Decline In Verbal Learning Research Articles

Hyperphosphorylated Tau and Cognition in Epilepsy

In light of the growing interest in the bidirectional relationship between epilepsy and dementia, this review aims to provide an overview of the role of hyperphosphorylated tau (pTau) in cognition in human epilepsy. A literature search identified five relevant studies. All of them examined pTau burden in surgical biopsy specimens from patients with temporal lobe epilepsy. The prevalence of pTau reported across the five studies, encompassing a total of 142 patients, ranged from 3.5% to 95%. Findings also varied regarding the location of pTau in the hippocampus and/or temporal cortex. Two of five studies (40%) demonstrated an inverse relationship between pTau burden and cognitive performance, one study with regard to executive functions and the other with regard to naming and verbal short-term memory. The only longitudinal study found a significant link between pTau and cognitive decline in verbal learning and memory, and in part also in naming, from the pre- to the postoperative assessment and from three to 12 months postoperatively. Given the heterogeneity of the study cohorts and the neuropsychological and neuropathological methodologies and findings, no clear picture emerges regarding the association between pTau and cognition in temporal lobe epilepsy. Added to this is the multifactorial etiology of cognitive impairment in epilepsy, including the active epilepsy, the underlying and sometimes dynamic pathology, and anti-seizure medication. Some of these factors may affect pTau expression. Further research should aim to investigate pTau longitudinally and noninvasively on a whole-brain level, using targeted neuropsychological outcome measures and controlling for age and other factors potentially influencing cognitive trajectories in epilepsy.

Neural correlates of episodic memory decline following electroconvulsive therapy: An exploratory functional magnetic resonance imaging study.

Electroconvulsive therapy (ECT) is an efficient and rapid-acting treatment indicated for severe depressive disorders. While ECT is commonly accompanied by transient memory decline, the brain mechanisms underlying these side effects remain unclear. In this exploratory functional magnetic resonance (fMRI) study, we aimed to compare effects of ECT versus pharmacological treatment on neural response during episodic memory encoding in patients with affective disorders. This study included 32 ECT-treated patients (major depressive disorder (MDD), n = 23; bipolar depression, n = 9) and 40 partially remitted patients in pharmacological treatment (MDD, n = 24; bipolar disorder, n = 16). Participants underwent neuropsychological assessment, a strategic picture encoding fMRI scan paradigm, and mood rating. The ECT group was assessed before ECT (pre-ECT) and 3 days after their eighth ECT session (post-ECT). Groups were comparable on age, gender, and educational years (ps ⩾ 0.05). Within-group analyses revealed a selective reduction in verbal learning and episodic memory pre- to post-ECT (p = 0.012) but no decline in global cognitive performance (p = 0.3). Functional magnetic resonance imaging analyses adjusted for mood symptoms revealed greater activity in ECT-treated patients than pharmacologically treated No-ECT patients across left precentral gyrus (PCG), right dorsomedial prefrontal cortex (dmPFC), and left middle frontal gyrus (MFG). In ECT-treated patients, greater decline in verbal learning and memory performance from pre- to post-ECT correlated with higher PCG response (r = -0.46, p = 0.008), but not with dmPFC or MFG activity (ps ⩾ 0.1), post-ECT. Episodic memory decline was related to greater neural activity in the left PCG, but unrelated to increased dmPFC and MFG activity, immediately after ECT.

Associations between normal cognitive aging and neurodegeneration

AbstractBackgroundMultiple cognitive domains, including learning, memory and psychomotor speed, show significant reductions with age. These changes are thought to reflect normal cognitive aging. However, since cerebrospinal fluid (CSF) neurodegenerative biomarkers, such as total‐tau (t‐tau) and Neurofilament light chain (NfL), also show age‐related increases in normal aging, we aimed to investigate whether age‐associated cognitive decline may be mediated by age‐associated neurodegenerative changes.MethodWe included 114 cognitively healthy participants aged 40‐80 years from The Norwegian Dementia Disease Initiation Study. All had normal concentrations of CSF Aβ42/40 ratio. Cognitively healthy was defined as demographically adjusted T‐scores ≥35 on standardized cognitive tests. We fitted mediation models using structural equation modelling (SEM), with either CSF NfL or t‐tau as a mediator between age and CERAD learning, CERAD recall, TMT‐A and TMT‐B. All variables were standardized prior to analyses; in addition, both t‐tau and NfL were log transformed due to skewness.ResultsSee table 1 for demographic and clinical characteristics. Whilst neither NfL nor t‐tau showed statistically significant mediation of age‐related cognitive decline, our results nevertheless suggest a partial mediation of NfL on age‐related cognitive decline. Here, relationships between age and CERAD learning, CERAD Recall, and TMT‐A performance were weakened whereas higher NfL was associated with worse performance, in particular for delayed memory recall. This was not observed for t‐tau in any models. See figure 1‐2.ConclusionAge‐related decline in verbal learning, memory and psychomotor speed may be partially attributable to NfL‐associated neurodegenerative changes in cognitively healthy adults. As NfL reflects axonal degeneration, these results may reflect white matter neurodegeneration in aging.

Psychosocial factors associated with changes in cognition among middle‐aged and older Hispanics/Latinos: Findings from the HCHS/SOL and the sociocultural and SOL‐Investigation of Neurocognitive Aging (SOL‐INCA) ancillary studies

AbstractBackgroundPsychosocial factors including intrapersonal and interpersonal resources and social stressors are associated with changes in cognition in older non‐Hispanic whites and Blacks. Few studies have examined these associations in Hispanics/Latinos, the largest ethnic/racial group in the US, or evaluated ethnically‐based psychosocial factors that may be more relevant to this population. We examined whether psychosocial factors predict seven‐year cognitive changes among US Hispanics/Latinos.MethodData from the parent HCHS/SOL, and Sociocultural and SOL‐Investigation of Neurocognitive Aging ancillary studies were used (n= 2,158; ages 45+). Baseline psychosocial factors included: intrapersonal factors (optimism; purpose in life), interpersonal factors (family cohesion; social network embeddedness; social support), social stressors (loneliness; subjective social status), and ethnically‐based factors (ethnic identity; familism; perceived ethnic discrimination). Outcomes were changes in individual test scores for episodic learning and memory (B‐SEVLT‐Sum and SEVLT‐Recall), word fluency (WF), and processing speed (Digit Symbol Substitution, DSS) derived using regressions adjusting for time between assessments. Survey linear regression models were used to examine the associations between each psychosocial factor (z‐scores) and 7‐year changes in cognitive outcomes adjusting for age, sex, education, income, Hispanic/Latino background, language preference, and depressive symptoms.ResultMean age was 55.9±7.9 years; females 54% of target population. Higher (baseline) levels of familism [(βSEVLT‐Sum (SE))= ‐0.08 (0.03), P<0.05)] predicted seven‐year decline in verbal learning. Higher optimism [βSEVLT‐Recall= 0.09 (0.03), P<0.01], social support [βSEVLT‐Recall= 0.07 (0.03), P<0.05], and ethnic identity [βSEVLT‐Recall= 0.06 (0.03), P<0.05] each predicted increase in memory. Higher familism [βSEVLT‐Recall= ‐0.08 (0.03), P<0.05] and loneliness [βSEVLT‐Recall= ‐0.06 (0.03), P<0.05] each predicted decline in memory. Higher purpose in life [βWF= 0.07 (0.03), P<0.05] predicted increase in word fluency. Higher family cohesion [βDSS= ‐0.08 (0.03, P<0.01) predicted decline in processing speed. Social network embeddedness, subjective social status, and perceived ethnic discrimination were not associated with any outcome.ConclusionPsychosocial factors differentially related to changes in cognition. Results confirm previous studies in non‐Hispanic whites on associations of optimism, purpose in life, social support, and loneliness with select cognitive tests. They also highlight that ethnic identity and familism are ethnically‐based psychosocial factors that should be considered when examining healthy cognitive aging in US Hispanics/Latinos.

Solid cooking fuel use and cognitive decline among older Mexican adults.

Studies of air pollution and cognition often rely on measures from outdoor environments. Many individuals in low- and middle-income countries are exposed to indoor air pollution from combustion of solid cooking fuels. Little is known about how solid cooking fuel use affects cognitive decline over time. This study uses data from the 2012, 2015, and 2018 Mexican Health and Aging Study (n=14245, age 50+) to assess how use of wood or coal for cooking fuel affects cognition of older adults relative to use of gas. It uses latent change score modeling to determine how using solid cooking fuel affected performance in Verbal Learning, Verbal Recall, Visual Scanning, and Verbal Fluency. Solid cooking fuel was used by 17% of the full sample but was more common in rural areas. Solid fuel users also had lower socioeconomic status. Compared to those using gas, solid fuel users had lower baseline scores and faster decline in Verbal Learning (β=-0.18, p<0.05), Visual Scanning (β=-1.00, p<0.001), and Verbal Fluency (β=-0.33, p<0.001). Indoor air pollution from solid cooking fuels may represent a modifiable risk factor for cognitive decline. Policy should focus on facilitating access to clean cooking fuels.

Working in old age in Mexico: Implications for Cognitive Functioning.

Previous studies indicate that occupation might affect cognitive functioning in late life. As people in low and middle income countries often have to work until late life, we sought to investigate if there are cognitive benefits to working later into life and whether cognitive function deteriorates after exiting the labor force. We analyzed longitudinal data from the Mexican Health and Aging Study (MHAS), a nationally representative sample of Mexican adults age 50+ (n=7,375), that assessed cognitive functioning by verbal learning, delayed recall, and visual scanning. Analyses were carried out using mixed-effects modeling corrected for the influence of gender, IADLs, diabetes, stroke, hypertension, depression, income, and marital status. Results suggest that working actively, compared to exiting the workforce, was associated with cognitive performance only in context with occupation. Domestic workers had a faster decline in verbal learning (b=-0.02, p=0.020) and delayed recall (b=-0.02, p=0.036) if they continued working actively and people working in administration (b=0.03, p=0.007), sales (b=0.02, p=0.044), and educators (b=0.03, p=0.049) had a slower decline in visual scanning if they continued working in old age. Our findings indicate that continued participation in the labor force in old age does not necessarily come with cognitive benefits. Whether or not working actively in later life protects or even harms cognitive functioning is likely to depend on the type of job.

CTNI-51. NEUROCOGNITIVE FUNCTION (NCF) OUTCOMES OF RTOG FOUNDATION 3508: A PHASE 3 TRIAL OF ABT-414 WITH CONCURRENT CHEMORADIATION AND ADJUVANT TEMOZOLOMIDE IN PATIENTS WITH EGFR-AMPLIFIED NEWLY DIAGNOSED GBM

Abstract RTOG 3508/AbbVie M13-813/INTELLANCE-1 was a phase 3 trial of depatuximab-mafodotin (depatux-m, formerly ABT-414) that accrued 639 patients with EGFR-amplified newly diagnosed GBM. At the pre-specified interim OS analysis, the futility criteria were met and there was no survival benefit from adding depatux-m to SOC. Pre-specified secondary NCF analyses included time to decline in verbal learning and memory as assessed by the HVLT-R Total Recall based on the reliable change index. Exploratory NCF analyses examined changes in other HVLT-R outcomes over time. As corneal epitheliopathy causing visual impairment is a known toxicity of depatux-m, NCF tests that did not depend on visual acuity were employed. NCF testing occurred at baseline, day 1 of the first cycle of adjuvant depatux-m, every other cycle (i.e., 8 weeks) thereafter, and at progression. Compliance with test completion was 95% at screening and 80%, 70%, 58%, 51%, 47% thereafter through cycle 9. The most common reasons for missing data was site error. Time to HVLT-R Total Recall decline trended worse in the depatux-m arm compared to placebo but the difference was not significant (12 month deterioration: 41.2%, 95% CI: 3.50–47.2 vs 32.4%, 95% CI: 26.6- 38.4, p=0.052). The depatux-m arm, in comparison to the placebo arm, showed greater decline from baseline on the HVLT-R at the following time points: cycle 3 (Total Recall: mean= -1.8, SD=5.7 vs mean= -0.5, SD=5.5, respectively, p=0.046; Delayed Recall: mean= -1.1, SD=3.0 vs. mean= -0.2, SD=2.7, respectively, p=0.01), cycle 7 (Total Recall: mean= -0.6, SD=5.1 vs mean= 1.4, SD=5.0, respectively, p=0.009; Delayed Recall: mean -0.6, SD=3.0 vs. mean= 0.5, SD=2.7, respectively, p=0.01), and cycle 9 (Delayed Recall: mean=-0.4, SD=2.7 vs. mean= 0.8, SD=2.4, respectively, p=0.003). Depatux-m added to concurrent chemoradiation and adjuvant temozolomide was associated with faster time to deterioration and worse episodic learning and memory over time than placebo.

Association between exposure to polycyclic aromatic hydrocarbons and brain cortical thinning: The Environmental Pollution-Induced Neurological EFfects (EPINEF) study

BackgroundAlthough some studies have suggested that exposure to polycyclic aromatic hydrocarbons (PAHs) induces neurodevelopmental disturbances in children and neurodegeneration in animals, the neurotoxic effect of PAH exposure is unclear in adults. The aim was to examine the associations of PAH exposure with brain structure and neuropsychological function in adults without known neurological diseases. MethodsThis study included 421 men and 528 women dwelling in four cities in the Republic of Korea. Urinary concentrations of four PAH metabolites (1-hydroxypyrene, 2-naphthol, 1-hydroxyphenanthrene, and 2-hydroxyfluorene) were obtained. Participants underwent brain 3 T magnetic resonance imaging and neuropsychological tests. Cortical thickness and volume were estimated using the region-of-interest method. Separate generalized linear models were constructed for each sex, adjusting for age, years of education, cohabitation status, income, tobacco use, alcohol consumption, and vascular risk factors. ResultsThe mean (standard deviation) age was 68.3 (6.6) years in men and 66.4 (6.1) years in women. In men, those in quartile 4 (versus quartile 1, the lowest) of urinary 2-naphthol concentration had cortical thinning in the global (β = −0.03, P = .02), parietal (β = −0.04, P = .01), temporal (β = −0.06, P < .001), and insular lobes (β = −0.05, P = .02). Higher quartiles of urinary 2-naphthol concentration were associated with cortical thinning in the global (P = .01), parietal (P = .004), temporal (P < .001), and insular lobes (P = .01). In women, those in quartile 4 (versus quartile 1) of urinary 1-hydroxypyrene concentration had cortical thinning in the frontal (β = −0.03, P = .006) and parietal lobes (β = −0.03, P = .003). Higher quartiles of urinary 1-hydroxypyrene concentration were associated with cortical thinning in the frontal (P = .006) and parietal lobes (P = .001). In both sexes, verbal learning and memory scores significantly declined with an increase in quartile of urinary 1-hydroxypyrene concentration. ConclusionsPAH exposure was associated with cortical thinning and decline in verbal learning and memory function in cognitively healthy adults. This suggests PAHs as an environmental risk factor for neurodegeneration.

Stressful Life Events and Racial Disparities in Cognition Among Middle-Aged and Older Adults.

It is well-documented that African Americans have elevated risk for cognitive impairment and dementia in late life, but reasons for the racial disparities remain unknown. Stress processes have been linked to premature age-related morbidity, including Alzheimer's and related dementias (ADRD), and plausibly contribute to social disparities in cognitive aging. We examined the relationship between stressful life events and cognitive decline among African American and White participants enrolled in the Wisconsin Registry for Alzheimer's Prevention (WRAP). Linear mixed models including demographic, literacy, and health-related covariates were used to estimate (1) relationships between a life event index score and decline in cognitive test performance in two domains of executive function (Speed & Flexibility, Working Memory) and one domain of episodic memory (Verbal Learning & Memory) among 1,241 WRAP enrollees, stratified by race, and (2) contributions of stressful life events to racial differences in cognition within the full sample. African Americans (N = 50) reported more stressful life events than Whites (N = 1,191). Higher stress scores associated with poorer Speed & Flexibility performance in both groups, though not with declines across time, and partially explained racial differentials in this domain. Among African Americans only, stressor exposure also associated with age-related decline in Verbal Learning & Memory. Stressor-cognition relationships were independent of literacy and health-related variables. Greater lifetime stress predicted poorer later-life cognition, and, in a small sample of African Americans, faster declines in a key domain of episodic memory. These preliminary findings suggest that future work in large minority aging cohorts should explore stress as an important source of modifiable, socially-rooted risk for impairment and ADRD in African Americans, who are disproportionately exposed to adverse experiences across the life course.

High-Sensitive Troponin T, Natriuretic Peptide, and Cognitive Change.

Cardiac troponin T, measured using a high-sensitive assay (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are associated with increased stroke risk and perhaps with cognitive decline. However, few well-designed prospective studies with extended follow-up have been conducted. We aimed to estimate the association of hs-cTnT and NT-proBNP with 15-year cognitive change in the Atherosclerosis Risk in Communities (ARIC) study. Prospective cohort study. Four US communities. A total of 9114 and 9108 participants from the Atherosclerosis Risk in Communities study for analyses of hs-cTnT and NT-proBNP, respectively. We examined association of hs-cTnT and NT-proBNP with 15-year change (1996-1998 to 2011-2013) in three cognitive tests of executive function (Digit Symbol Substitution Test), verbal learning memory (Delayed Word Recall Test), and semantic fluency (Word Fluency Test), and an overall score combining the three tests using multivariable linear mixed effect models. We conducted several sensitivity analyses including multiple imputations to address bias due to missing data and attrition, and we compared associations within groups combining hs-cTnT and NT-proBNP into a three-level categorical variable. At baseline (1996-1998), mean age was 63.4 (standard deviation [SD] = 5.7) years; 56.4% were women, and 17.5% were black. The hs-cTnT at baseline was not associated with cognitive change in any measure. Some evidence indicated accelerated decline in verbal learning and memory when comparing those in the highest with the lowest NT-proBNP quintiles; however, this association was not replicated when considering clinically relevant cutoffs or deciles of exposure in survivors. Sensitivity analyses were consistent with our primary analyses. There was little evidence to support effect modification by any considered factors. People with highest levels of both biomarkers had excessive decline in global z scores vs people with lowest levels (-.34; 95% confidence interval = -.63 to -.04). Markers of myocardial injury and stretch were not associated with cognitive decline following 15 years among survivors, but when combined together they were suggestive in post hoc analysis. Whether this represents targets of intervention should be examined in the future. J Am Geriatr Soc 67:2353-2361, 2019.

Cognitive Functioning I

AbstractThe intellectual stimulation provided by occupation throughout the life course seems to be an important determinant of cognitive function in late life. It is unclear if there are cognitive benefits to working later into life and whether cognitive function deteriorates after exiting the labor force. As the context of labor in Mexico requires Mexican adults to work later into life, we used longitudinal data from the Mexican Health and Aging Study (MHAS). Analyses of the impact of participation in the labor force on cognitive functioning (verbal learning, delayed recall, visual scanning) were carried out using mixed-effects modeling corrected for the influence of gender, IADLs, diabetes, stroke, hypertension, depression, income, and marital status. Compared to production workers, those who worked in agriculture or with livestock had a significantly faster decline in verbal learning (0.02 words per year) and delayed recall (0.05 words per year), whereas those who worked in administration, education, or professional occupations had a significantly slower decline in delayed recall (0.06 per year). A continued participation in the labor force was, on one hand, associated with a faster decline in verbal learning for technicians (b=-0.073) and, on the other hand, associated with a slower faster decline in visual scanning for drivers (b=0.573). Our findings suggest that a continued participation in the labor force in old age does not necessarily come with cognitive benefits. Whether or not working actively in later life protects cognitive functioning probably depends on the type of job and individual characteristics.

Abstract B39: A pilot study of neuropsychological functions, APOE, and amyloid imaging in patients with gliomas

Abstract Patients with brain tumors treated with radiotherapy (RT) often develop cognitive dysfunction, and recent studies suggest that the apolipoprotein (APOE) ε-4 allele may influence cognitive outcome. The ε-4 allele promotes beta (β) amyloid deposition in the cortex, and preliminary evidence suggests that RT may be associated with β-amyloid deposition. In this pilot study, we assessed neuropsychological functions and β-amyloid retention using 18F-florbetaben PET in a subset of brain tumor patients who participated in our study of APOE polymorphisms and cognitive functions. Twenty glioma patients treated with conformal RT ± chemotherapy participated in the study: 6 were APOE ε-4 carriers and 14 were non-ε-4 carriers. Patients completed a neuropsychological reevaluation and brain MRI and 18F-florbetaben PET scans. The results of Wilcoxon rank sums test comparisons between prior and current assessments showed a significant decline in selective attention (Brief Test of Attention, p=0.018), and a near-significant decline in verbal learning (Hopkins Verbal Learning Test-Learning, p=0.07). Comparisons between assessments by APOE status showed a significant decline in attention and working memory (WAIS-III digits forward, p=0.028 and digits backward, p=0.032) among APOE ε-4 carriers. Comparisons of PET regional standard uptake value ratios (SUVRs) showed near-significant differences for the medial temporal cortex (p=0.069) and the putamen (p=0.069), with non-ε-4 carriers having higher SUVRs. The findings suggest that glioma patients may experience progressive worsening in attention and executive functions several years after treatment with RT ± chemotherapy, and that the APOE ε-4 allele may moderate cognitive decline. Note: This abstract was not presented at the conference. Citation Format: Denise Correa, Maria Kryza-Lacombe, Xiaosun Zhou, Raymond Baser, Brad Beattie, Zodina Beiene, Irene Orlow, John Humm, Lisa DeAngelis, Wolfgang Weber, Joseph Osborne. A pilot study of neuropsychological functions, APOE, and amyloid imaging in patients with gliomas [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B39.

A pilot study of neuropsychological functions, APOE and amyloid imaging in patients with gliomas.

Brain tumor patients treated with radiotherapy (RT) often develop cognitive dysfunction, and recent studies suggest that the APOE ε-4 allele may influence cognitive outcome. The ε-4 allele is known to promote beta (β) amyloid deposition in the cortex, and preliminary evidence suggests that RT may be associated with this process. However, it is unknown whether β-amyloid accumulation contributes to treatment neurotoxicity. In this pilot study, we assessed neuropsychological functions and β-amyloid retention using 18F-florbetaben (FBB) PET in a subset of brain tumor patients who participated in our study of APOE polymorphisms and cognitive functions. Twenty glioma patients treated with conformal RT ± chemotherapy participated in the study: 6 were APOE ε-4 carriers and 14 were non-ε-4 carriers. Patients completed a neuropsychological re-evaluation (mean time interval = 5 years, SD = 0.83) and brain MRI and FBB PET scans. Wilcoxon signed-rank test comparisons between prior and current neuropsychological assessments showed a significant decline in attention (Brief Test of Attention, p = 0.018), and a near significant decline in verbal learning (Hopkins Verbal learning Test-Learning, p = 0.07). Comparisons by APOE status showed significant differences over time in attention/working memory (WAIS-III digits forward, p = 0.028 and digits backward, p = 0.032), with a decline among APOE ε-4 carriers. There were no significant differences in any of the FBB PET analyses between APOE ε-4 carriers and non-ε-4 carriers. The findings suggest that glioma patients may experience worsening in attention and executive functions several years after treatment, and that the APOE ε-4 allele may modulate cognitive decline, but independent of increased β-amyloid deposition.

Prospective Trial of Quantitative Neuroimaging Correlates of Verbal and Nonverbal Memory Decline

To analyze clinical and quantitative neuroimaging parameters associated with verbal and nonverbal memory changes in a longitudinal, prospective clinical trial of brain tumor patients undergoing radiotherapy (RT). We hypothesized that volume and white matter (WM) diffusion changes in memory-associated regions would correlate with post-RT cognitive decline. We prospectively evaluated 25 patients with primary brain tumors undergoing fractionated partial-brain RT. Patients underwent high-resolution 3D volumetric brain MRI and diffusion-weighted imaging, along with neurocognitive testing prior to and 6 months after RT. Semi-automated software was used to segment discrete neuroanatomic regions, quantifying volume and diffusion biomarkers of WM damage (MD = mean diffusivity; FA = fractional anisotropy). Tumor, surgical effects, and edema were censored. Memory-associated regions of interest included the hippocampus and WM subadjacent to entorhinal, parahippocampal, and temporal pole neocortex. Reliable change indices (RCI) were calculated to measure changes in verbal (Hopkins Verbal Learning Test [HVLT]) and nonverbal (Brief Visuospatial Memory Test [BVMT]) learning and memory from pre- to post-RT. Pearson correlation coefficients were calculated to assess associations between clinical and imaging parameters (change from baseline in hippocampal volume, MD, FA) and memory outcomes. Statistical significance was set at α = 0.05 for two-tailed tests. Patients showed a significant decline in nonverbal learning (BVMT total recall, P = 0.009, one sample t-test) but not in verbal learning or memory/HVLT. Glioma patients had a greater decline in nonverbal learning and memory (BVMT total and delayed recall) at 6 months post-RT (r = -.44, P = 0.047 for both tests), as did patients with seizures (r = -.58, P = 0.035; r = -.44, P = 0.035) and those receiving concurrent (r = -.57, P = 0.005; r = -.56, P = 0.005) or adjuvant chemotherapy (r = -.44, P = 0.035 for both tests). Right hippocampal volume significantly decreased after RT (mean change -.036; one sample t-test; P = 0.01). While hippocampal volume loss was not significantly associated with memory decline, changes in WM microstructure were associated with verbal memory decline. Increased left parahippocampal WM FA was associated with decline in verbal learning and memory (HVLT total and delayed recall, r = -.68, P = 0.008; r = -.70, P = 0.004, respectively) and increased MD was associated with decline in verbal learning (HVLT total recall, r = -.65, P = 0.01). Increased mean dose to left entorhinal and temporal pole WM was associated with verbal memory decline (HVLT delayed recall, r = -.54, P = 0.02; r = -.54, P = 0.02, respectively). WM microstructure in the medial temporal lobe, but not hippocampal atrophy, is associated with memory decline in brain tumors patients receiving RT. These data suggest that damage to medial temporal lobe WM may serve as an important biomarker for RT-associated memory decline.

BDNF Val66Met predicts cognitive decline in the Wisconsin Registry for Alzheimer's Prevention.

To examine the influence of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on longitudinal cognitive trajectories in a large, cognitively healthy cohort enriched for Alzheimer disease (AD) risk and to understand whether β-amyloid (Aβ) burden plays a moderating role in this relationship. One thousand twenty-three adults (baseline age 54.94 ± 6.41 years) enrolled in the Wisconsin Registry for Alzheimer's Prevention underwent BDNF genotyping and cognitive assessment at up to 5 time points (average follow-up 6.92 ± 3.22 years). A subset (n = 140) underwent 11C-Pittsburgh compound B (PiB) scanning. Covariate-adjusted mixed-effects regression models were used to elucidate the effect of BDNF on cognitive trajectories in 4 cognitive domains, including verbal learning and memory, speed and flexibility, working memory, and immediate memory. Secondary mixed-effects regression models were conducted to examine whether Aβ burden, indexed by composite PiB load, modified any observed BDNF-related cognitive trajectories. Compared to BDNF Val/Val homozygotes, Met carriers showed steeper decline in verbal learning and memory (p = 0.002) and speed and flexibility (p = 0.017). In addition, Aβ burden moderated the relationship between BDNF and verbal learning and memory such that Met carriers with greater Aβ burden showed even steeper cognitive decline (p = 0.033). In a middle-aged cohort with AD risk, carriage of the BDNF Met allele was associated with steeper decline in episodic memory and executive function. This decline was exacerbated by greater Aβ burden. These results suggest that the BDNF Val66Met polymorphism may play an important role in cognitive decline and could be considered as a target for novel AD therapeutics.

Amyloid β–associated cognitive decline in the absence of clinical disease progression and systemic illness

IntroductionHigh levels of amyloid β (Aβ) are associated with cognitive decline in cognitively normal (CN) older adults. This study investigated the nature of cognitive decline in healthy individuals who did not progress to mild cognitive impairment or dementia. MethodCognition was measured over 72 months and compared between low (Aβ−) and high (Aβ+) CN older adults (n = 335) who did not progress to mild cognitive impairment or dementia and who remained free of severe or uncontrolled systemic illness. ResultsCompared to the Aβ− group, the Aβ+ group showed no cognitive impairment at baseline but showed substantial decline in verbal learning, episodic memory, and attention over 72 months. DiscussionModerate cognitive decline, particularly for learning and memory, was associated with Aβ+ in CN older adults in the absence of clinical disease progression and uncontrolled or serious comorbid illness.

Hyperphosphorylated tau in patients with refractory epilepsy correlates with cognitive decline: a study of temporal lobe resections.

SEE BERNASCONI DOI101093/AWW202 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Temporal lobe epilepsy, the most prevalent form of chronic focal epilepsy, is associated with a high prevalence of cognitive impairment but the responsible underlying pathological mechanisms are unknown. Tau, the microtubule-associated protein, is a hallmark of several neurodegenerative diseases including Alzheimer's disease and chronic traumatic encephalopathy. We hypothesized that hyperphosphorylated tau pathology is associated with cognitive decline in temporal lobe epilepsy and explored this through clinico-pathological study. We first performed pathological examination on tissue from 33 patients who had undergone temporal lobe resection between ages 50 and 65 years to treat drug-refractory temporal lobe epilepsy. We identified hyperphosphorylated tau protein using AT8 immunohistochemistry and compared this distribution to Braak patterns of Alzheimer's disease and patterns of chronic traumatic encephalopathy. We quantified tau pathology using a modified tau score created specifically for analysis of temporal lobectomy tissue and the Braak staging, which was limited without extra-temporal brain areas available. Next, we correlated tau pathology with pre- and postoperative cognitive test scores and clinical risk factors including age at time of surgery, duration of epilepsy, history of secondary generalized seizures, history of head injury, handedness and side of surgery. Thirty-one of 33 cases (94%) showed hyperphosphorylated tau pathology in the form of neuropil threads and neurofibrillary tangles and pre-tangles. Braak stage analysis showed 12% of our epilepsy cohort had a Braak staging III-IV compared to an age-matched non-epilepsy control group from the literature (8%). We identified a mixture of tau pathology patterns characteristic of Alzheimer's disease and chronic traumatic encephalopathy. We also found unusual patterns of subpial tau deposition, sparing of the hippocampus and co-localization with mossy fibre sprouting, a feature of temporal lobe epilepsy. We demonstrated that the more extensive the tau pathology, the greater the decline in verbal learning (Spearman correlation, r = -0.63), recall (r = -0.44) and graded naming test scores (r = -0.50) over 1-year post-temporal lobe resection (P < 0.05). This relationship with tau burden was also present when examining decline in verbal learning from 3 months to 1 year post-resection (r = -0.54). We found an association between modified tau score and history of secondary generalized seizures (likelihood-ratio χ(2), P < 0.05) however there was no clear relationship between tau pathology and other clinical risk factors assessed. Our findings suggest an epilepsy-related tauopathy in temporal lobe epilepsy, which contributes to accelerated cognitive decline and has diagnostic and treatment implications.

DISTINCT COGNITIVE TRAJECTORIES IN LATE MIDDLE-AGE AND THEIR ASSOCIATIONS WITH BRAIN STRUCTURE AND ALZHEIMER'S DISEASE BIOMARKERS: FINDINGS FROM THE WISCONSIN REGISTRY FOR ALZHEIMER’S PREVENTION

Late middle-age is an important period to identify mild cognitive decline expected to precede clinical diagnoses of mild cognitive impairment and dementia. This study aimed to characterize patterns of longitudinal cognitive change in late middle-age and to identify a subgroup at highest risk for dementia. 677 late middle-aged participants enriched for AD risk (mean age at baseline 53.5, 69% female, 77% parental history of AD) who were cognitively healthy at baseline completed 4 or 5 neuropsychological assessments over a period of 8-10 years. Using linear mixed-effects regression, unconditional growth models were conducted for six neuropsychological variables, and the fixed and random effect estimates were combined to obtain slope estimates for each participant. Hierarchical cluster analysis was conducted on slope estimates, and resulting clusters were compared on slopes, intercepts, demographics, AD risk, and clinical outcomes. A subset underwent MRI scans (n=235) and cerebrospinal fluid assays (n=88). ANCOVA models (covarying age and gender) compared clustered groups on brain structure and AD biomarkers. Cluster analysis resulted in three groups: 1) Multi-domain group declining on learning, memory, and executive function measures (n=188), 2) dysexecutive group with mild decline in verbal learning and executive functioning (n=152), and 3) group with normal age-related decline in processing speed only (n=337) (Table 1, Figure 1). The multi-domain cluster was older (F=19.32, p<.001), comprised of more men (X2 = 9.20; p=.01), and endorsed more depressive symptoms (F=3.51, p<.05) at baseline. The multi-domain group included a greater percentage of APOE ε4 carriers (X2 = 5.27, p=.07), individuals with mild clinical symptoms (CDR=0.5, X2 = 20.39, p<.001) and clinical diagnoses (X2 = 52.69, p<.001) at follow-up, and individuals classified as AD biomarker positive (18% total-tau/Aβ-42 positive; X2 = 7.26; p<.05). The dysexecutive cluster had less education (F=5.06, p<.01) and lower literacy estimates (F=14.06, p<.001). The normally aging cluster exhibited higher intercepts on neuropsychological measures (p'S < .02) and less global atrophy (F=6.80, p=.001) (Figure 2). Annual rates of change on neuropsychological measures included in cluster analysis projected over 20-year period (note: Increase in Trailmaking Test Part B = worse performance). Mean global atrophy in three clusters. Full model also included age, gender, and intracranial Cluster analysis of slopes reflecting annual rates of cognitive change provides a data-driven method to identify mild cognitive decline in late middle-age that may indicate increased risk for dementia due to AD.

Visual and verbal learning deficits in Veterans with alcohol and substance use disorders

BackgroundThis study examined visual and verbal learning in the early phase of recovery for 48 Veterans with alcohol use (AUD) and substance use disorders (SUD, primarily cocaine and opiate abusers). Previous studies have demonstrated visual and verbal learning deficits in AUD, however little is known about the differences between AUD and SUD on these domains. Since the DSM-5 specifically identifies problems with learning in AUD and not in SUD, and problems with visual and verbal learning have been more prevalent in the literature for AUD than SUD, we predicted that people with AUD would be more impaired on measures of visual and verbal learning than people with SUD. MethodsParticipants were enrolled in a comprehensive rehabilitation program and were assessed within the first 5 weeks of abstinence. Verbal learning was measured using the Hopkins Verbal Learning Test (HVLT) and visual learning was assessed using the Brief Visuospatial Memory Test (BVMT). ResultsResults indicated significantly greater decline in verbal learning on the HVLT across the three learning trials for AUD participants but not for SUD participants (F=4.653, df=48, p=0.036). Visual learning was less impaired than verbal learning across learning trials for both diagnostic groups (F=0.197, df=48, p=0.674); there was no significant difference between groups on visual learning (F=0.401, df=14, p=0.538). DiscussionOlder Veterans in the early phase of recovery from AUD may have difficulty learning new verbal information. Deficits in verbal learning may reduce the effectiveness of verbally-based interventions such as psycho-education.

Changes in verbal learning and memory in schizophrenia and non-psychotic controls in midlife: A nine-year follow-up in the Northern Finland Birth Cohort study 1966

Findings on longitudinal change of cognitive performance in schizophrenia are extremely variable in the case of verbal learning and memory, and it is still unclear which dimensions of verbal learning and memory exhibit possible deterioration over the long-term. Our aim was to compare the change in verbal learning and memory in individuals with schizophrenia 10–20 years after the illness onset and healthy controls during a nine-year follow-up in a general population sample. Our sample included 41 schizophrenia spectrum subjects and 73 controls from the Northern Finland Birth Cohort study 1966. The California Verbal Learning Test (CVLT) was used to estimate the degree of change in verbal learning and memory during a nine-year follow-up from age 34-years to 43- years. Both cases and controls deteriorated. There was statistically significant decline in two out of 20 CVLT items among cases and in 13 out of 20 CVLT items among controls. With the exception of two variables, the decline in verbal learning and memory over nine years was not significantly larger in cases. We conclude that during midlife verbal learning and memory in schizophrenia mostly declines in a normative fashion with aging at the same rate as the general population.