Predictors of treatment-response to caffeine combination products, acetaminophen, acetylsalicylic acid (aspirin), and nonsteroidal anti-inflammatory drugs in acute treatment of episodic migraine.

OBJECTIVE: To identify predictors of acute treatment optimization for migraine with "over-the-counter" (OTC) or prescription nonsteroidal anti-inflammatory drugs (NSAIDs) as well as other widely used OTCs including acetaminophen, caffeine combination products (CCP), and acetylsalicylic acid (ASA, aspirin) among people with episodic migraine and to develop models that predict treatment response to each class of OTCs. BACKGROUND: Efficacy of acute OTC medications for migraine varies greatly. Identifying predictors of treatment response to particular classes of medication is a step toward evidence-based personalized therapy. METHODS: For this prediction model development study, we used data from 2224 participants from the American Migraine Prevalence and Prevention (AMPP) study who were aged ≥18 years, met criteria for migraine, had <15 monthly headache days, and reported being on monotherapy for acute migraine attacks with one of the following classes medications: CCP (N = 711), acetaminophen (N = 643), ASA (N = 110), and prescription or OTC NSAIDs (N = 760). The primary outcome measures of treatment optimization were adequate 2-h pain freedom (2hPF) and adequate 24-h pain relief (24hPR), which were defined by responses of half the time or more to the relevant items on the Migraine Treatment Optimization Questionnaire-6. RESULTS: The mean (SD) age of the participants was 46.2 (13.1) years, 79.4% (1765/2224) were female, 43.7% (972/2224) reported adequate 2hPF, and 46.1% (1025/2224) reported adequate 24hPR. Those taking CCP had better 2hPF and 24PR outcomes. For those taking NSAIDs, better outcomes were associated with lower average pain intensity (2hPF: odds ratio [OR] 0.89, 95% confidence interval [CI] 0.80-0.99; 24PR: OR 0.86, 95% CI 0.77-0.96), cutaneous allodynia (2hPF: OR 0.92, 95% CI 0.89-0.96; 24PR: OR 0.91, 95% CI 0.87-0.95), depressive symptoms (2hPF: OR 0.95, 95% CI 0.92-0.98; 24PR: OR 0.95, 95% CI 0.91-0.99), and Migraine Disability Assessment Scale (MIDAS) grade (2hPF: OR 0.76, 95% CI 0.64-0.90; 24PR: OR 0.79, 95% CI 0.65-0.95). Adequate 2hPF for those taking CCP was associated with male gender (OR 1.83, 95% CI 1.21-2.77), lower average pain intensity (OR 0.80, 95% CI 0.70-0.91), lower cutaneous allodynia (OR 0.94, 95% CI 0.90-0.97), and lower Migraine Symptom Severity Scale Score (MSSS; OR 0.91, 95% CI 0.86-0.97). Adequate 24hPR for those taking CCP was associated with lower average pain intensity (OR 0.85, 95% CI 0.75-0.96), lower cutaneous allodynia (OR 0.92, 95% CI 0.89-0.96), and lower MIDAS grade (OR 0.81, 95% CI 0.68-0.96). Participants who were married (OR 1.51, 95% CI 1.05-2.19), had lower average pain intensity (OR 0.79, 95% CI 0.70-0.89), lower MSSS (OR 0.93, 95% CI 0.88-0.99), less depression (OR 0.96, 95% CI 0.93-0.99), and lower MIDAS grade (OR 0.72, 95% CI 0.59-0.87) had adequate 2hPF after taking acetaminophen. Participants who were married (OR 1.50, 95% CI 1.02-2.21), had lower pain intensity (OR 0.78, 95% CI 0.69-0.88), less depression (OR 0.95, 95% CI 0.91-0.98) and lower MIDAS grade (OR 0.53, 95% CI 0.42-0.67) had higher 24hPR following use of acetaminophen. A lower MSSS was the only factor associated with higher 2hPF and 24PR after using ASA (OR 0.78, 95% CI 0.67-0.92 and OR 0.79, 95% CI 0.67-0.93). Predictive models had modest performance in identifying responders to each class of OTC. CONCLUSION: A large subgroup of people with migraine had an inadequate response to their usual acute OTC migraine treatment 2- and 24-h after dosing. These findings suggest a need to improve OTC treatment for some and to offer prescription acute medications for others. Predictive models identified several factors associated with better treatment-response in each OTC class. Selecting OTC treatment based on factors predictive of treatment optimization might improve patient outcomes.

Comparing Performance of Different Predictive Models in Estimating Disease Progression in Alzheimer Disease.

BACKGROUND: Automatic classification techniques provide tools to analyze complex data and predict disease progression. METHODS: A total of 305 cognitively normal; 475 patients with amnestic mild cognitive impairment (aMCI); and 162 patients with dementia were included in this study. We compared the performance of 3 different methods in predicting progression from aMCI to dementia: (1) index-based model; (2) logistic regression (LR); and (3) ensemble linear discriminant (ELD) machine learning models. LR and ELD models were trained using data from cognitively normal and dementia subgroups, and subsequently were applied to aMCI subgroup to predict their disease progression. RESULTS: Performance of ELD models were better than LR models in prediction of conversion from aMCI to Alzheimer dementia at all time frames. ELD models performed better when a larger number of features were used for prediction. CONCLUSION: Machine learning models have substantial potential to improve the predictive ability for cognitive outcomes.

Predictive models for determining treatment response to nonprescription acute medications in migraine: Results from the American Migraine Prevalence and Prevention Study.

OBJECTIVE: To identify predictors of acute treatment response for nonprescription (over-the-counter [OTC]) medications among people with migraine and develop improved models for predicting treatment response. BACKGROUND: Pain freedom and sustained pain relief are important priorities in the acute treatment of migraine. OTC medications are widely used for migraine; however, it is not clear which treatment works best for each patient without going through the trial and error process. METHODS: A prediction model development study was completed using the 2006 American Migraine Prevalence and Prevention Study survey, from participants who were aged ≥18, met criteria and headache day frequency for episodic migraine, did not take prescription medication for migraine, and used ≥1 of the following acute migraine medication classes: acetaminophen, aspirin, NSAIDs, or caffeine containing combination products (CCP). Two items from the Migraine Treatment Optimization Questionnaire were used to evaluate treatment response, adequate 2-h pain freedom (2hPF) and 24-h pain relief (24hPR), which were defined by a response to treatment ≥half the time at 2 h and 24 h post treatment, respectively. We identified predictors of adequate treatment response and developed models to predict probability of treatment response to each medication class. RESULTS: The sample included 3852 participants (3038 [79.0%] females) with an average age of 45.0 years (SD = 12.8). Only 1602/3852 (41.6%) and 1718/3852 (44.6%) of the participants reported adequate 2hPF and 24hPR, respectively. Adequate treatment-response was significantly predicted by lower average headache pain intensity, less cutaneous allodynia, and lower depressive symptom scores. Lower migraine symptom severity was predictive of adequate 2hPF and fewer monthly headache days was predictive of adequate 24hPR. Among participants reporting OTC monotherapy (n = 2168, 56.3%) individuals taking CCP were more likely to have adequate 2hPF (OR = 1.55, 95% CI 1.23-1.95) and 24hPR (OR = 1.79, 95% CI 1.18-1.88) in comparison with those taking acetaminophen. Predictive models were modestly predictive of responders to OTC medications (c-statistics = 0.65; 95% CI 0.62-0.68). CONCLUSION: These results show that response to acute migraine treatments is not optimized in the majority of people with migraine treating with OTC medications. Predictive models can improve our ability to choose the best therapeutic option for individuals with episodic migraine and increase the proportion of patients with optimized response to treatments.

Anterior cervical corpectomy and fusion with stand-alone cages in patients with multilevel degenerative cervical spine disease is safe.

BACKGROUND: In case of spinal cord compression behind the vertebral body, anterior cervical corpectomy and fusion (ACCF) proves to be a more feasible approach than cervical discectomy. The next step was the placement of an expandable titanium interbody in order to restore the vertebral height. The need for additional anterior plating with ACCF has been debatable and such technique has been evaluated by very few studies. The objective of the study is to evaluate radiographic and clinical outcomes in patients with multilevel degenerative cervical spine disease treated by stand-alone cages for anterior cervical corpectomy and fusion (ACCF). METHODS: Thirty-one patients (66.5 ± 9.75 years, range 53-85 years) were analyzed. Visual Analog Scale (VAS) and the 10-item Neck Disability Index (NDI) were assessed preoperatively and during follow-up on a regular basis after surgery and after one year at least. Assessment of radiographic fusion, subsidence, and lordosis measurement of Global cervical lordosis (GCL); fusion site lordosis (FSL); the anterior interbody space height (ant. DSH); the posterior interbody space height (post. DSH); the distance of the cage to the posterior wall of the vertebral body (CD) were done retrospectively. Mean clinical and radiographic follow-up was 20.0 ± 4.39 months. RESULTS: VAS-neck (p = 0.001) and VAS-arm (p < 0.001) improved from preoperatively to postoperatively. The NDI improved at the final follow-up (p < 0.001). Neither significant subsidence of the cages nor significant loss of lordotic correction were seen. All patients showed a radiographic union of the surgically addressed segments at the last follow up. CONCLUSIONS: Application of a stand-alone expandable cage in the cervical spine after one or two-level ACCF without additional posterior fixation or anterior plating is a safe procedure that results in fusion. Neither significant subsidence of the cages nor significant loss of lordotic correction were seen. TRIAL REGISTRATION: Retrospectively registered. According to the Decision of the ethics committee, Jena on 25th of July 2018, that this study doesn't need any registration.  https://www.laek-thueringen.de/aerzte/ethikkommission/registrierung/ .

Radiofrequency ablation and balloon kyphoplasty for palliation of painful spinal metastases.

PURPOSE: This study was designed with an aim to assess the safety and early postoperative outcomes of the combined Radiofrequency ablation (RFA) and Balloon Kyphoplasty (BKP) used for the treatment of painful neoplastic spinal lesions palliatively. PATIENTS AND METHODS: Between December 2015 and December 2018, 60 patients (35 men and 25 women) with spinal metastases were operated using RFA and BKP at our institution. Transpedicular biopsy was performed in all cases. Patients' demographics, lesion characteristics, concurrent palliative therapies and complications were recorded. All patients were clinically (Pain score VAS 0-10) and radiologically evaluated pre- and postoperatively. Retrospective analysis of data for this cohort was performed. RESULTS: Seventy-five painful spinal metastases (46 in the lumbar spine and 29 in the thoracic region) in 60 patients were operated [transpedicular RFA alone in 5 lesions, and in combination with BKP in 70 lesions (93%)]. The mean pre-procedure and post-procedure VAS for back pain was 7.2/10 and 2.7/10, respectively (p value = 0.0001). No neurological complications related to RFA were found and no cement extravasation into the spinal canal was observed. In two patients, asymptomatic leaks into the needle track, in two patients into draining veins and in one patient into the disk space were detected. CONCLUSION: Combined RFA and BKP appears to be a safe, practical, effective and reproducible palliative treatment for painful spinal osteolytic metastasis. In carefully indicated cases, it relieves pain and maintains stability in a minimal invasive way without adding significant surgical trauma or complications.

Predictive value of ATN biomarker profiles in estimating disease progression in Alzheimer's disease dementia.

We aimed to evaluate the value of ATN biomarker classification system (amyloid beta [A], pathologic tau [T], and neurodegeneration [N]) for predicting conversion from mild cognitive impairment (MCI) to dementia. In a sample of people with MCI (n = 415) we assessed predictive performance of ATN classification using empirical knowledge-based cut-offs for each component of ATN and compared it to two data-driven approaches, logistic regression and RUSBoost machine learning classifiers, which used continuous clinical or biomarker scores. In data-driven approaches, we identified ATN features that distinguish normals from individuals with dementia and used them to classify persons with MCI into dementia-like and normal groups. Both data-driven classification methods performed better than the empirical cut-offs for ATN biomarkers in predicting conversion to dementia. Classifiers that used clinical features performed as well as classifiers that used ATN biomarkers for prediction of progression to dementia. We discuss that data-driven modeling approaches can improve our ability to predict disease progression and might have implications in future clinical trials.

Health-related Quality of Life, Cognitive Performance, and Incident Dementia in a Community-based Elderly Cohort.

BACKGROUND: We hypothesized that higher quality of life would be associated with better cognitive function and a reduced risk of incident all cause dementia and Alzheimer disease (AD) in older adults. MATERIALS AND METHODS: Participants included 1183 older adults with an average age of 78.2 (SD=5.3) from Einstein Aging Study. The 36-Item Short-Form Health Survey was used to measure health-related quality of life (HRQoL). We investigated baseline associations between the cognitive domains of memory, executive function, and general fluid ability with 8 subscales of the 36-Item Short-Form Health Survey (physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, social functioning, role limitations due to emotional problems, vitality, and general mental health) and the 2 component summary scores of physical component summary (PCS) and mental component summary (MCS). Next, we used Cox proportional hazard models to assess the predictive validity of HRQoL subscales for the onset of incident dementia and incident AD. RESULTS: At baseline, higher scores (better HRQoL) on MCS and its 4 subscales (social functioning, role limitations due to emotional problems, vitality, and general mental health) were associated with higher performance on both memory and executive function domains. Higher scores in role limitation due to physical problems, role limitation due to emotional problems, and general mental health subscales were associated with reduced risk of incident dementia. Higher MCS, but not PCS, predicted a reduced incident of all-cause dementia and AD. CONCLUSIONS: These findings suggest that diminution of HRQoL precedes the onset of diagnosable dementia and may be useful in the prediction of dementia onset.

Depressive Symptoms Predict Incident Dementia in a Community Sample of Older Adults: Results From the Einstein Aging Study.

BACKGROUND:: There is increasing evidence that depressive symptoms are associated with increased risk of cognitive impairment and dementia in older adults. In current study, we aimed to investigate the effect of depressive symptoms on incident Alzheimer disease and all-cause dementia in a community sample of older adults. METHODS:: Participants were 1219 older adults from the Einstein Aging Study, a longitudinal cohort study of community-dwelling older adults in Bronx County, New York. The Geriatric Depression Scale (GDS, 15-item) was used as a measure of depressive symptoms. The primary outcome was incident dementia diagnosed using the Diagnostic and Statistical Manual, Fourth Edition, criteria. Cox proportional hazard models were used to estimate the risk of incident dementia as a function of GDS score for the whole population and also for 2 different time intervals, <3 years and ≥3 years after baseline assessment. RESULTS:: Among participants, 132 individuals developed dementia over an average 4.5 years (standard deviation [SD] = 3.5) of follow-up. Participants had an average age of 78.3 (SD = 5.4) at baseline, and 62% were women. Among all participants, after controlling for demographic variables and medical comorbidities, a 1-point increase in GDS was associated with higher incidence of dementia (hazard ratio [HR] = 1.11, P = .007). After up to 3 years of follow-up, depressive symptoms were not significantly associated with dementia incidence (HR = 1.09; P = .070). However, after more than 3 years, GDS score was a significant predictor of incident dementia (HR = 1.13, P = .028). CONCLUSIONS:: Our results suggest that depressive symptoms are associated with an increased risk of incident dementia in older adults.

Neuropsychological latent classes at enrollment and postmortem neuropathology.

INTRODUCTION: We classified individuals based on their baseline performance on cognitive measures and investigated the association between cognitive classifications and neuropathological findings ∼7 years later, as an external validator. METHODS: Brain autopsies of 779 decedents were examined. Baseline latent class analysis on 10 neuropsychological measures was previously assigned: mixed-domains impairment (n = 39, 5%), memory-specific impairment (n = 210, 27%), frontal impairment (n = 113, 14.5%), average cognition (n = 360, 46.2%), and superior cognition (n = 57, 7.3%). Linear regressions and risks ratios were used to examine the relation of latent class assignment at enrollment with neuropathological indices. RESULTS: Amyloid ß, tau, and transactive response DNA-binding protein 43 were associated with mixed-domains impairment and memory-specific impairment classes ∼7 years before death. Moderate arteriolosclerosis was associated with membership in the frontal impairment class. DISCUSSION: Our findings support the use of latent class models that incorporate more comprehensive neuropsychological measures to classify cognitive impairment.

Pain Intensity and Pain Interference in Older Adults: Role of Gender, Obesity and High-Sensitivity C-Reactive Protein.

BACKGROUND: Among older adults, pain intensity and pain interference are more common in women than men and associated with obesity and inflammatory markers. OBJECTIVE: We examined whether the obesity and pain relationship is mediated by the high-sensitivity C-reactive protein (hsCRP), a nonspecific marker of systemic inflammation, and whether this relationship differs by sex. METHODS: Items from Medical Outcomes Study Short Form-36 were used to measure pain intensity and pain interference in daily life. Ordinal logistic regression was used to assess the cross-sectional association among body mass index (BMI), hsCRP levels, pain intensity and pain interference using gender-stratified models adjusted for demographic variables. RESULTS: Participants included 667 community-residing adults over the age of 70 years, free of dementia, enrolled in the Einstein Aging Study (EAS). In women (n = 410), pain intensity was associated with obesity [BMI ≥30 vs. normal, odds ratio (OR) = 2.29, 95% confidence interval (CI) 1.43-3.68] and higher hsCRP (OR = 1.28, 95% CI 1.08-1.51). In a model with obesity and hsCRP, both remained significant, but the association between hsCRP and pain intensity was somewhat attenuated. Obesity (OR = 3.04, 95% CI 1.81-5.11) and higher hsCRP levels (OR = 1.30, 95% CI 1.08-1.56) were also independently associated with greater pain interference in women. After adjustment for pain intensity and BMI, hsCRP was no longer associated with pain interference in women. Greater pain intensity and being overweight or obese continued to be significantly associated with pain interference in women. In men (n = 257), obesity and hsCRP were not associated with pain intensity or pain interference. CONCLUSIONS: In women, the relationship between obesity and higher levels of pain intensity or interference may be accounted for by factors related to hsCRP.

Influence of Perceived Stress on Incident Amnestic Mild Cognitive Impairment: Results From the Einstein Aging Study.

Stress is a potentially remediable risk factor for amnestic mild cognitive impairment (aMCI). Our objective is to determine whether perceived stress predicts incident aMCI and to determine if the influence of stress on aMCI is independent of known aMCI risk factors, particularly demographic variables, depression, and apolipoprotein genotype. The Einstein Aging Study is a longitudinal community-based study of older adults. The Perceived Stress Scale (PSS) was administered annually in the Einstein Aging Study to participants (N=507; 71 developed incident aMCI; mean follow-up time=3.6 y, SD=2.0) who were aged 70 years and older, free of aMCI and dementia at baseline PSS administration, and had at least 1 subsequent annual follow-up. Cox hazard models were used to examine time to aMCI onset adjusting for covariates. High levels of perceived stress are associated with a 30% greater risk of incident aMCI (per 5-point increase in PSS: hazard ratio=1.30; 95% confidence interval, 1.08-1.58) independent of covariates. The consistency of results after covariate adjustment and the lack of evidence for reverse causation in longitudinal analyses suggest that these findings are robust. Understanding of the effect of perceived stress on cognition may lead to intervention strategies that prevent the onset of aMCI and Alzheimer dementia.

The association of brain structure with gait velocity in older adults: a quantitative volumetric analysis of brain MRI.

INTRODUCTION: While cortical processes play an important role in controlling locomotion, the underlying structural brain changes associated with slowing of gait in aging are not yet fully established. Our study aimed to examine the relationship between cortical gray matter volume (GM), white matter volume (WM), ventricular volume (VV), hippocampal and hippocampal subfield volumes, and gait velocity in older adults free of dementia. METHODS: Gait and cognitive performance was tested in 112 community-residing adults, age 70 years and over, participating in the Einstein Aging Study. Gait velocity (cm/s) was obtained using an instrumented walkway. Volumetric MRI measures were estimated using a FreeSurfer software. We examined the cross-sectional relationship of GM, WM, VV, and hippocampal total and subfield volumes and gait velocity using linear regression models. In complementary models, the effect of memory performance on the relationship between gait velocity and regional volumes was evaluated. RESULTS: Slower gait velocity was associated with smaller cortical GM and total hippocampal volumes. There was no association between gait velocity and WM or VV. Among hippocampal subfields, only smaller presubiculum volume was significantly associated with decrease in gait velocity. Addition of the memory performance to the models attenuated the association between gait velocity and all volumetric measures. CONCLUSIONS: Our findings indicate that total GM and hippocampal volumes as well as specific hippocampal subfield volumes are inversely associated with locomotor function. These associations are probably affected by cognitive status of study population.

Validation of the Perceived Stress Scale in a community sample of older adults.

BACKGROUND: Three versions of Perceived Stress Scale (PSS-14, PSS-10, and PSS-4) are among the most widely used measures of stress. The aim of the current study was to validate this instrument in a sample of nondemented older adults to facilitate studies of the impact of stress on health. METHODS: Seven hundred sixty-eight nondemented adults over the age of 70 years completed the PSS-14 questionnaire and other neuropsychological tests. Exploratory factor analysis was used to determine the underlying factor structure of all PSS versions, and confirmatory factor analysis was used to test the construct validity of factors. The internal consistency reliability of the scales was assessed using Cronbach's alpha, and concurrent validity was evaluated by examining PSS relation with age, gender, depression, anxiety, and Positive Affect and Negative Affect Schedule. RESULTS: A two-factor model was the optimal fit for the 14-item and 10-item versions of PSS. For PSS-14, all items' loadings exceeded 0.4 for one of the two factors except item 12. Therefore, we studied a 13-item version of PSS and 10-item and 4-item subsets representing PSS-10 and PSS-4. Internal consistency coefficients were satisfactory for the full scale of PSS-13 and PSS-10 but not for PSS-4. Women reported higher levels of stress than men. Higher levels of total PSS scores showed association with higher levels of depression, anxiety, and negative affect, and lower level of positive affect. CONCLUSIONS: The 13-item and 10-item versions of PSS may be used to understand the experience of stress among older adults.

Plasma Biomarkers as Predictors of Progression to Dementia in Individuals with Mild Cognitive Impairment.

Background: Blood-based biomarkers (BBMs) are of growing interest in the field of Alzheimer's disease (AD) and related dementias. Objective: This study aimed to assess the ability of plasma biomarkers to 1) predict disease progression from mild cognitive impairment (MCI) to dementia and 2) improve the predictive ability of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) measures when combined. Methods: We used data from the Alzheimer's Disease Neuroimaging Initiative. Machine learning models were trained using the data from participants who remained cognitively stable (CN-s) and with Dementia diagnosis at 2-year follow-up visit. The models were used to predict progression to dementia in MCI individuals. We assessed the performance of models with plasma biomarkers against those with CSF and MRI measures, and also in combination with them. Results: Our models with plasma biomarkers classified CN-s individuals from AD with an AUC of 0.75±0.03 and could predict conversion to dementia in MCI individuals with an AUC of 0.64±0.03 (17.1% BP, base prevalence). Models with plasma biomarkers performed better when combined with CSF and MRI measures (CN versus AD: AUC of 0.89±0.02; MCI-to-AD: AUC of 0.76±0.03, 21.5% BP). Conclusions: Our results highlight the potential of plasma biomarkers in predicting conversion to dementia in MCI individuals. While plasma biomarkers could improve the predictive ability of CSF and MRI measures when combined, they also show the potential to predict non-progression to AD when considered alone. The predictive ability of plasma biomarkers is crucially linked to reducing the costly and effortful collection of CSF and MRI measures.

Genetic and Clinical Correlates of AI-Based Brain Aging Patterns in Cognitively Unimpaired Individuals.

Importance: Brain aging elicits complex neuroanatomical changes influenced by multiple age-related pathologies. Understanding the heterogeneity of structural brain changes in aging may provide insights into preclinical stages of neurodegenerative diseases. Objective: To derive subgroups with common patterns of variation in participants without diagnosed cognitive impairment (WODCI) in a data-driven manner and relate them to genetics, biomedical measures, and cognitive decline trajectories. Design, Setting, and Participants: Data acquisition for this cohort study was performed from 1999 to 2020. Data consolidation and harmonization were conducted from July 2017 to July 2021. Age-specific subgroups of structural brain measures were modeled in 4 decade-long intervals spanning ages 45 to 85 years using a deep learning, semisupervised clustering method leveraging generative adversarial networks. Data were analyzed from July 2021 to February 2023 and were drawn from the Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) international consortium. Individuals WODCI at baseline spanning ages 45 to 85 years were included, with greater than 50 000 data time points. Exposures: Individuals WODCI at baseline scan. Main Outcomes and Measures: Three subgroups, consistent across decades, were identified within the WODCI population. Associations with genetics, cardiovascular risk factors (CVRFs), amyloid ß (Aß), and future cognitive decline were assessed. Results: In a sample of 27 402 individuals (mean [SD] age, 63.0 [8.3] years; 15 146 female [55%]) WODCI, 3 subgroups were identified in contrast with the reference group: a typical aging subgroup, A1, with a specific pattern of modest atrophy and white matter hyperintensity (WMH) load, and 2 accelerated aging subgroups, A2 and A3, with characteristics that were more distinct at age 65 years and older. A2 was associated with hypertension, WMH, and vascular disease-related genetic variants and was enriched for Aß positivity (ages ≥65 years) and apolipoprotein E (APOE) ε4 carriers. A3 showed severe, widespread atrophy, moderate presence of CVRFs, and greater cognitive decline. Genetic variants associated with A1 were protective for WMH (rs7209235: mean [SD] B = -0.07 [0.01]; P value = 2.31 × 10-9) and Alzheimer disease (rs72932727: mean [SD] B = 0.1 [0.02]; P value = 6.49 × 10-9), whereas the converse was observed for A2 (rs7209235: mean [SD] B = 0.1 [0.01]; P value = 1.73 × 10-15 and rs72932727: mean [SD] B = -0.09 [0.02]; P value = 4.05 × 10-7, respectively); variants in A3 were associated with regional atrophy (rs167684: mean [SD] B = 0.08 [0.01]; P value = 7.22 × 10-12) and white matter integrity measures (rs1636250: mean [SD] B = 0.06 [0.01]; P value = 4.90 × 10-7). Conclusions and Relevance: The 3 subgroups showed distinct associations with CVRFs, genetics, and subsequent cognitive decline. These subgroups likely reflect multiple underlying neuropathologic processes and affect susceptibility to Alzheimer disease, paving pathways toward patient stratification at early asymptomatic stages and promoting precision medicine in clinical trials and health care.

Hippocampal correlates of depression in healthy elderly adults.

Mixed findings have been reported on the relationship between hippocampal integrity and major depression in clinical populations. Few neuroimaging studies have investigated associations between hippocampal measures and depressive symptoms in nondemented older adults. Here, we address this issue by imaging 36 nondemented adults over age 70 from the Einstein Aging Study, a community-based sample from the Bronx, NY. Depressive symptoms were assessed using the 15-item Geriatric Depression scale (GDS). Clinically significant depression was defined using a cut-off score of 5 or greater. Hippocampal data included MRI-derived volume data normalized to midsagittal area and MRS-derived N-acetylaspartate to creatine ratios (NAA/Cr). Our result indicates that smaller total hippocampal volume was associated with higher GDS scores, but there were no significant association between hippocampal NAA/Cr and GDS score. These effects were consistent after controlling for age, education, and gender. Reduction in hippocampal volume could represent a risk factor or a consequence of depression in older adults. Further studies are needed to better understand the role of the hippocampus in the development and experience of depression in older adults.

Association of Alcohol Consumption with Cognition in Older Population: The A4 Study.

BACKGROUND: Alcohol use disorders have been categorized as a 'strongly modifiable' risk factor for dementia. OBJECTIVE: To investigate the cross-sectional association between alcohol consumption and cognition in older adults and if it is different across sexes or depends on amyloid-ß (Aß) accumulation in the brain. METHODS: Cognitively unimpaired older adults (N = 4387) with objective and subjective cognitive assessments and amyloid positron emission tomography (PET) imaging were classified into four categories based on their average daily alcohol use. Multivariable linear regression was then used to test the main effects and interactions with sex and Aß levels. RESULTS: Individuals who reported no alcohol consumption had lower scores on the Preclinical Alzheimer Cognitive Composite (PACC) compared to those consuming one or two drinks/day. In sex-stratified analysis, the association between alcohol consumption and cognition was more prominent in females. Female participants who consumed two drinks/day had better performance on PACC and Cognitive Function Index (CFI) than those who reported no alcohol consumption. In an Aß-stratified sample, the association between alcohol consumption and cognition was present only in the Aß- subgroup. The interaction between Aß status and alcohol consumption on cognition was not significant. CONCLUSION: Low or moderate consumption of alcohol was associated with better objective cognitive performance and better subjective report of daily functioning in cognitively unimpaired individuals. The association was present only in Aß- individuals, suggesting that the pathophysiologic mechanism underlying the effect of alcohol on cognition is independent of Aß pathology. Further investigation is required with larger samples consuming three or more drinks/day.

Tracking cognition with the T-MoCA in a racially/ethnically diverse older adult cohort.

Introduction: We investigated the utility of the Telephone-Montreal Cognitive Assessment (T-MoCA) to track cognition in a diverse sample from the Einstein Aging Study. Methods: Telephone and in-person MoCA data, collected annually, were used to evaluate longitudinal cognitive performance. Joint models of T-MoCA and in-person MoCA compared changes, variance, and test-retest reliability measured by intraclass correlation coefficient by racial/ethnic group. Results: There were no significant differences in baseline performance or longitudinal changes across three study waves for both MoCA formats. T-MoCA performance improved over waves 1-3 but declined afterward. Test-retest reliability was lower for the T-MoCA than for the in-person MoCA. In comparison with non-Hispanic Whites, non-Hispanic Blacks and Hispanics performed worse at baseline on both MoCA formats and showed lower correlations between T-MoCA and in-person versions. Conclusions: The T-MoCA provides valuable information on cognitive change, despite racial/ethnic disparities and practice effects. We discuss implications for health disparity populations. Highlights: We assessed the comparability of Telephone-Montreal Cognitive Assessment (T-MoCA) and in-person MoCA for tracking cognition.Changes within 3 years in T-MoCA were similar to that for the in-person MoCA.T-MoCA is subject to practice effects and shows difference in performance by race/ethnicity.Test-retest reliability of T-MoCA is lower than that for in-person MoCA.

Association of Stages of Objective Memory Impairment With Incident Symptomatic Cognitive Impairment in Cognitively Normal Individuals.

BACKGROUND AND OBJECTIVES: Increasing evidence indicates that a subset of cognitively normal individuals has subtle cognitive impairment at baseline. We sought to identify them using the Stages of Objective Memory Impairment (SOMI) system. Symptomatic cognitive impairment was operationalized by a Clinical Dementia Rating (CDR) ≥0.5. We hypothesized that incident impairment would be higher for participants with subtle retrieval impairment (SOMI-1), higher still for those with moderate retrieval impairment (SOMI-2), and highest for those with storage impairment (SOMI-3/4) after adjusting for demographics and APOE ε4 status. A secondary objective was to determine whether including biomarkers of ß-amyloid, tau pathology, and neurodegeneration in the models affect prediction. We hypothesized that even after adjusting for in vivo biomarkers, SOMI would remain a significant predictor of time to incident symptomatic cognitive impairment. METHODS: Among 969 cognitively normal participants, defined by a CDR = 0, from the Knight Alzheimer Disease Research Center, SOMI stage was determined from their baseline Free and Cued Selective Reminding Test scores, 555 had CSF and structural MRI measures and comprised the biomarker subgroup, and 144 of them were amyloid positive. Cox proportional hazards models tested associations of SOMI stages at baseline and biomarkers with time to incident cognitive impairment defined as the transition to CDR ≥0.5. RESULTS: Among all participants, the mean age was 69.35 years, 59.6% were female, and mean follow-up was 6.36 years. Participants in SOMI-1-4 had elevated hazard ratios for the transition from normal to impaired cognition in comparison with those who were SOMI-0 (no memory impairment). Individuals in SOMI-1 (mildly impaired retrieval) and SOMI-2 (moderately impaired retrieval) were at nearly double the risk of clinical progression compared with persons with no memory problems. When memory storage impairment emerges (SOMI-3/4), the hazard ratio for clinical progression increased approximately 3 times. SOMI stage remained an independent predictor of incident cognitive impairment after adjusting for all biomarkers. DISCUSSION: SOMI predicts the transition from normal cognition to incident symptomatic cognitive impairment (CDR ≥0.5). The results support the use of SOMI to identify those cognitively normal participants most likely to develop incident cognitive impairment who can then be referred for biomarker screening.

Four-level anterior cervical discectomies and cage-augmented fusion with and without fixation.

PURPOSE: Anterior cervical decompression and fusion is a well-established procedure for the treatment of cervical spinal canal stenosis. In this study, we evaluated the necessity of spinal instrumentation after four-level anterior cervical decompression and cage fusion. METHODS: From January 2006 until August 2008, 25 patients (8 females and 17 males) (mean age 63.9 ± 7.9 years) suffering from spinal stenosis C3-C7 underwent anterior decompression and interbody fusion. The patients were divided into two groups. Four-level discectomy and cage fusion was performed in all patients. In group A including nine patients, posterior instrumentation with a lateral mass screw-rod system was added, while in group B including 16 patients, additional instrumentation was not performed. The mean duration of follow-up was 48.6 months (average 25-67 months). RESULTS: Clinically, the mean value for the Neck Disability Index improved from 40 ± 23.25 at presentation to 16.31 ± 15.09 at the final follow-up. The difference between the two groups was statistically not significant. Radiologically, the criteria for solid bony fusion were achieved successfully in all patients of group A, and in 87.5 % of patients in group B. The difference between the two groups was statistically not significant. The fused segment was then evaluated in the sagittal radiographs as regards the height and the lordosis angle. The loss in the height as well as the loss in the lordosis angle was more when posterior instrumentation was not added. However, the difference between the two groups was not statistically significant. CONCLUSION: Stand-alone intersomatic cage fusion is an acceptable line of treatment for four-level cervical disc disease, both clinically and radiologically. Although the addition of posterior instrumentation yields better radiological results, the difference does not reach the statistical significance level.