Faster Cognitive Decline Research Articles

Association of CSF α-synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer's Disease Neuroimaging Initiative study.

Cerebrospinal fluid (CSF) α-synuclein (α-syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co-pathology in Alzheimer's disease. A total of 1637 cross-sectional and 407 longitudinal CSF samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined longitudinal dynamics of amyloid beta (Aβ), α-syn seeds, and phosphorylated tau181 (p-tau181), along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-. SAA+ individuals had faster cognitive decline than SAA-, notably in mild cognitive impairment, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42 positivity but did not impact the progression of either CSF Aβ42 or CSF p-tau181 status. CSF Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly CSF Aβ42. In vitro, CSF α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline. These results highlight the interplay between amyloid and α-syn and their association with disease progression. Seed amplification assay (SAA) positivity was associated with greater cognitive decline and earlier symptom onset. Thirty-four Alzheimer's Disease Neuroimaging Initiative (ADNI) individuals progressed from SAA- to SAA+, that is, ≈ 5% conversion. SAA conversion was associated with amyloid beta (Aβ) pathology and greater cognitive decline. SAA status did not impact the progression of either CSF Aβ42 or phosphorylated tau181 biomarkers. Change in clinical diagnosis was associated with both Alzheimer's disease biomarkers and SAA. SAA kinetic parameters were associated with clinical features and progression.

Plasma neurofilament light chain as prognostic marker of cognitive decline in neurodegenerative diseases, a clinical setting study.

Analysis of selected research cohorts has highlighted an association between plasma neurofilament light (NfL) protein and cross-sectional cognitive impairment as well as longitudinal cognitive decline. However, the findings have yielded inconsistent results regarding its possible application in clinical practice. Despite its potential prognostic significance, the role of plasma NfL in daily clinical practice with unselected patients suffering from cognitive impairment remains largely unexplored. This retrospective, cross-sectional and longitudinal monocentric study enrolled 320 patients with Alzheimer's disease ([AD], n = 158), dementia with Lewy body ([DLB], n = 30), frontotemporal dementia ([FTD], n = 32), non-neurodegenerative diseases ([NND], n = 59) or subjective cognitive decline ([SCD], n = 41). Plasma NfL levels were measured at baseline on the Simoa platform. AD, DLB, and FTD patients were also analyzed altogether as a 'degenerative conditions' subgroup, whereas SCD and NND were grouped as a 'non-degenerative conditions' subgroup. We assessed the relationship between plasma NfL levels and cross-sectional cognitive performance, including global cognition and six specific cognitive domains. A subset of 239 patients had follow-up mini-mental state examinations (MMSE) up to 60 months. Models were adjusted on age, education level, glomerular filtration rate and body mass index. In 320 patients, baseline plasma NfL levels were negatively associated with global cognition (β=-1.28 (-1.81 ; -0.75) P < 0.001), memory (β=-1.48 (-2.38 ; -0.59), P = 0.001), language (β=-1.72(-2.49 ; -0.95) P < 0.001), praxis (β=-2.02 (-2.91 ; -1.13) P < 0.001) and executive functions (β=-0.81, P < 0.001). Across diagnosis, plasma NfL levels were negatively associated with cross-sectional global cognition in all but the SCD subgroup, specifically with executive functions and memory in AD (respectively β=-0.71(-1.21 ; -0.211), P = 0.005 and β=-1.29 (-2.17 ; -0.42), P = 0.004), and with attention in LBD (β=-0.81(-1.16 ; -0.002), P = 0.03). Linear mixed-effects models showed that plasma NfL predicted MMSE decline in the global population (βPlasmaNfLxTime=-0.15 (-0.26 ; -0.04), P = 0.006), as in the neurodegenerative condition subgroup (βPlasmaNfLxTime=-0.21 (-0.37 ; - 0.06), P = 0.007), but not in non-neurodegenerative condition subgroup. In our clinical cohort, plasma NfL was associated with faster cognitive decline in neurodegenerative dementia, which corroborates data obtained in research cohorts. Yet, plasma NfL was not predictive of accelerated cognitive decline in individuals without neurodegeneration, suggesting its use as a neurodegeneration-specific predictive biomarker.

Cholinesterase inhibitor use in amyloid PET-negative mild cognitive impairment and cognitive changes

BackgroundCholinesterase inhibitors (ChEIs) are prescribed for Alzheimer’s disease (AD) and sometimes for mild cognitive impairment (MCI) without knowing underlying pathologies and its effect on cognition. We investigated the frequency of ChEI prescriptions in amyloid-negative MCI and their association with cognitive changes in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.MethodsWe included participants with amyloid positron emission tomography (PET)-negative MCI from the ADNI. We analyzed the associations of ChEI use with cognitive changes, brain volume, and cerebrospinal fluid (CSF) total tau (t-tau), hyperphosphorylated tau181 (p-tau181), and p-tau181/t-tau ratio.ResultsChEIs were prescribed in 27.4% of amyloid PET-negative MCI and were associated with faster cognitive decline, reduced baseline hippocampal volume and entorhinal cortical thickness, and a longitudinal decrease in the frontal lobe cortical thickness.ConclusionsThe association between ChEI use and accelerated cognitive decline may stem from underlying pathologies involving reduced hippocampal volume, entorhinal cortical thickness and faster frontal lobe atrophy. We suggest that ChEI use in amyloid PET-negative MCI patients might need further consideration, and studies investigating the causality between ChEI use and cognitive decline are warranted in the future.

CYP1B1-RMDN2 Alzheimer’s disease endophenotype locus identified for cerebral tau PET

Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Neuropsychiatric symptoms and lifelong mental activities in cerebral amyloid angiopathy – a cross-sectional study

BackgroundWhile several studies in cerebral amyloid angiopathy (CAA) focus on cognitive function, data on neuropsychiatric symptoms (NPS) and lifelong mental activities in these patients are scarce. Since NPS are associated with functional impairment, faster cognitive decline and faster progression to death, replication studies in more diverse settings and samples are warranted.MethodsWe prospectively recruited n = 69 CAA patients and n = 18 cognitively normal controls (NC). The number and severity of NPS were assessed using the Alzheimer’s Disease (AD) Assessment Scale’s (ADAS) noncognitive subscale. We applied different regression models exploring associations between NPS number or severity and group status (CAA vs. NC), CAA severity assessed with magnetic resonance imaging (MRI) or cognitive function (Mini-Mental State Examination (MMSE), ADAS cognitive subscale), adjusting for age, sex, years of education, arterial hypertension, AD pathology, and apolipoprotein E status. Mediation analyses were performed to test indirect effects of lifelong mental activities on CAA severity and NPS.ResultsPatients with CAA had 4.86 times (95% CI 2.20-10.73) more NPS and 3.56 units (95% CI 1.94–5.19) higher expected NPS severity than NC. Higher total CAA severity on MRI predicted 1.14 times (95% CI 1.01.-1.27) more NPS and 0.57 units (95% CI 0.19–0.95) higher expected NPS severity. More severe white matter hyperintensities were associated with 1.21 times more NPS (95% CI 1.05–1.39) and 0.63 units (95% CI 0.19–1.08) more severe NPS. NPS number (MMSE mean difference − 1.15, 95% CI -1.67 to -0.63; ADAS cognitive mean difference 1.91, 95% CI 1.26–2.56) and severity (MMSE − 0.55, 95% CI -0.80 to -0.30; ADAS cognitive mean difference 0.89, 95% CI 0.57–1.21) predicted lower cognitive function. Greater lifelong mental activities partially mediated the relationship between CAA severity and NPS (indirect effect 0.05, 95% CI 0.0007-0.13), and greater lifelong mental activities led to less pronounced CAA severity and thus to less NPS (indirect effect − 0.08, 95% CI -0.22 to -0.002).DiscussionThis study suggests that NPS are common in CAA, and that this relationship may be driven by CAA severity. Furthermore, NPS seem to be tied to lower cognitive function. However, lifelong mental activities might mitigate the impact of NPS in CAA.

Serial Cerebrospinal Fluid Sampling Reveals Trajectories of Potential Synaptic Biomarkers in Early Stages of Alzheimer's Disease.

Synaptic dysfunction is closely associated with cognitive function in Alzheimer's disease (AD), and is present already in an early stage of the disease. Using serial cerebrospinal fluid (CSF) sampling, we aimed to investigate slopes of CSF synaptic proteins, and their relation with cognition along the AD continuum. We included subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) (n = 50 amyloid-β+ [A +], n = 50 A-) and 50 patients with AD dementia from the Amsterdam dementia cohort, with CSF at two time points (median[IQR] 2.1[1.4-2.7] years). We analyzed 17 synaptic proteins and neurofilament light (NfL). Using linear mixed models we assessed trajectories of protein levels, and associations with cognitive decline (repeated Mini-Mental State Examination). We used Cox regression models to assess predictive value of protein levels for progression to AD dementia. At baseline most proteins showed increased levels in AD dementia compared to the other groups. In contrast NPTX2 levels were lower in AD dementia. Higher baseline levels of SNAP25, β-syn, and 14-3-3 proteins were associated with faster cognitive decline (St.B[SE] -0.27[0.12] to -0.61[0.12]). Longitudinal analyses showed that SYT1 and NPTX levels decreased over time in AD dementia (st.B[SE] -0.10[0.04] to -0.15[0.05]) and SCD/MCI-A+ (St.B[SE] -0.07[0.03] to -0.12[0.03]), but not in SCD/MCI-A- (pinteraction < 0.05). Increase over time in NfL levels was associated with faster cognitive decline in AD dementia (St.B[SE] -1.75[0.58]), but not in the other groups (pinteraction < 0.05). CSF synaptic proteins showed different slopes over time, suggesting complex synaptic dynamics. High levels of especially SNAP-25 may have value for prediction of cognitive decline in early AD stages, while increase in NfL over time correlates better with cognitive decline in later stages.

Associations of Amyloid Burden, White Matter Hyperintensities, and Hippocampal Volume With Cognitive Trajectories in the 90+ Study.

Amyloid pathology, vascular disease pathology, and pathologies affecting the medial temporal lobe are associated with cognitive trajectories in older adults. However, only limited evidence exists on how these pathologies influence cognition in the oldest old. We evaluated whether amyloid burden, white matter hyperintensity (WMH) volume, and hippocampal volume (HV) are associated with cognitive level and decline in the oldest old. This was a longitudinal, observational community-based cohort study. We included participants with 18F-florbetapir PET and MRI data from the 90+ Study. Amyloid load was measured using the standardized uptake value ratio in the precuneus/posterior cingulate with eroded white matter mask as reference. WMH volume was log-transformed. All imaging measures were standardized using sample means and SDs. HV and log-WMH volume were normalized by total intracranial volume using the residual approach. Global cognitive performance was measured by the Mini-Mental State Examination (MMSE) and modified MMSE (3MS) tests, repeated every 6 months. We used linear mixed-effects models with random intercepts; random slopes; and interaction between time, time squared, and imaging variables to estimate the associations of imaging variables with cognitive level and cognitive decline. Models were adjusted for demographics, APOE genotype, and health behaviors. The sample included 192 participants. The mean age was 92.9 years, 125 (65.1%) were female, 71 (37.0%) achieved a degree beyond college, and the median follow-up time was 3.0 years. A higher amyloid load was associated with a lower cognitive level (βMMSE = -0.82, 95% CI -1.17 to -0.46; β3MS = -2.77, 95% CI -3.69 to -1.84). A 1-SD decrease in HV was associated with a 0.70-point decrease in the MMSE score (95% CI -1.14 to -0.27) and a 2.27-point decrease in the 3MS score (95% CI -3.40 to -1.14). Clear nonlinear cognitive trajectories were detected. A higher amyloid burden and smaller HV were associated with faster cognitive decline. WMH volume was not significantly associated with cognitive level or decline. Amyloid burden and hippocampal atrophy are associated with both cognitive level and cognitive decline in the oldest old. Our findings shed light on how different pathologies contributed to driving cognitive function in the oldest old.

Plasma neurofilament light, glial fibrillary acid protein, and phosphorylated tau 181 as biomarkers for neuropsychiatric symptoms and related clinical disease progression

BackgroundNeuropsychiatric symptoms (NPS) are common in older people, may occur early in the development of dementia disorders, and have been associated with faster cognitive decline. Here, our objectives were to investigate whether plasma levels of neurofilament light chain (NfL), glial fibrillary acid protein (GFAP), and tau phosphorylated at threonine 181 (pTau181) are associated with current NPS and predict future NPS in non-demented older people. Furthermore, we tested whether the presence of NPS combined with plasma biomarkers are useful to predict Alzheimer’s disease (AD) pathology and cognitive decline.MethodsOne hundred and fifty-one participants with normal cognition (n = 76) or mild cognitive impairment (n = 75) were examined in a longitudinal brain aging study at the Memory Centers, University Hospital of Lausanne, Switzerland. Plasma levels of NfL, GFAP, and pTau181 along with CSF biomarkers of AD pathology were measured at baseline. NPS were assessed through the Neuropsychiatric Inventory Questionnaire (NPI-Q), along with the cognitive and functional performance at baseline and follow-up (mean: 20 months). Different regression and ROC analyses were used to address the associations of interest.ResultsNone of the three plasma biomarker was associated with NPS at baseline. Higher GFAP levels were associated with the presence of NPS at follow-up (OR = 2.8, p = .002) and both, higher NfL and higher GFAP with an increase in the NPI-Q severity score over time (β = 0.25, p = .034 and β = 0.30, p = .013, respectively). Adding NPS and the plasma biomarkers to a reference model improved the prediction of future NPS (AUC 0.72 to 0.88, p = .002) and AD pathology (AUC 0.78 to 0.87, p = .010), but not of cognitive decline (AUC 0.79 to 0.85, p = .081).ConclusionPlasma NfL and GFAP are both associated with future NPS and NPS severity change. Considering the presence of NPS along with blood-based AD-biomarkers may improve the prediction of clinical progression of NPS over time and inform clinical decision-making in non-demented older people.

Heterogeneity of cerebral atrophic rate in mild cognitive impairment and its interactive association with proteins related to microglia activity on longitudinal cognitive changes

BackgroundHeterogeneity of cerebral atrophic rate commonly exists in mild cognitive impairment (MCI), which may be associated with microglia-involved neuropathology and have an influence on cognitive outcomes. ObjectiveWe aim to explore the heterogeneity of cerebral atrophic rate among MCI and its association with plasma proteins related to microglia activity, with further investigation of their interaction effects on long-term cognition. SubjectsA total of 630 MCI subjects in the ADNI database were included, of which 260 subjects were available with baseline data on plasma proteins. MethodsGroup-based multi-trajectory modeling (GBMT) was used to identify the latent classes with heterogeneous cerebral atrophic rates. Associations between latent classes and plasma proteins related to microglia activity were investigated with generalized linear models. Linear mixed effect models (LME) were implemented to explore the interaction effects between proteins related to microglia activity and identified latent classes on longitudinal cognitive changes. ResultsTwo latent classes were identified and labeled as the slow-atrophy class and the fast-atrophy class. Associations were found between such heterogeneity of atrophic rates and plasma proteins related to microglia activity, especially AXL receptor tyrosine kinase (AXL), CD40 antigen (CD40), and tumor necrosis factor receptor-like 2 (TNF-R2). Interaction effects on longitudinal cognitive changes showed that higher CD40 was associated with faster cognitive decline in the slow-atrophy class and higher AXL or TNF-R2 was associated with slower cognitive decline in the fast-atrophy class. ConclusionsHeterogeneity of atrophic rates at the MCI stage is associated with several plasma proteins related to microglia activity, which show either protective or adverse effects on long-term cognition depending on the variability of atrophic rates.

Association of CSF α-Synuclein Seed Amplification Assay Positivity with Disease Progression and Cognitive Decline: A Longitudinal Alzheimer's Disease Neuroimaging Initiative Study.

CSF α-synuclein seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body (LB) co-pathology in AD. 1637 cross-sectional and 407 longitudinal CSF samples from ADNI were tested with SAA. We examined longitudinal dynamics of Aβ, α-synuclein seeds, and p-tau181, along with global and domain-specific cognition in stable SAA+, stable SAA-, and those who converted to SAA+ from SAA-. SAA+ individuals had faster cognitive decline than SAA-, notably in MCI, and presented with earlier symptom onset. SAA+ conversion was associated with CSF Aβ42-positivity but did not impact progression of either Aβ42 or p-tau181 status. Aβ42, p-tau181, and α-syn SAA were all strong predictors of clinical progression, particularly Aβ42. In vitro α-syn SAA kinetic parameters were associated with participant demographics, clinical profiles, and cognitive decline. These results highlight the interplay between Aβ and α-synuclein and their association with disease progression.

Long-Term Visit-to-Visit Blood Pressure Variability and Cognitive Decline Among Patients With Hypertension: A Pooled Analysis of 3 National Prospective Cohorts.

A limited number of studies investigated the association between blood pressure variability (BPV) and cognitive impairment in patients with hypertension. This study aimed to identify the longitudinal association between BPV and cognitive decline and the role of blood pressure (BP) control in this association. Participants with hypertension from the HRS (Health and Retirement Study), the ELSA (English Longitudinal Study of Ageing), and the CHARLS (China Health and Retirement Longitudinal Study) were included. Variation independent of the mean (VIM) was adopted to measure BPV. Cognitive function was measured by standard questionnaires, and a standardized Z score was calculated. Linear mixed-model and restricted cubic splines were adopted to explore the association between BPV and cognitive decline. The study included 4853, 1616, and 1432 eligible patients with hypertension from the HRS, ELSA, and CHARLS, respectively. After adjusting for covariates, per-SD increment of VIM of BP was significantly associated with global cognitive function decline in Z scores in both systolic BP (pooled β, -0.045 [95% CI, -0.065 to -0.029]) and diastolic BP (pooled β, -0.022 [95% CI, -0.040 to -0.004]) among hypertensive patients. Similar inverse associations were observed in patients with hypertension taking antihypertensive drugs and in patients with hypertension with well-controlled BP. High BPV was independently associated with a faster cognitive decline among patients with hypertension, even those with antihypertensive medications or well-controlled BP. Further studies are needed to confirm our results and determine whether reducing BPV can prevent or delay cognitive decline.

Association Between Subclinical Thyroid Dysfunction and Cognitive Decline: Findings From the ELSA-Brasil Study.

Thyroid dysfunction has been associated with cognitive decline and dementia. However, the role of subtle thyroid hormone alterations in cognitive function is still debatable. Participants without overt thyroid dysfunction aged 35-74 years at baseline were evaluated in 3 study waves (2008-2010, 2012-2014, and 2017-2019). We assessed baseline thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3). Cognitive performance was evaluated every 4 years in each wave using 10-word immediate and late recall, word recognition, semantic (animals category) and phonemic (letter f) verbal fluency, and the trail-making B-version tests. A global composite z-score was derived from these tests. The associations of TSH, FT4, and FT3 levels with cognitive decline over time were evaluated using linear mixed-effect models adjusted for sociodemographic, clinical, and lifestyle variables. In 9524 participants (mean age 51.2 ± 8.9 years old, 51% women, 52% White), there was no association between baseline TSH, FT4, and FT3 levels and cognitive decline during the follow-up. However, increase in FT4 levels over time was associated with faster memory (β = -0.004, 95% CI = -0.007; -0.001, p = .014), verbal fluency (β = -0.003, 95% CI = -0.007; -0.0005, p = .021), executive function (β = -0.004, 95% CI = -0.011; -0.003, p < .001), and global cognition decline (β = -0.003, 95% CI = -0.006; -0.001, p = .001). Decrease in FT4 levels over time was associated with faster verbal fluency (β = -0.003, 95% CI = -0.007; -0.0004, p = .025) and executive function (β = -0.004, 95% CI = -0.007; -0.0003, p = .031) decline. An increase or decrease in FT4 levels over time was associated with faster cognitive decline in middle-aged and older adults without overt thyroid dysfunction during 8 years of follow-up.

Association of Plasma Amyloid, P-Tau, GFAP, and NfL With CSF, Clinical, and Cognitive Features in Patients With Dementia With Lewy Bodies.

Plasma β-amyloid-1-42/1-40 (Aβ42/40), phosphorylated-tau (P-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) have been widely examined in Alzheimer disease (AD), but little is known about their reflection of copathologies, clinical importance, and predictive value in dementia with Lewy bodies (DLB). We aimed to evaluate associations of these biomarkers with CSF amyloid, cognition, and core features in DLB. This cross-sectional multicenter cohort study with prospective component included individuals with DLB, AD, and healthy controls (HCs), recruited from 2002 to 2020 with an annual follow-up of up to 5 years, from the European-Dementia With Lewy Bodies consortium. Plasma biomarkers were measured by single-molecule array (Neurology 4-Plex E kit). Amyloid status was determined by CSF Aβ42 concentrations, and cognition was assessed by Mini-Mental State Examination (MMSE). Biomarker differences across groups, associations with amyloid status, and clinical core features were assessed by analysis of covariance. Associations with cognitive impairment and decline were assessed by linear regression and linear mixed-effects models. In our cohort consisting of 562 individuals (HC n = 89, DLB n = 342, AD n = 131; 250 women [44.5%], mean [SD] age of 71 [8] years), sex distribution did not differ between groups. Patients with DLB were significantly older, and had less years of education and worse baseline cognition than HC, but not AD. DLB participants stratified for amyloid status differed significantly in plasma Aβ42/40 ratio (decreased in amyloid abnormal: β = -0.008, 95% CI -0.016 to -0.0003, p = 0.01) and P-tau (increased in amyloid abnormal, P-tau181: β = 0.246, 95% CI 0.011-0.481; P-tau231: β = 0.227, 95% CI 0.035-0.419, both p < 0.05), but not in GFAP (β = 0.068, 95% CI -0.018 to 0.153, p = 0.119), and NfL (β = 0.004, 95% CI -0.087 to 0.096, p = 0.923) concentrations. Higher baseline GFAP, NfL, and P-tau concentrations were associated with lower MMSE scores in DLB, and GFAP and NfL were associated with a faster cognitive decline (GFAP: annual change of -2.11 MMSE points, 95% CI -2.88 to -1.35 MMSE points, p < 0.001; NfL: annual change of -2.13 MMSE points, 95% CI -2.97 to -1.29 MMSE points, p < 0.001). DLB participants with parkinsonism had higher concentrations of NfL (β = 0.08, 95% CI 0.02-0.14, p = 0.006) than those without. Our study suggests a possible utility of plasma Aβ42/40, P-tau181, and P-tau231 as a noninvasive biomarkers to assess amyloid copathology in DLB, and plasma GFAP and NfL as monitoring biomarkers for cognitive symptoms in DLB.

A Two-Year Observational Study to Evaluate Conversion Rates from High- and Low-Risk Patients with Amnestic Mild Cognitive Impairment to Probable Alzheimer's Disease in a Real-World Setting.

Predicting conversion to probable Alzheimer&s disease (AD) from amnestic mild cognitive impairment (aMCI) is difficult but important. A nomogram was developed previously for determining the risk of 3-year probable AD conversion in aMCI. To compare the probable AD conversion rates with cognitive and neurodegenerative changes for 2 years from high- and low risk aMCI groups classified using the nomogram. This prospective, multicenter, observational study was conducted in Korea. A total of patients were classified as high- or low-risk aMCI according to the nomogram and followed-up for 2 years to compare the annual conversion rate to probable AD and brain structure changes between the two groups. In total, 176 (high-risk, 85; low-risk, 91) and 160 (high-risk, 77; low-risk, 83) patients completed the 1-year and 2-year follow-up, respectively. The probable AD conversion rate was significantly higher in the high-risk (Year 1, 28.9%; Year 2, 46.1%) versus low-risk group (Year 1, 0.0%; Year 2, 4.9%, both p < 0.0001). Mean changes from baseline in Seoul Neuropsychological Screening Battery-Dementia Version, Clinical Dementia Rating-Sum of Box, and Korean version of the Instrumental Activities of Daily Living scores and cortical atrophy index at Years 1 and 2 were significantly greater in the high-risk group (p < 0.0001). The high-risk aMCI group, as determined by the nomogram, had a higher conversion rate to probable AD and faster cognitive decline and neurodegeneration change than the low-risk group. These real-world results have clinical implications that help clinicians in accurately predicting patient outcomes and facilitating early decision-making.Trial Registration: ClinicalTrials.gov (NCT03448445).

Deep learning model for individualized trajectory prediction of clinical outcomes in mild cognitive impairment.

Accurately predicting when patients with mild cognitive impairment (MCI) will progress to dementia is a formidable challenge. This work aims to develop a predictive deep learning model to accurately predict future cognitive decline and magnetic resonance imaging (MRI) marker changes over time at the individual level for patients with MCI. We recruited 657 amnestic patients with MCI from the Samsung Medical Center who underwent cognitive tests, brain MRI scans, and amyloid-β (Aβ) positron emission tomography (PET) scans. We devised a novel deep learning architecture by leveraging an attention mechanism in a recurrent neural network. We trained a predictive model by inputting age, gender, education, apolipoprotein E genotype, neuropsychological test scores, and brain MRI and amyloid PET features. Cognitive outcomes and MRI features of an MCI subject were predicted using the proposed network. The proposed predictive model demonstrated good prediction performance (AUC = 0.814 ± 0.035) in five-fold cross-validation, along with reliable prediction in cognitive decline and MRI markers over time. Faster cognitive decline and brain atrophy in larger regions were forecasted in patients with Aβ (+) than with Aβ (-). The proposed method provides effective and accurate means for predicting the progression of individuals within a specific period. This model could assist clinicians in identifying subjects at a higher risk of rapid cognitive decline by predicting future cognitive decline and MRI marker changes over time for patients with MCI. Future studies should validate and refine the proposed predictive model further to improve clinical decision-making.

Change in cardiovascular health and rate of cognitive decline in older adults: a 15-year population-based study

BackgroundPrevious research on associations between cardiovascular health, measured at a single timepoint, and rate of age-related cognitive decline shows divergent findings dependent on the participants’ age and the health metric studied. The aim of this study was to add to the knowledge in this field by investigating whether change in cardiovascular health, assessed with Life’s Simple 7 (LS7) score, is associated with rate of cognitive change in young-old and old-old adults.MethodsThe study included 1022 participants aged ≥ 60 years from the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), who underwent repeated neuropsychological testing (episodic memory, semantic memory, verbal fluency, and perceptual speed) across up to 15 years. LS7, composed of seven cardiovascular health metrics (smoking, diet, physical activity, body mass index, plasma glucose, total serum cholesterol, and blood pressure), was assessed at baseline and at the 6-year follow-up. Change in LS7 was calculated as the difference between baseline and 6 years (range − 5 to 8 points) and categorised into worse (−5 to −2 points), stable (−1 to 1 points), and improved (2 to 8 points). Change in cognitive performance as a function of LS7 change categories was estimated using linear mixed-effects models.ResultsParticipants were classified as stable (67.1%), improved (21.0%), or worse (11.8%) according to changes in LS7 score. Both the worse and improved categories were associated with faster cognitive decline. Age-stratified analyses revealed that worsening of LS7 was clearly associated with faster cognitive decline in the old-old (≥ 78 years), whereas improvement tended be associated with faster cognitive decline in the young-old (< 78 years) group.ConclusionsChange in cardiovascular health in old age may lead to accelerated cognitive decline, particularly in late senescence. These results suggest that it is important to monitor and maintain cardiovascular health status in very old adults.

Long-term exposure to transportation noise in relation to global cognitive decline and cognitive impairment: Results from a Swedish longitudinal cohort

Background and aimsTransportation noise is an environmental exposure with mounting evidence of adverse health effects. Besides the increased risk of cardiovascular and metabolic diseases, recent studies suggest that long-term noise exposure might accelerate cognitive decline in older age. We examined the association between transportation noise and cognitive function in a cohort of older adults. MethodsThe present study is based on 2594 dementia-free participants aged 60 + years from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K). Global cognition score and CIND (cognitive impairment, no dementia) were assessed with a comprehensive neuropsychological battery at baseline and up to 16 years. Residential transportation noise resulting from road traffic, railway, and aircraft were estimated at the most exposed façade and the time-weighted average exposure was assessed. Linear mixed-effect models were used to assess the effect of long-term traffic noise exposure on the rate of change in global cognition score. Hazard ratios (HRs) and 95 % confidence intervals (CIs) of CIND by transportation noise exposure were obtained with Cox proportional hazard models. ResultsGlobal cognition score decreased at an average rate of −0.041 (95 %CI −0.043, −0.039) per year. Aircraft noise was associated with a 0.007 (per 10 dB Lden; 95 %CI −0.012, −0.001) faster annual rate of decline. Global cognition score seems to be not affected by road traffic and railway noise. During the follow-up, 422 (21 %) participants developed CIND. A 10-dB Lden difference in exposure to aircraft and railway noise was associated with a 16 % (HR 1.16, 95 %CI 0.91, 1.49) and 26 % (HR 1.26, 95 %CI 1.01, 1.56) increased hazard of CIND in the multi-pollutant model, respectively. No association was found for road traffic (HR 1.00, 95 %CI 0.83, 1.21). ConclusionsTransportation noise was linked to cognitive impairment and faster cognitive decline among older adults. Future studies are warranted to confirm our results.

Increased intraindividual variability in reaction time performance is associated with emerging cognitive decline in cognitively unimpaired adults.

To investigate whether intraindividual variability (IIV) in reaction time (RT) over monthly administered cognitive tasks is increased in cognitively unimpaired older adults who are at risk for cognitive decline, and whether this is independent of mean RT performance. N = 109 cognitively unimpaired individuals (age 77.4 ± 5.0, 61.5% female, Mini-Mental State Examination 29.1 ± 1.3) from the Harvard Aging Brain Study completed the self-administered Computerized Cognitive Composite (C3) monthly at home for up to 1 year (12.7 ± 3.2 C3 assessments). Baseline C3 assessment coincided with routine in-clinic visits, including amyloid and tau positron emission tomography imaging and standardized cognitive testing, with cognitive testing repeated annually (1.6 ± 1.2 years follow-up). The C3 includes two simple RT tasks and two complex RT tasks. IIV estimates were derived by computing intraindividual standard deviations on residual RT scores after regressing out age and session order effects. Cross-sectional associations of IIV with cognition (global cognition, memory, executive functions [EF], processing speed) and amyloid and tau burden were examined using linear regression analyses correcting for demographics and mean RT. The association between IIV and cognitive decline was assessed using linear mixed models correcting for demographic factors, mean RT, and amyloid burden. After adjusting for mean RT, increased IIV on complex RT tasks was independently associated with worse EF performance (β = -0.10, 95% CI [-.16, -0.03], p = .004), greater inferior-temporal tau deposition (β = 0.18, 95% CI [0.02, 0.34], p = .024), and faster cognitive decline in those with elevated amyloid (β = -0.62, 95% CI [-1.18, -0.06], p = .033). Increased variability in monthly RT may reflect subtle EF deficits and provide unique information about short-term cognitive decline in preclinical Alzheimer's disease. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A national longitudinal dyadic analysis of spousal education and cognitive decline in the United States

Education plays a significant role in shaping cognitive functioning throughout an individual's life. However, existing research has not adequately explored how the educational attainment of the spouse can impact cognitive functioning over time. This study presents one of the first longitudinal analyses of how spousal education is linked to cognitive trajectories of each member within couples during their later life in the United States. Guided by the linked lives perspective, we analyze data from 8370 couples in the Health and Retirement Study spanning from 2000 to 2018. Results from the Actor-Partner Interdependence Model (APIM) integrated with latent growth curve models reveal that cognitive trajectories exhibit a correlation between spouses over time. Moreover, our analysis uncovers gender-specific effects of spousal education on cognition, shedding light on the underlying mechanisms driving this connection. Notably, the lower educational attainment of husbands is associated with a faster cognitive decline in both themselves and their wives. This association is partially explained by economic resources, but not by health and social behaviors. The lower educational attainment of wives is linked to their own faster cognitive decline as well as lower initial cognitive levels of their husbands, in part via economic resources. However, wives' educational attainment is largely unrelated to their husbands' cognitive decline. Intriguingly, wives' education has a more pronounced impact on the health and social behaviors of their husbands than vice versa, although these health and social behaviors do not appear to influence husbands' cognitive decline. In conclusion, these results underscore the importance of considering spousal education in comprehending the complexities of cognitive decline within dyadic relationships.

Cognitive change in prevalent and incident hearing loss: The Maastricht Aging Study.

Hearing loss (HL) has been associated with cognitive decline and dementia. We examined the temporal association between prevalent and incident HL and cognitive change. A total of 1823 participants (24-82 years) from the Maastricht Aging Study (MAAS) were assessed at baseline, 6 and 12 years, including pure-tone audiometry. Linear-mixed models were used to test the association between HL and cognition, adjusted for demographics and other dementia risk factors. Participants with prevalent and incident HL showed a faster decline in verbal memory, information processing speed, and executive function than participants without HL. Decline was steady from baseline to 6 and 12 years for prevalent HL, but time-delayed from 6 to 12 years for incident HL. Having a hearing aid did not change associations. Findings support the notion that HL is a risk factor for cognitive decline independent of other dementia risk factors. Onset of HL preceded onset of cognitive decline. We examined cognitive change in prevalent and incident hearing loss. Prevalent and incident hearing loss were associated with faster cognitive decline. For prevalent hearing loss, decline was steady from baseline to 6 and 12 years. Onset of hearing loss preceded the onset of cognitive decline. Having a hearing aid did not change the observed associations.