Predicting CDR status over 36 months with a recall-based digital cognitive biomarker.

INTRODUCTION: Word-list recall tests are routinely used for cognitive assessment, and process scoring may improve their accuracy. We examined whether Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) derived, process-based digital cognitive biomarkers (DCBs) at baseline predicted Clinical Dementia Rating (CDR) longitudinally and compared them to standard metrics. METHODS: Analyses were performed with Alzheimer's Disease Neuroimaging Initiative (ADNI) data from 330 participants (mean age = 71.4 ± 7.2). We conducted regression analyses predicting CDR at 36 months, controlling for demographics and genetic risk, with ADAS-Cog traditional scores and DCBs as predictors. RESULTS: The best predictor of CDR at 36 months was M, a DCB reflecting recall ability (area under the curve = 0.84), outperforming traditional scores. Diagnostic results suggest that M may be particularly useful to identify individuals who are unlikely to decline. DISCUSSION: These results suggest that M outperforms ADAS-Cog traditional metrics and supports process scoring for word-list recall tests. More research is needed to determine further applicability with other tests and populations. HIGHLIGHTS: Process scoring and latent modeling were more effective than traditional scoring. Latent recall ability (M) was the best predictor of Clinical Dementia Rating decline at 36 months. The top digital cognitive biomarker model had odds ≈ 90 times greater than the top Alzheimer's Disease Assessment Scale-Cognitive subscale model. Particularly high negative predictive value supports literature on cognitive testing as a useful screen. Consideration of both cognitive and pathological outcomes is needed.

Story recall performance and AT classification via positron emission tomography: A comparison of logical memory and Craft Story 21.

BACKGROUND: Early detection of Alzheimer's disease (AD) is one of the critical components of the global response to the growing dementia crisis. Analysis of serial position performance in story recall tests has yielded sensitive metrics for the prediction of AD at low cost. In this study, we examined whether serial position markers in two story recall tests (the logical memory test, LMT, and the Craft Story 21 test, CST) were sensitive to cross-sectional biomarker-based assessment of in vivo neuropathology. METHODS: Participants were selected from the Wisconsin Registry of Alzheimer's Prevention (n = 288; WRAP) and the Alzheimer's Disease Research Center (n = 156; ADRC), both from the University of Wisconsin-Madison. Average age at PET was 68.9 (6.7) and 67.0 (8.0), respectively. Data included tau and PiB PET, and LMT for WRAP participants and CST for ADRC participants. Two sets of Bayesian analyses (logistic regressions and ANCOVAs) were conducted within each cohort, separately. RESULTS: Results indicated that the A+T+ classification was best predicted, cross-sectionally, by the recency ratio (Rr), indexing how much of the end of the story was forgotten between initial learning and delayed assessment. Rr outperformed traditional scores and discriminated between A+T+ and A+T-/A-T-, in both cohorts. CONCLUSIONS: Overall, this study confirms that serial position analysis of LMT and CST data, and particularly Rr as an index of recency loss, is a valuable tool for the identification of in vivo tau pathology in individuals free of dementia. Diagnostic considerations are discussed.

The role of cognitive reserve and depression on executive function in older adults: A 10-year study from the Wisconsin Registry for Alzheimer's Prevention.

Objective: The current study examined the longitudinal relationship between cognitive reserve (CR), depression, and executive function (EF) in a cohort of older adults. Methods: 416 participants were selected from the Wisconsin Registry for Alzheimer's Prevention. They were native English speakers, aged ≥50+, and cognitively unimpaired at baseline, with no history of neurological or other psychiatric disorders aside from depression. Depression was assessed with the 20-item Center for Epidemiologic Studies Depression Scale (CES-D). A composite score, based on the premorbid IQ (WRAT-3 Reading subtest) and years of education was used to estimate CR. Another composite score from four cognitive tests was used to estimate EF. A moderation analysis was performed to evaluate the effects of CR and Depression on EF at follow-up after controlling for age, gender, and APOE risk score. Moreover, a multinomial logistic regression was used to predict conversion to Mild Cognitive Impairment (MCI) from the healthy baseline. Results: The negative relationship between depression and EF was stronger in individuals with higher CR levels, suggesting a possible floor effect at lower CR levels. In the multinomial regression, the interaction between CR and depression predicted conversion to MCI status, indicating that lower CR paired with more severe depression at baseline was associated with a higher risk of subsequent impairment. Conclusions: This study sheds light on the intricate relationship between depression and EF over time, suggesting that the association may be influenced by varying levels of CR. Further studies may replicate these findings in clinical populations.

Evidence for reduced anti-inflammatory microglial phagocytic response in late-life major depression.

Major depressive disorder (MDD) is associated with Alzheimer's disease (AD) but the precise mechanisms underlying this relationship are not understood. While it is well established that cerebrospinal fluid (CSF) soluble levels of triggering receptor expressed on myeloid cells 2 (sTREM2) increase during early stages of AD, how sTREM2 levels behave in subjects with MDD is not known. In a longitudinal study, we measured CSF sTREM2 levels in 27 elderly cognitively intact individuals with late-life major depression (LLMD) and in 19 healthy controls. We tested the hypothesis that, similarly to what happens in early stages of AD, CSF sTREM2 would be elevated in MDD. In addition, we compared the associations of CSF sTREM2, pro- and anti- inflammatory, and AD biomarkers in LLMD and control subjects. Surprisingly, we found that mean CSF sTREM2 levels were significantly reduced in LLMD compared to controls. This reduction was no longer significant at the 3-year follow-up visit when depression severity improved. In addition, we found that CSF sTREM2 was associated with AD biomarkers and proinflammatory cytokines in controls but not in LLMD. These findings suggest that impaired microglia phagocytic response to AD pathology may be a novel link between MDD and AD.

Association of latent factors of neuroinflammation with Alzheimer's disease pathology and longitudinal cognitive decline.

INTRODUCTION: We investigated the association of inflammatory mechanisms with markers of Alzheimer's disease (AD) pathology and rates of cognitive decline in the AD spectrum. METHODS: We studied 296 cases from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study (DELCODE) cohort, and an extension cohort of 276 cases of the Alzheimer's Disease Neuroimaging Initiative study. Using Bayesian confirmatory factor analysis, we constructed latent factors for synaptic integrity, microglia, cerebrovascular endothelial function, cytokine/chemokine, and complement components of the inflammatory response using a set of inflammatory markers in cerebrospinal fluid. RESULTS: We found strong evidence for an association of synaptic integrity, microglia response, and cerebrovascular endothelial function with a latent factor of AD pathology and with rates of cognitive decline. We found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline. DISCUSSION: Latent factors provided access to directly unobservable components of the neuroinflammatory response and their association with AD pathology and cognitive decline.

Delayed primacy recall performance predicts post mortem Alzheimer's disease pathology from unimpaired ante mortem cognitive baseline.

We propose a novel method to assess delayed primacy in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) memory test. We then examine whether this measure predicts post mortem Alzheimer's disease (AD) neuropathology in individuals who were clinically unimpaired at baseline. A total of 1096 individuals were selected from the Rush Alzheimer's Disease Center database registry. All participants were clinically unimpaired at baseline, and had subsequently undergone brain autopsy. Average age at baseline was 78.8 (6.92). A Bayesian regression analysis was carried out with global pathology as an outcome; demographic, clinical, and apolipoprotein E (APOE) data as covariates; and cognitive predictors, including delayed primacy. Global AD pathology was best predicted by delayed primacy. Secondary analyses showed that delayed primacy was mostly associated with neuritic plaques, whereas total delayed recall was associated with neurofibrillary tangles. Sex differential associations were observed. We conclude that CERAD-derived delayed primacy is a useful metric for early detection and diagnosis of AD in unimpaired individuals. Highlights: We propose a novel method to analyse serial position in the CERAD memory test.We analyse data from 1096 individuals who were cognitively unimpaired at baseline.Delayed primacy predicts post mortem pathology better than traditional metrics.

A comparison of story-recall metrics to predict hippocampal volume in older adults with and without cognitive impairment.

Objective: Process-based scores of episodic memory tests, such as the recency ratio (Rr), have been found to compare favourably to, or to be better than, most conventional or "traditional" scores employed to estimate memory ability in older individuals (Bock et al., 2021; Bruno et al., 2019). We explored the relationship between process-based scores and hippocampal volume in older adults, while comparing process-based to traditional story recall-derived scores, to examine potential differences in their predictive abilities. Methods: We analysed data from 355 participants extracted from the WRAP and WADRC databases, who were classified as cognitively unimpaired, or exhibited mild cognitive impairment (MCI) or dementia. Story Recall was measured with the Logical Memory Test (LMT) from the Weschler Memory Scale Revised, collected within twelve months of the magnetic resonance imaging scan. Linear regression analyses were conducted with left or right hippocampal volume (HV) as outcomes separately, and with Rr, Total ratio, Immediate LMT, or Delayed LMT scores as predictors, along with covariates. Results: Higher Rr and Tr scores significantly predicted lower left and right HV, while Tr showed the best model fit of all, as indicated by AIC. Traditional scores, Immediate LMT and Delayed LMT, were significantly associated with left and right HV, but were outperformed by both process-based scores for left HV, and by Tr for right HV. Conclusions: Current findings show the direct relationship between hippocampal volume and all the LMT scores examined here, and that process-based scores outperform traditional scores as markers of hippocampal volume.

Associations between recall of proper names in story recall and CSF amyloid and tau in adults without cognitive impairment.

Neuropsychological measures sensitive to decline in the preclinical phase of Alzheimer's disease are needed. We previously demonstrated that higher amyloid-beta (Aß) assessed by positron emission tomography in adults without cognitive impairment was associated with recall of fewer proper names in Logical Memory story recall. The current study investigated the association between proper names and cerebrospinal fluid biomarkers (Aß42/40, phosphorylated tau181 [pTau181], neurofilament light) in 223 participants from the Wisconsin Registry for Alzheimer's Prevention. We assessed associations between biomarkers and delayed Logical Memory total score and proper names using binary logistic regressions. Sensitivity analyses used multinomial logistic regression and stratified biomarker groups. Lower Logical Memory total score and proper names scores from the most recent visit were associated with biomarker positivity. Relatedly, there was a 27% decreased risk of being classified Aß42/40+/pTau181+ for each additional proper name recalled. A linear mixed effects model found that longitudinal change in proper names recall was predicted by biomarker status. These results demonstrate a novel relationship between proper names and Alzheimer's disease-cerebrospinal fluid pathology.

Comparison of the 10-, 14- and 20-Item CES-D Scores as Predictors of Cognitive Decline.

The association between depressive symptomatology and cognitive decline has been examined using the Centre for Epidemiologic Studies-Depression Scale (CES-D); however, concerns have been raised about this self-report measure. Here, we examined how the CES-D total score from the 14- and 10-item versions compared to the 20-item version in predicting progression to cognitive decline from a cognitively unimpaired baseline. Data from 1054 participants were analysed using ordinal logistic regression, alongside moderator and receiver-operating characteristics curve analyses. All baseline total scores significantly predicted progression to cognitive decline. The 14-item version was better than the 20-item version in predicting consensus diagnosis, as shown by their AICs, while also showing the highest accuracy when discriminating between participants by diagnosis at last visit. We did not find sex to moderate the relationship between CES-D score and cognitive decline. Current findings suggest the 10- and 14-item versions of the CES-D are comparable to the 20-item version, and that the 14-item version may be better at predicting longitudinal consensus diagnosis compared to the 20-item version.

A comparison of diagnostic performance of word-list and story recall tests for biomarker-determined Alzheimer's disease.

BACKGROUND: Wordlist and story recall tests are routinely employed in clinical practice for dementia diagnosis. In this study, our aim was to establish how well-standard clinical metrics compared to process scores derived from wordlist and story recall tests in predicting biomarker determined Alzheimer's disease, as defined by CSF ptau/Aß42 ratio. METHODS: Data from 295 participants (mean age = 65 ± 9.) were drawn from the University of Wisconsin - Madison Alzheimer's Disease Research Center (ADRC) and Wisconsin Registry for Alzheimer's Prevention (WRAP). Rey's Auditory Verbal Learning Test (AVLT; wordlist) and Logical Memory Test (LMT; story) data were used. Bayesian linear regression analyses were carried out with CSF ptau/Aß42 ratio as outcome. Sensitivity analyses were carried out with logistic regressions to assess diagnosticity. RESULTS: LMT generally outperformed AVLT. Notably, the best predictors were primacy ratio, a process score indexing loss of information learned early during test administration, and recency ratio, which tracks loss of recently learned information. Sensitivity analyses confirmed this conclusion. CONCLUSIONS: Our study shows that story recall tests may be better than wordlist tests for detection of dementia, especially when employing process scores alongside conventional clinical scores.

Delayed primacy recall performance predicts post mortem Alzheimer's disease pathology from unimpaired ante mortem cognitive baseline.

INTRODUCTION: We propose a novel method to assess delayed primacy in the CERAD memory test. We then examine whether this measure predicts post mortem Alzheimer's disease (AD) neuropathology in individuals who were clinically unimpaired at baseline. METHODS: A total of 1096 individuals were selected from the Rush Alzheimer's Disease Center database registry. All participants were clinically unimpaired at baseline, and had subsequently undergone brain autopsy. Average age at baseline was 78.8 (6.92). A Bayesian regression analysis was carried out with global pathology as outcome; demographic, clinical and APOE data as covariates; and cognitive predictors, including delayed primacy. RESULTS: Global AD pathology was best predicted by delayed primacy. Secondary analyses showed that delayed primacy was mostly associated with neuritic plaques, whereas total delayed recall was associated with neurofibrillary tangles. DISCUSSION: We conclude that CERAD-derived delayed primacy is a useful metric for early detection and diagnosis of AD in unimpaired individuals.

The recency ratio assessed by story recall is associated with cerebrospinal fluid levels of neurodegeneration biomarkers.

Recency refers to the information learned at the end of a study list or task. Recency forgetting, as tracked by the ratio between recency recall in immediate and delayed conditions, i.e., the recency ratio (Rr), has been applied to list-learning tasks, demonstrating its efficacy in predicting cognitive decline, conversion to mild cognitive impairment (MCI), and cerebrospinal fluid (CSF) biomarkers of neurodegeneration. However, little is known as to whether Rr can be effectively applied to story recall tasks. To address this question, data were extracted from the database of the Alzheimer's Disease Research Center at the University of Wisconsin - Madison. A total of 212 participants were included in the study. CSF biomarkers were amyloid-beta (Aß) 40 and 42, phosphorylated (p) and total (t) tau, neurofilament light (NFL), neurogranin (Ng), and α-synuclein (a-syn). Story Recall was measured with the Logical Memory Test (LMT). We carried out Bayesian regression analyses with Rr, and other LMT scores as predictors; and CSF biomarkers (including the Aß42/40 and p-tau/Aß42 ratios) as outcomes. Results showed that models including Rr consistently provided best fits with the data, with few exceptions. These findings demonstrate the applicability of Rr to story recall and its sensitivity to CSF biomarkers of neurodegeneration, and encourage its inclusion when evaluating risk of neurodegeneration with story recall.

Cross-sectional associations of CSF tau levels with Rey's AVLT: A recency ratio study.

OBJECTIVE: The preeminent in vivo cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are amyloid ß 1-42 (Aß42), phosphorylated Tau (p-tau), and total Tau (t-tau). The goal of this study was to examine how well traditional (total and delayed recall) and process-based (recency ratio [Rr]) measures derived from Rey's Auditory Verbal Learning test (AVLT) were associated with these biomarkers. METHOD: Data from 235 participants (Mage = 65.5, SD = 6.9), who ranged from cognitively unimpaired to mild cognitive impairment, and for whom CSF values were available, were extracted from the Wisconsin Registry for Alzheimer's Prevention. Bayesian regression analyses were carried out using CSF scores as outcomes, AVLT scores as predictors, and controlling for demographic data and diagnosis. RESULTS: We found moderate evidence that Rr was associated with both CSF p-tau (Bayesian factor [BFM] = 5.55) and t-tau (BFM = 7.28), above and beyond the control variables, while it did not correlate with CSF Aß42 levels. In contrast, total and delayed recall scores were not linked with any of the AD biomarkers, in separate analyses. When comparing all memory predictors in a single regression, Rr remained the strongest predictor of CSF t-tau levels (BFM = 3.57). CONCLUSIONS: Our findings suggest that Rr may be a better cognitive measure than commonly used AVLT scores to assess CSF levels of p-tau and t-tau in nondemented individuals. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Health-related quality of life among people living with HIV in the era of universal test and treat: results from a cross-sectional study in KwaZulu-Natal, South Africa.

BACKGROUND: The World Health Organisation's (WHO) key population-based strategy for ending the human immunodeficiency virus (HIV) epidemic is universal HIV test and treat (UTT) along with pre-exposure prophylaxis (PrEP), and post-exposure prophylaxis (PEP). Despite the successful scale-up of the UTT strategy in sub-Saharan Africa (SSA), the quality of life (QoL) of people living with HIV (PLHIV) remains sub-optimal. Poor QoL in PLHIV may threaten the UNAIDS 95-95-95 programme targets. Monitoring QoL of PLHIV has become a key focus of HIV research among other outcomes so as to understand health-related QoL (HRQoL) profiles and identify interventions to improve programme performance. This study aimed to describe HRQoL profiles and identify their predictors in PLHIV in KwaZulu Natal, South Africa. METHODS: We conducted a secondary data analysis of a cross-sectional survey conducted between May and June 2022 among PLHIV (n = 105) accessing HIV services at an outpatient clinic in KwaZulu-Natal, South Africa. Socio-demographic, HRQoL (EQ-5D-5L index scores), clinical data, depressive symptoms (CES-D-10), and viral load data were collected from all participants. We examined predictors of HRQoL using generalised linear models controlling for age and sex. RESULTS: The mean age of the participants was 45 years (SD = 13). The proportion of participants with disabilities and comorbidities were 3% and 18%, respectively. Depressive symptoms were present in 49% of the participants. Participant's mean EQ-5D-5L index score was 0.87 (SD = 0.21) and ranged from 0.11 to 1.0. The mean general health state (EQ-VAS) was 74.7 (SD = 18.8) and ranged from 6 to 100. Factors that reduced HRQoL were disability (ß = -0.607, p ≤ 0.001), comorbidities (ß = - 0.23, p ≤ 0.05), presence of depressive symptoms (ß = -0.10, p ≤ 0.05), and old age (ß = -0.04, p ≤ 0.05). Factors that increased HRQoL were a good perceived health state (ß = 0.147, p ≤ 0.001) and availability of social support (ß = 0.098, p ≤ 0.05). CONCLUSION: A combination of old age (60 years and above), any disability and comorbidities had a considerable effect on HRQoL among PLHIV. Our findings support the recommendation for an additional fourth UNAIDS target that should focus on ensuring that 95% of PLHIV have the highest possible HRQoL. Psycho-social support interventions are recommended to improve the HRQoL of PLHIV.

Item-Level Story Recall Predictors of Amyloid-Beta in Late Middle-Aged Adults at Increased Risk for Alzheimer's Disease.

Background: Story recall (SR) tests have shown variable sensitivity to rate of cognitive decline in individuals with Alzheimer's disease (AD) biomarkers. Although SR tasks are typically scored by obtaining a sum of items recalled, item-level analyses may provide additional sensitivity to change and AD processes. Here, we examined the difficulty and discrimination indices of each item from the Logical Memory (LM) SR task, and determined if these metrics differed by recall conditions, story version (A vs. B), lexical categories, serial position, and amyloid status. Methods: n = 1,141 participants from the Wisconsin Registry for Alzheimer's Prevention longitudinal study who had item-level data were included in these analyses, as well as a subset of n = 338 who also had amyloid positron emission tomography (PET) imaging. LM data were categorized into four lexical categories (proper names, verbs, numbers, and "other"), and by serial position (primacy, middle, and recency). We calculated difficulty and discriminability/memorability by item, category, and serial position and ran separate repeated measures ANOVAs for each recall condition, lexical category, and serial position. For the subset with amyloid imaging, we used a two-sample t-test to examine whether amyloid positive (Aß+) and amyloid negative (Aß-) groups differed in difficulty or discrimination for the same summary metrics. Results: In the larger sample, items were more difficult (less memorable) in the delayed recall condition across both story A and story B. Item discrimination was higher at delayed than immediate recall, and proper names had better discrimination than any of the other lexical categories or serial position groups. In the subsample with amyloid PET imaging, proper names were more difficult for Aß+ than Aß-; items in the verb and "other" lexical categories and all serial positions from delayed recall were more discriminate for the Aß+ group compared to the Aß- group. Conclusion: This study provides empirical evidence that both LM stories are effective at discriminating ability levels and amyloid status, and that individual items vary in difficulty and discrimination by amyloid status, while total scores do not. These results can be informative for the future development of sensitive tasks or composite scores for early detection of cognitive decline.

Plasma Amyloid-ß dynamics in late-life major depression: a longitudinal study.

Depressed individuals are twice as likely to develop Alzheimer's disease (AD) as compared to controls. Brain amyloid-ß (Aß) deposition is believed to have a major role in AD pathogenesis but studies also suggest associations of Aß dynamics and depression. The aim of this study was to test if plasma Aß levels are longitudinally associated to late-life depression. We measured plasma levels of amyloid-ß1-40 (Aß40) and amyloid-ß1-42 (Aß42) peptides longitudinally for three consecutive years in 48 cognitively intact elderly subjects with late-life major depressive disorder (LLMD) and 45 age-matched cognitively healthy controls. We found that the Aß42/Aß40 plasma ratio was significantly and steadily lower in depressed subjects compared to controls (p < 0.001). At screening, Aß42/Aß40 plasma did not correlate with depression severity (as measured with Hamilton Depression Scale) or cognitive performance (as measured with Mini-Mental State Examination) but was associated to depression severity at 3 years after adjustment for age, education, cognitive performance, and antidepressants use. This study showed that reduced plasma Aß42/Aß40 ratio is consistently associated with LLMD diagnosis and that increased severity of depression at baseline predicted low Aß42/Aß40 ratio at 3 years. Future studies are needed to confirm these findings and examine if the consistently lower plasma Aß42/Aß40 ratio in LLMD reflects increased brain amyloid deposition, as observed in AD subjects, and an increased risk for progressive cognitive decline and AD.

Cognitive ability in former professional football (soccer) players is associated with estimated heading frequency.

OBJECTIVES: The link between football (soccer) headings and dementia risk is a concern given the popularity of this sport worldwide. To assess this link, the cognitive ability of former professional players was tested and self-reported estimates on heading frequency were collected. METHODS: A survey was co-designed with former players to gather demographics data; information on playing career, including playing position; estimates of total head injuries sustained in training and match play; and estimates of heading frequency during training and match play. Data then were collected by post from 60 males (mean age = 67.5; SD = 9.5), who had played professionally for teams in England. In addition to the survey, each individual also completed the Test Your Memory (TYM) self-administered cognitive test to evaluate overall ability. RESULTS: Bayesian and traditional linear regression analyses were carried out using the TYM score as outcome. Predictors were estimated career head injuries and estimated career headers, while we controlled for age and reported non-football head injuries. The results of our analyses showed that estimated career headers, but not estimated career head injuries, predicted TYM scores. CONCLUSION: To our knowledge, this is the first study to provide direct evidence supporting a link between heading the ball and cognitive impairment in retired professional football players.

Association of Cholinergic Basal Forebrain Volume and Functional Connectivity with Markers of Inflammatory Response in the Alzheimer's Disease Spectrum.

BACKGROUND: Inflammation has been described as a key pathogenic event in Alzheimer's disease (AD), downstream of amyloid and tau pathology. Preclinical and clinical data suggest that the cholinergic basal forebrain may moderate inflammatory response to different pathologies. OBJECTIVE: To study the association of cholinergic basal forebrain volume and functional connectivity with measures of neuroinflammation in people from the AD spectrum. METHODS: We studied 261 cases from the DELCODE cohort, including people with subjective cognitive decline, mild cognitive impairment, AD dementia, first degree relatives, and healthy controls. Using Bayesian ANCOVA, we tested associations of MRI indices of cholinergic basal forebrain volume and functional connectivity with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglia activation, and serum levels of complement C3. Using Bayesian elastic net regression, we determined associations between basal forebrain measures and a large inflammation marker panel from CSF and serum. RESULTS: We found anecdotal to moderate evidence in favor of the absence of an effect of basal forebrain volume and functional connectivity on CSF sTREM2 and serum C3 levels both in Aß42/ptau-positive and negative cases. Bayesian elastic net regression identified several CSF and serum markers of inflammation that were associated with basal forebrain volume and functional connectivity. The effect sizes were moderate to small. CONCLUSION: Our data-driven analyses generate the hypothesis that cholinergic basal forebrain may be involved in the neuroinflammation response to Aß42 and phospho-tau pathology in people from the AD spectrum. This hypothesis needs to be tested in independent samples.

Association of CSF sTREM2, a marker of microglia activation, with cholinergic basal forebrain volume in major depressive disorder.

BACKGROUND: Inflammatory mechanisms are believed to contribute to the manifestation of major depressive disorder (MDD). Central cholinergic activity may moderate this effect. Here, we tested if volume of the cholinergic basal forebrain is associated with cerebrospinal fluid (CSF) levels of sTREM2 as a marker of microglial activation in people with late life MDD. METHODS: Basal forebrain volume was determined from structural MRI scans and levels of CSF sTREM2 with immunoassay in 29 people with late-life MDD and 20 healthy older controls at baseline and 3 years follow-up. Associations were determined using Bayesian analysis of covariance. RESULTS: We found moderate level of evidence for an association of lower CSF levels of sTREM2 at 3 years follow up with MDD (Bayes factor in favor of an effect = 7.9). This level of evidence prevailed when controlling for overall antidepressant treatment and CSF levels of markers of AD pathology, i.e., Aß42/Aß40, ptau181 and total tau. Evidence was in favor of absence of an effect for baseline levels of CSF sTREM2 in MDD cases and for baseline and follow up data in controls. LIMITATIONS: The sample size of repeated CSF examinations was relatively small. Therefore, we used Bayesian sequential analysis to assess if effects were affected by sample size. Still, the number of cases was too small to stratify effects for different antidepressive treatments. CONCLUSIONS: Our data agree with the assumption that central cholinergic system integrity may contribute to regulation of microglia activity in late-life MDD.

Evidence of upregulation of the cholinergic anti-inflammatory pathway in late-life depression.

BACKGROUND: Decreased cholinergic tone associated with increased proinflammatory cytokines has been observed in several human diseases associated with low-grade inflammation. We examined if this attenuated cholinergic anti-inflammatory pathway (CAP) mechanism contributed to increased neuroinflammation observed in depression. METHODS: We measured cerebrospinal fluid (CSF) cholinergic markers (AChE and BChE activities) in 28 individuals with longstanding late-life major depression (LLMD) and 19 controls and their relationship to central and peripheral levels of pro-inflammatory cytokines (IL-6 and IL-8). Additionally, we examined if these cholinergic indices were related to CSF markers of microglial activation and neuroinflammation (sTREM2 and complement C3). RESULTS: Compared with controls, LLMD patients had a significant reduction in CSF BChE levels. Lower CSF BChE and AChE activities were associated with lower CSF markers of microglial and neuroinflammation (sTREM2 and C3). In addition, in LLMD patients we found an inverse relationship between peripheral marker of inflammation (plasma IL-6) and CSF BChE and AChE levels. CONCLUSIONS: Our results suggest an upregulation of the CAP mechanism in LLMD with an elevation in peripheral markers of inflammation and concomitant reduction in markers of glial activation associated with a higher cholinergic tone. Future studies should confirm these findings in a larger sample including individuals with acute and more severe depressive episodes and across all ages.