" (yes/no) for memory, attention, organization and language), and "Does this worry you? (yes/no)." The Rivermead Behavioral Memory Test (RBMT)-Stories (immediate and delayed recall) was used to assess objective episodic memory. To investigate the level of self-awareness, we calculated a memory deficit awareness index (Z-transformed (inverted self-reported CCI minus episodic memory); higher index, heightened self-awareness) and a self-proxy index (Z-transformed self- minus informant-reported CCI). Mean cortical [18F]florbetapir binding potential (BPND) was derived from the PET data. Logistic and linear regression analyses, adjusted for age, sex, education, and depressive symptoms, were used to investigate associations between BPND and measures of SCD. Results: Higher mean cortical [18F]florbetapir BPND was associated with SCD-related worries (odds ratio = 1.76 [95%CI = 1.07 ± 2.90]), but not with other SCD questionnaires (informant and self-report CCI or SCF, total scores or individual items, all p > 0.05). In addition, higher mean cortical [18F]florbetapir BPND was associated with a higher memory deficit awareness index (Beta = 0.55), with an interaction between BPND and education (p = 0.002). There were no associations between [18F]florbetapir BPND and self-proxy index (Beta = 0.11). Conclusion: Amyloid-? deposition was associated with SCD-related worries and heightened memory deficit awareness (i.e., hypernosognosia), but not with severity of cognitive complaints. Our findings indicate that worries about self-perceived decline may reflect an early symptom of amyloid-? related pathology rather than subjective cognitive functioning.
Project description:Subjective cognitive decline (SCD) is a risk factor for mild cognitive impairment (MCI) and Alzheimer's disease (AD). Although sleep has been shown to be altered in MCI and AD, little is known about sleep in SCD.Seventy cognitively normal community-dwelling participants were classified as SCD (32) or controls (38) using the Subjective Cognitive Decline Questionnaire. Sleep was assessed using actigraphy and diaries. FreeSurfer was used for performing medial temporal lobes (MTLs) and brain cortical parcellation of 3T magnetic resonance images. Multiple regression models were used to assess the presence of sleep, MTL, or regional cortical differences between groups.Objective sleep was disrupted in SCD participants, which showed increased nighttime wakefulness and reduced sleep efficiency. No group differences emerged in subjective sleep or magnetic resonance imaging outcomes.Objective sleep resulted disrupted in community-dwelling SCD, without any subjective sleep or cortical change. Sleep assessment/intervention in SCD might help prevent/delay AD onset.
Project description:Introduction:Amyloid beta (A?) pathology is an Alzheimer's disease early hallmark. Here we assess the value of longitudinal self- and informant reports of cognitive decline to predict A? positron emission tomography (PET) outcome in cognitively unimpaired middle-aged individuals. Methods:A total of 261 participants from the ALFA+ study underwent [18F]flutemetamol PET and Subjective Cognitive Decline Questionnaire (SCD-Q) concurrently, and 3 years before scan. We used logistic regressions to evaluate the ability of SCD-Q scores (self and informant) to predict A? PET visual read, and repeated analysis of variance to assess whether changes in SCD-Q scores relate to A? status. Results:Self-perception of decline in memory (odds ratio [OR] = 1.2), and informant perception of executive decline (OR = 1.6), increased the probability of a positive scan. Informant reports 3 years before scanning predicted A? PET outcome. Longitudinal increase of self-reported executive decline was predictive of A? in women (P = .003). Discussion:Subjective reports of cognitive decline are useful to predict A? and may improve recruitment strategies.
Project description:BACKGROUND:Multimorbidity (defined as ≥2 chronic conditions) has been associated with increased risk of mild cognitive impairment and cross-sectionally with imaging biomarkers of neurodegeneration in cognitively unimpaired persons aged ≥70 years. Its association with preclinical Alzheimer's disease stages has not been studied in detail yet. The objective of the study was to assess the cross-sectional association of multimorbidity with preclinical Alzheimer's disease stages and suspected non-amyloid pathophysiology in cognitively unimpaired participants of the Mayo Clinic Study of Aging (≥50 years of age). METHODS:The study included 1,535 cognitively unimpaired participants with multimorbidity, 11C-PiB positron emission topography and magnetic resonance imaging data available. Abnormal (elevated) 11C-PiB-positron emission topography retention ratio (A+; standardized uptake value ratio >1.42) and abnormal (reduced) Alzheimer's disease signature cortical thickness (N+; <2.67 mm) were used to define biomarker combinations (A-N-, A+N-, A-N+, A+N+). Chronic medical conditions were ascertained by using the Rochester Epidemiology Project medical records linkage system and International Classification of Diseases criteria. Cross-sectional associations were examined using multinomial logistic regression models adjusting for age, sex, education, and apolipoprotein E ɛ4 allele status. RESULTS:Frequency of A+, N+, A+N+, and A-N+ biomarker groups increased significantly with increasing number of chronic conditions. Multimorbidity was significantly associated with A+N+ (vs A-N-; odds ratio, 1.76, 95% confidence interval 1.02, 2.90) and A-N+ (vs A-N-; odds ratio, 2.16, 95% confidence interval 1.47, 3.18). There was a dose-response relationship between increasing number of chronic conditions (eg, 0-1, 2-3, and 4+) and the odds of A+N+ and A-N+ (vs A-N-). CONCLUSIONS:Multimorbidity was associated with biomarker combinations that included neurodegeneration with or without elevated amyloid deposition (ie, A-N+, A+N+). The associations should be validated in longitudinal studies.