Subjective cognitive complaints and blood biomarkers of neurodegenerative diseases: a longitudinal cohort study

Background Subjective cognitive complaints (SCC) have been mostly studied in the context of Alzheimer's disease in memory clinic settings. The potential of combining SCC with genetic information and blood biomarkers of neurodegenerative diseases for risk assessment of dementia and depression in the absence of dementia among community-dwelling older adults has so far not been explored.Methods Data were based on a population-based cohort of 6357 participants with a 17-year follow-up (ESTHER study) and a clinic-based cohort of 422 patients. Participants of both cohorts were grouped according to the diagnosis of dementia (yes/no) and the diagnosis of depression in the absence of dementia (yes/no). Participants without dementia included both cognitively unimpaired participants and cognitively impaired participants. Genetic information (APOE epsilon 4 genotype) and blood-based biomarkers of neurodegenerative diseases (glial fibrillary acidic protein;GFAP, neurofilament light chain;NfL, phosphorylated tau181;p-tau181) were available in the ESTHER study and were determined with Simoa Technology in a nested case-control design. Logistic regression models adjusted for relevant confounders were run for the outcomes of all-cause dementia and depression in the absence of dementia.Results The results showed that persistent SCC were associated both with increased risk of all-cause dementia and of depression without dementia, independently of the diagnostic setting. However, the results for the ESTHER study also showed that the combination of subjective complaints with APOE epsilon 4 and with increased GFAP concentrations in the blood yielded a substantially increased risk of all-cause dementia (OR 5.35;95%CI 3.25-8.81, p-value < 0.0001 and OR 7.52;95%CI 2.79-20.29, p-value < 0.0001, respectively) but not of depression. Associations of NfL and p-tau181 with risk of all-cause dementia and depression were not statistically significant, either alone or in combination with SCC, but increased concentrations of p-tau181 seemed to be associated with an increased risk for depression.Conclusion In community and clinical settings, SCC predict both dementia and depression in the absence of dementia. The addition of GFAP could differentiate between the risk of all-cause dementia and the risk of depression among individuals without dementia

Associations between sex, body mass index and the individual microglial response in Alzheimer's disease

Background and objectives18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer's disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between beta-amyloid-accumulation and microglial activation in AD.Methods49 patients with AD (29 females, all A beta-positive) and 15 A beta-negative CN (8 female) underwent TSPO-PET ([18F]GE-180) and beta-amyloid-PET ([18F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([18F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional A beta-PET on TSPO-PET was used to determine the A beta-plaque-dependent microglial response (slope) and the A beta-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI).ResultsIn AD, females showed higher mean cortical TSPO-PET z-scores (0.91 +/- 0.49;males 0.30 +/- 0.75;p = 0.002), while A beta-PET z-scores were similar. The A beta-plaque-independent microglial response was stronger in females with AD (+ 0.37 +/- 0.38;males with AD - 0.33 +/- 0.87;p = 0.006), pronounced at the prodromal stage. On the contrary, the A beta-plaque-dependent microglial response was not different between sexes. The A beta-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the A beta-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F(3,52) = 3.077, p = 0.005).ConclusionWhile microglia response to fibrillar A beta is similar between sexes, women with AD show a stronger A beta-plaque-independent microglia response. This sex difference in A beta-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the A beta-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD

Microglial activation and connectivity in Alzheimer disease and aging

OBJECTIVE Alzheimer disease (AD) is characterized by amyloid β (Aβ) plaques and neurofibrillary tau tangles, but increasing evidence suggests that neuroinflammation also plays a key role, driven by the activation of microglia. Aβ and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive whether microglial activation follows a similar distribution pattern. Here, we assess whether connectivity is associated with microglia activation patterns. METHODS We included 32 Aβ-positive early AD subjects (18 women, 14 men) and 18 Aβ-negative age-matched healthy controls (10 women, 8 men) from the prospective ActiGliA (Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease) study. All participants underwent microglial activation positron emission tomography (PET) with the third-generation mitochondrial 18 kDa translocator protein (TSPO) ligand [18 F]GE-180 and magnetic resonance imaging (MRI) to measure resting-state functional and structural connectivity. RESULTS We found that inter-regional covariance in TSPO-PET and standardized uptake value ratio was preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation. AD patients showed increased TSPO-PET tracer uptake bilaterally in the anterior medial temporal lobe compared to controls, and higher TSPO-PET uptake was associated with cognitive impairment and dementia severity in a disease stage-dependent manner. INTERPRETATION Microglial activation distributes preferentially along highly connected brain regions, similar to tau pathology. These findings support the important role of microglia in neurodegeneration, and we speculate that pathology spreads throughout the brain along vulnerable connectivity pathways. ANN NEUROL 2022

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

& beta;-amyloid (A & beta;) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, A & beta;-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of A & beta;(A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional A & beta;(AD: & beta;(T) = 0.412 & PLUSMN;0.196 vs. & beta;(A) = 0.142 & PLUSMN;0.123, p < 0.001;AD-CBS: & beta;(T) = 0.385 & PLUSMN;0.176 vs. & beta;(A) = 0.131 & PLUSMN;0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (& beta;(T) = 0.418 & PLUSMN;0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and A & beta;related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies.

β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases

Cognitive Trajectories in Preclinical and Prodromal Alzheimer's Disease Related to Amyloid Status and Brain Atrophy: A Bayesian Approach

Background: Cognitive decline is a key outcome of clinical studies in Alzheimer's disease (AD). Objective: To determine effects of global amyloid load as well as hippocampus and basal forebrain volumes on longitudinal rates and practice effects from repeated testing of domain specific cognitive change in the AD spectrum, considering non-linear effects and heterogeneity across cohorts. Methods: We included 1,514 cases from three cohorts, ADNI, AIBL, and DELCODE, spanning the range from cognitively normal people to people with subjective cognitive decline and mild cognitive impairment (MCI). We used generalized Bayesian mixed effects analysis of linear and polynomial models of amyloid and volume effects in time. Robustness of effects across cohorts was determined using Bayesian random effects meta-analysis. Results: We found a consistent effect of amyloid and hippocampus volume, but not of basal forebrain volume, on rates of memory change across the three cohorts in the meta-analysis. Effects for amyloid and volumetric markers on executive function were more heterogeneous. We found practice effects in memory and executive performance in amyloid negative cognitively normal controls and MCI cases, but only to a smaller degree in amyloid positive controls and not at all in amyloid positive MCI cases. Conclusions: We found heterogeneity between cohorts, particularly in effects on executive functions. Initial increases in cognitive performance in amyloid negative, but not in amyloid positive MCI cases and controls may reflect practice effects from repeated testing that are lost with higher levels of cerebral amyloid

Cognitive Trajectories in Preclinical and Prodromal Alzheimer's Disease Related to Amyloid Status and Brain Atrophy:A Bayesian Approach

Background: Cognitive decline is a key outcome of clinical studies in Alzheimer’s disease (AD). Objective: To determine effects of global amyloid load as well as hippocampus and basal forebrain volumes on longitudinal rates and practice effects from repeated testing of domain specific cognitive change in the AD spectrum, considering non-linear effects and heterogeneity across cohorts. Methods: We included 1,514 cases from three cohorts, ADNI, AIBL, and DELCODE, spanning the range from cognitively normal people to people with subjective cognitive decline and mild cognitive impairment (MCI). We used generalized Bayesian mixed effects analysis of linear and polynomial models of amyloid and volume effects in time. Robustness of effects across cohorts was determined using Bayesian random effects meta-analysis. Results: We found a consistent effect of amyloid and hippocampus volume, but not of basal forebrain volume, on rates of memory change across the three cohorts in the meta-analysis. Effects for amyloid and volumetric markers on executive function were more heterogeneous. We found practice effects in memory and executive performance in amyloid negative cognitively normal controls and MCI cases, but only to a smaller degree in amyloid positive controls and not at all in amyloid positive MCI cases. Conclusions: We found heterogeneity between cohorts, particularly in effects on executive functions. Initial increases in cognitive performance in amyloid negative, but not in amyloid positive MCI cases and controls may reflect practice effects from repeated testing that are lost with higher levels of cerebral amyloid

Relevance of Minor Neuropsychological Deficits in Patients With Subjective Cognitive Decline

peer reviewed[en] BACKGROUND AND OBJECTIVES: To determine the relevance of minor neuropsychological deficits (MNPD) in patients with subjective cognitive decline (SCD) with regard to CSF levels of Alzheimer disease (AD) biomarkers, cognitive decline, and clinical progression to mild cognitive impairment (MCI). METHODS: This study included patients with clinical SCD and SCD-free, healthy control (HC) participants with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia study. We defined MNPD as a performance of at least 0.5SD below the mean on a demographically adjusted total score derived from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery. We compared SCD patients with MNPD and those without MNPD with regard to CSF amyloid-β (Aβ)42/Aβ40, phosphorylated tau (p-tau181), total tau and Aβ42/p-tau181 levels, longitudinal cognitive composite trajectories, and risk of clinical progression to incident MCI (follow-up M ± SD: 40.6 ± 23.7 months). In addition, we explored group differences between SCD and HC in those without MNPD. RESULTS: In our sample (N = 672, mean age: 70.7 ± 5.9 years, 50% female), SCD patients with MNPD (n = 55, 12.5% of SCD group) showed significantly more abnormal CSF biomarker levels, increased cognitive decline, and a higher risk of progression to incident MCI (HR: 4.07, 95% CI 2.46-6.74) compared with SCD patients without MNPD (n = 384). MNPD had a positive predictive value of 57.0% (95% CI 38.5-75.4) and a negative predictive value of 86.0% (95% CI 81.9-90.1) for the progression of SCD to MCI within 3 years. SCD patients without MNPD showed increased cognitive decline and a higher risk of incident MCI compared with HC participants without MNPD (n = 215; HR: 4.09, 95% CI 2.07-8.09), while AD biomarker levels did not differ significantly between these groups. DISCUSSION: Our results suggest that MNPD are a risk factor for AD-related clinical progression in cognitively normal patients seeking medical counseling because of SCD. As such, the assessment of MNPD could be useful for individual clinical prediction and for AD risk stratification in clinical trials. However, SCD remains a risk factor for future cognitive decline even in the absence of MNPD

Relevance of Minor Neuropsychological Deficits in Patients With Subjective Cognitive Decline

Background and ObjectivesTo determine the relevance of minor neuropsychological deficits (MNPD) in patients with subjective cognitive decline (SCD) with regard to CSF levels of Alzheimer disease (AD) biomarkers, cognitive decline, and clinical progression to mild cognitive impairment (MCI).MethodsThis study included patients with clinical SCD and SCD-free, healthy control (HC) participants with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia study. We defined MNPD as a performance of at least 0.5SD below the mean on a demographically adjusted total score derived from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery. We compared SCD patients with MNPD and those without MNPD with regard to CSF amyloid-beta (A beta)42/A beta 40, phosphorylated tau (p-tau181), total tau and A beta 42/p-tau181 levels, longitudinal cognitive composite trajectories, and risk of clinical progression to incident MCI (follow-up M +/- SD: 40.6 +/- 23.7 months). In addition, we explored group differences between SCD and HC in those without MNPD.ResultsIn our sample (N = 672, mean age: 70.7 +/- 5.9 years, 50% female), SCD patients with MNPD (n = 55, 12.5% of SCD group) showed significantly more abnormal CSF biomarker levels, increased cognitive decline, and a higher risk of progression to incident MCI (HR: 4.07, 95% CI 2.46-6.74) compared with SCD patients without MNPD (n = 384). MNPD had a positive predictive value of 57.0% (95% CI 38.5-75.4) and a negative predictive value of 86.0% (95% CI 81.9-90.1) for the progression of SCD to MCI within 3 years. SCD patients without MNPD showed increased cognitive decline and a higher risk of incident MCI compared with HC participants without MNPD (n = 215;HR: 4.09, 95% CI 2.07-8.09), while AD biomarker levels did not differ significantly between these groups.DiscussionOur results suggest that MNPD are a risk factor for AD-related clinical progression in cognitively normal patients seeking medical counseling because of SCD. As such, the assessment of MNPD could be useful for individual clinical prediction and for AD risk stratification in clinical trials. However, SCD remains a risk factor for future cognitive decline even in the absence of MNPD