Direct Heterocycle C-H Alkenylation via Dual Catalysis Using a Palladacycle Precatalyst: Multifactor Optimization and Scope Exploration Enabled by High-Throughput Experimentation.

One of the major challenges in developing catalytic methods for C-C bond formation is the identification of generally applicable reaction conditions, particularly if multiple substrate structural classes are involved. Pd-catalyzed direct arylation reactions are powerful transformations that enable direct functionalization of C-H bonds; however, the corresponding direct alkenylation reactions, using vinyl (pseudo) halide electrophiles, are less well developed. Inspired by process development efforts toward GSK3368715, an investigational active pharmaceutical ingredient, we report that a Pd(II) palladacycle derived from tri-tert-butylphosphine and Pd(OAc)2 is an effective single-component precatalyst for a variety of direct alkenylation reactions. High-throughput experimentation identified optimal solvent/base combinations for a variety of HetAr-H substrate classes undergoing C-H activation without the need for cocatalysts or stoichiometric silver bases (e.g., Ag2CO3). We propose this reaction proceeds via a dual cooperative catalytic mechanism, where in situ-generated Pd(0) supports a canonical Pd(0)/(II) cross-coupling cycle and the palladacycle effects C-H activation via CMD in a redox-neutral cycle. In all, 192 substrate combinations were tested with a hit rate of approximately 40% and 24 isolated examples. Importantly, this method was applied to prepare a key intermediate in the synthesis of GSK3368715 on multigram scale.

Construct validation of NIH Toolbox Cognition Battery premorbid cognitive functioning scores in Black and White older Americans with and without mild cognitive impairment.

OBJECTIVE: Valid estimates of premorbid cognitive functioning (PMIQ) are crucial for the assessment of older adults at risk for Alzheimer's disease. We investigated the relationship between the NIH Toolbox-Cognition Battery's (NIHTB-CB) Oral Reading Recognition (ORR) subtest and Wechsler Test of Adult Reading scores (WTAR, convergent validity). We also compared ORR to NIHTB-CB Flanker scores, where null relationships were expected (discriminant validity). METHODS: The WTAR and NIHTB-CB were administered to 130 cognitively normal (CN) and 113 participants with mild cognitive impairment (MCI). Participants were community-dwelling, older Black and White adults, ages 55-88 years. Data analysis used uncorrected standard scores and Bayesian bivariate correlations. Supplemental materials include intraclass correlations. RESULTS: ORR and WTAR scores were strongly positively associated, while ORR and Flanker scores were unrelated. This pattern held when restricting analyses to the two cognitive status groups, the two racial groups, and the four race-by-diagnosis subgroups. CONCLUSION: The findings demonstrate convergent and discriminant validity and support NIHTB-CB ORR scores as valid estimates of scores on a PMIQ measure in older Black and White adults with and without MCI.

Cross-cultural evaluation of learning and memory using a consonant-vowel-consonant trigram list.

OBJECTIVE: Word list-learning tasks are commonly used to evaluate auditory-verbal learning and memory. However, different frequencies of word usage, subtle meaning nuances, unique word phonology, and different preexisting associations among words make translation across languages difficult. We administered lists of consonant-vowel-consonant (CVC) nonword trigrams to independent American and Italian young adult samples. We evaluated whether an auditory list-learning task using CVC nonword trigrams instead of words could be applied cross-culturally to evaluate similar learning and associative memory processes. PARTICIPANTS AND METHODS: Seventy-five native English-speaking (USA) and 104 native Italian-speaking (Italy) university students were administered 15-item lists of CVC trigrams using the Rey Auditory Verbal Learning Test paradigm with five study-test trials, an interference trial, and short- and long-term delayed recall. Bayesian t tests and mixed-design ANOVAs contrasted the primary learning indexes across the two samples and biological sex. RESULTS: Performance was comparable between nationalities on all primary memory indices except the interference trial (List B), where the Italian group recalled approximately one item more than the American sample. For both nationalities, recall increased across the five learning trials and declined significantly on the postinterference trial, demonstrating susceptibility to retroactive interference. No effects of sex, age, vocabulary, or depressive symptoms were observed. CONCLUSIONS: Using lists of unfamiliar nonword CVC trigrams, Italian and American younger adults showed a similar performance pattern across immediate and delayed recall trials. Whereas word list-learning performance is typically affected by cultural, demographic, mood, and cognitive factors, this trigram list-learning task does not show such effects, demonstrating its utility for cross-cultural memory assessment.

Metacognition in Community-Dwelling Older Black and African American Adults During the COVID-19 Pandemic.

BACKGROUND: Cognitive assessment of older adults typically includes symptom reports and objective evaluations. However, there is often poor agreement between these measures. Cultural norms, stress, and anxiety may also influence cognitive self-appraisal and performance. Little research describes how other factors affect the self-report/objective test discrepancies noted in the literature. OBJECTIVE: This study investigated whether the disparity between subjective cognitive concerns and objective cognitive performance is related to measures of anxiety and stress in older Black and African American adults. METHODS: Telephone screenings were administered to 206 older adults (ages 64-94) during the first year of the pandemic. Demographic data, objective memory (Telephone Interview for Cognitive Status [TICS-m]), an adaptation of the subjective memory measure, the Cognitive Change Questionnaire, emphasizing executive functioning in everyday life [CCQ-e]), Generalized Anxiety Disorder-7 (GAD-7), and Perceived Stress Scale-4 (PSS4) were measured. Metacognition Discrepancy Index (MDI) was calculated from the standardized residual after regressing TICS-m on CCQ-e scores to quantify the discrepancy between cognitive self-appraisal and objective cognitive functioning. RESULTS: Neither GAD-7 nor PSS-4 moderated the relationship between TICS-m and CCQ-e, and TICS-m scores weakly predicted subjective CCQ-e scores (F(1, 197)=4.37, p = 0.038, R2 = 0.022). The MDI correlated with stress and anxiety (rs = 0.294, 0.396, ps < 0.001). CONCLUSION: Discrepancies exist between objectively measured and self-evaluated cognition. Elevations in stress and anxiety are associated with greater overestimation of cognitive difficulties relative to objective performance. Pandemic-related stressors may have worsened anxiety and diminished self-appraisal of cognitive abilities for some individuals, while others may remain reluctant to acknowledge impairments. Social and emotional factors are meaningful considerations in assessing cognitive difficulties.

Cognitive Reserve and Cognitive Functioning among Oldest Old Adults: Findings from the Georgia Centenarian Study.

OBJECTIVES: Living a long life does not guarantee the maintenance of optimal cognitive functioning; however, similar to older adults in general, cognitive reserve may also protect oldest-old adults from cognitive decline. The purpose of this study was to assess cognitive reserve among centenarians and octogenarians and to evaluate a process model of cognitive reserve. METHODS: A total of 321 centenarians and octogenarians from the Georgia Centenarian Study were included in this study. Cognitive reserve components included level of education, occupational responsibility, current social engagement, past engaged lifestyle, and activity. Cognitive functioning was measured with the Mini-Mental Status Examination. RESULTS: Structural equation modeling was computed, and the overall model fit well, χ2 (df = 3) = 5.02, p = .17; CFI = .99, RMSEA = .05. Education is directly and indirectly related to cognitive functioning through occupational responsibility and past engaged lifestyle. Current social engagement is related to cognitive functioning directly and indirectly through current activities. The four direct predictors (i.e., education, current social engagement, current activity, and past engaged lifestyle) explained 35% of the variance in cognitive functioning. CONCLUSION: The results provide important information for cognitive reserve theories with implications for interventions that build cognitive reserve.

Neuroimaging Markers for Determining Former American Football Players at Risk for Alzheimer's Disease.

NFL players, by virtue of their exposure to traumatic brain injury (TBI), are at higher risk of developing dementia and Alzheimer's disease (AD) than the general population. Early recognition and intervention before the onset of clinical symptoms could potentially avert/delay the long-term consequences of these diseases. Given that AD is thought to have a long pre-clinical incubation period, the aim of the current research was to determine whether former NFL players show evidence of incipient dementia in their structural imaging before diagnosis of AD. To identify neuroimaging markers of AD, against which former NFL players would be compared, we conducted a whole-brain volumetric analysis using a cohort of AD patients (ADNI clinical database) to produce a set of brain regions demonstrating sensitivity to early AD pathology (i.e., the "AD fingerprint"). A group of 46 former NFL players' brain magnetic resonance images were then interrogated using the AD fingerprint, that is, the former NFL subjects were compared volumetrically to AD patients using a T1-weighted magnetization-prepared rapid gradient echo sequence. The FreeSurfer image analysis suite (version 6.0) was used to obtain volumetric and cortical thickness data. The Automated Neuropsychological Assessment Metric-Version 4 was used to assess current cognitive functioning. A total of 55 brain regions demonstrated significant atrophy or ex vacuo dilatation bilaterally in AD patients versus controls. Of the 46 former NFL players, 41% demonstrated a greater than expected number of atrophied/dilated AD regions compared with age-matched controls, presumably reflecting AD pathology.

Hypertension and cognition are minimally associated in late life.

Hypertension impacts approximately 65% of persons over 60 years of age. Although previous studies have proposed an association between mid-life hypertension and late-life cognition, reports of associations between late-life hypertension and cognition have been mixed in the direction and magnitude of the observed associations and in the cognitive domains that may be affected. This study contrasted older adults with and without self-reported hypertension at two time points in late life (MBaseline age = 64.3 years, SD1 = 0.7; MFollow-up age = 71.2 years, SD2 = 0.9), separated by approximately seven years. Participants included 4314 1957 high school graduates from the Wisconsin Longitudinal Study who were followed longitudinally until 2011. Cognitive, demographic, and health variables from the 2003-2005 and 2011 data collection waves were used. Cognitive measures included letter and category fluency, digit ordering, similarities, and immediate and delayed recall. Bayesian independent t tests and regressions examined the association between self-reported hypertension status and cognition at baseline and follow-up. Persons with self-reported hypertension over seven years showed slightly worse letter fluency and digit ordering performance at follow-up than persons without self-reported hypertension. No baseline cognitive differences were observed between groups. Participants with self-reported hypertension showed no improvement in letter fluency or digit ordering compared to persons without self-reported hypertension. After controlling for cardiovascular risk factors, hypertension was associated only with a slight decline in letter fluency. Finally, hypertension duration was not associated with cognitive performance. Self-reported hypertension was associated with minimal to no effects on cognition in older adults. Controlling for cardiovascular risk factors eliminated virtually all associations between self-reported hypertension and cognition.

Forward-focused coping predicts better mental health outcomes in mid- to late-life during the COVID-19 pandemic.

Objectives: Psychosocial stressors associated with the COVID-19 pandemic may increase the risk of depression and anxiety in the general population. Individuals approaching or within older adulthood may be especially vulnerable to these psychosocial stressors and their impact on mental health outcomes. Consequently, there is an urgent need to identify protective factors for older adults. The purpose of the present study was to determine the relative contribution of coping flexibility (CF) and two distinct coping strategies, forward-focused and trauma-focused, on negative affect in persons 50 years of age and older during the COVID-19 pandemic. Method: Data were collected using an online survey, including questions about demographic information, coping, depression, and anxiety. Participants aged 50 and over were included in our analyses of depression (N = 800) and anxiety (N = 638). Results: Both higher CF and higher forward-focused coping predicted lower depression and lower anxiety. In contrast, higher trauma-focused coping predicted slightly higher depressive symptoms but was not a significant predictor of anxiety. Conclusion: Our findings suggest that higher forward-focused coping may serve as a protective factor in older adults during the pandemic and, therefore, may be an effective treatment target for mental health interventions.

Five-Year Change in Body Mass Index Predicts Conversion to Mild Cognitive Impairment or Dementia Only in APOE ɛ4 Allele Carriers.

BACKGROUND: Body mass index (BMI) has been identified as an important modifiable lifestyle risk factor for dementia, but less is known about how BMI might interact with Apolipoprotein E ɛ4 (APOE ɛ4) carrier status to predict conversion to mild cognitive impairment (MCI) and dementia. OBJECTIVE: The aim of this study was to investigate the interaction between APOE ɛ4 status and baseline (bBMI) and five-year BMI change (ΔBMI) on conversion to MCI or dementia in initially cognitively healthy older adults. METHODS: The associations between bBMI, ΔBMI, APOE ɛ4 status, and conversion to MCI or dementia were investigated among 1,289 cognitively healthy elders from the National Alzheimer's Coordinating Center (NACC) database. RESULTS: After five years, significantly more carriers (30.6%) converted to MCI or dementia than noncarriers (17.6%), p < 0.001, OR = 2.06. Neither bBMI (OR = 0.99, 95%CI = 0.96-1.02) nor the bBMI by APOE interaction (OR = 1.02, 95%CI = 0.96-1.08) predicted conversion. Although ΔBMI also did not significantly predict conversion (OR = 0.90, 95%CI = 0.78-1.04), the interaction between ΔBMI and carrier status was significant (OR = 0.72, 95%CI = 0.53-0.98). For carriers only, each one-unit decline in BMI over five years was associated with a 27%increase in the odds of conversion (OR = 0.73, 95%CI = 0.57-0.94). CONCLUSION: A decline in BMI over five years, but not bBMI, was strongly associated with conversion to MCI or dementia only for APOE ɛ4 carriers. Interventions and behaviors aimed at maintaining body mass may be important for long term cognitive health in older adults at genetic risk for AD.

Spouse-Appraised Memory Functioning Predicts Memory Decline Better Than Subjective Memory Complaints in Community Dwelling Older Adults at Genetic Risk for Alzheimer's Disease.

Objective: Alzheimer's disease (AD) begins with subtle memory decline, years before dementia onset. The presence of subjective memory complaints (SMC) has been proposed as a marker of preclinical AD. However, recent evidence has demonstrated early and progressive loss of awareness of memory difficulties in non-demented older adults harboring AD pathology. We investigated the respective contributions of SMC and spouse-appraised memory functioning (SAM) to predict memory decline in a large cohort of community dwelling older adults. Methods: The Wisconsin Longitudinal Study collected cognitive data from a community-based cohort of 3,583 participants in both 2005 and 2011. The participant and the participant's spouse were each asked to rate the participant's memory functioning using a Likert scale. We predicted change in objective episodic memory with models including baseline SMC, baseline SAM, or both SMC and SAM. We also evaluated an awareness index (SMC minus SAM). We then tested the interaction between Apolipoprotein E (APOE ε4) carrier status and SMC/SAM to evaluate whether the effects were driven by individuals at-risk for AD pathology. Results: In separate models, SMC (-0.081 ± 0.036, p = 0.025) and SAM (-0.084 ± 0.278, p = 0.003) were both associated with memory decline over ~6 years. However, the AI was not significantly associated with memory decline (0.031 ± 0.024, p = 0.19). When both predictors were included in the same model, SAM (-0.074 ± 0.03, p = 0.0092) was associated with memory decline, while SMC was not significant (-0.061 ± 0.04, p = 0.99). The association between SAM and memory decline was stronger in the APOE ε4 carriers than in the non-carriers (APOE-by-SAM interaction: F = 6.07; p = 0.002), and follow up analyses revealed that SAM was particularly predictive of decline only for APOE ε4 carriers. The association between SMC and memory decline was independent of APOE ε4 carrier status (APOE-by-SMC interaction: F = 2.29; p = 0.13). Conclusions: Spouse-appraised memory functioning was more predictive of memory decline than SMC or an awareness index, particularly in APOE ε4 carriers, who are at increased risk for AD pathology.

Defining a Centiloid scale threshold predicting long-term progression to dementia in patients attending the memory clinic: an [18F] flutemetamol amyloid PET study.

PURPOSE: To evaluate cerebral amyloid-ß(Aß) pathology in older adults with cognitive complaints, visual assessment of PET images is approved as the routine method for image interpretation. In research studies however, Aß-PET semi-quantitative measures are associated with greater risk of progression to dementia; but until recently, these measures lacked standardization. Therefore, the Centiloid scale, providing standardized Aß-PET semi-quantitation, was recently validated. We aimed to determine the predictive values of visual assessments and Centiloids in non-demented patients, using long-term progression to dementia as our standard of truth. METHODS: One hundred sixty non-demented participants (age, 54-86) were enrolled in a monocentric [18F] flutemetamol Aß-PET study. Flutemetamol images were interpreted visually following the manufacturers recommendations. SUVr values were converted to the Centiloid scale using the GAAIN guidelines. Ninety-eight persons were followed until dementia diagnosis or were clinically stable for a median of 6 years (min = 4.0; max = 8.0). Twenty-five patients with short follow-up (median = 2.0 years; min = 0.8; max = 3.9) and 37 patients with no follow-up were excluded. We computed ROC curves predicting subsequent dementia using baseline PET data and calculated negative (NPV) and positive (PPV) predictive values. RESULTS: In the 98 participants with long follow-up, Centiloid = 26 provided the highest overall predictive value = 87% (NPV = 85%, PPV = 88%). Visual assessment corresponded to Centiloid = 40, which predicted dementia with an overall predictive value = 86% (NPV = 81%, PPV = 92%). Inclusion of the 25 patients who only had a 2-year follow-up decreased the PPV = 67% (NPV = 88%), reflecting the many positive cases that did not progress to dementia after short follow-ups. CONCLUSION: A Centiloid threshold = 26 optimally predicts progression to dementia 6 years after PET. Visual assessment provides similar predictive value, with higher specificity and lower sensitivity. TRIAL REGISTRATION: Eudra-CT number: 2011-001756-12.

The Mental Health Benefits of Physical Activity in Older Adults Survive the COVID-19 Pandemic.

OBJECTIVE: To determine the relationship between the amount and intensity of physical activity performed by older adults in North America (United States and Canada) and their depression and anxiety symptoms while currently under social distancing guidelines (SDG) for the COVID-19 pandemic. DESIGN: Descriptive cross-sectional study. SETTING: Online survey conducted between April 9 and April 30, 2020, during the COVD-19 pandemic. PARTICIPANTS: About 1,046 older adults over the age of 50 who live in North America. MEASUREMENTS: Participants were asked about their basic demographic information, current health status, and the impact of the current SDG on their subjective state of mental health. Participants completed the Physical Activity Scale for the Elderly, to determine the amount and intensity of physical activity performed, as well as both the Geriatric Depression Scale and Geriatric Anxiety Scale, to ascertain the extent of their depression and anxiety-like symptoms. RESULTS: Ninety-seven percent of participants indicated that they adhered to current SDG "Most of the time" or "Strictly." Participants who performed greater levels of physical activity experienced lower levels of depression-like symptoms when age, sex, and education were accounted for; however, no relationship between physical activity and anxiety-like symptoms was found. A hierarchical regression analysis that incorporated the intensity of physical activity performed (light, moderate, and vigorous) in the model indicated that greater light and strenuous activity, but not moderate, predicted lower depression-like symptoms. CONCLUSIONS: These results suggest that performing even light physical activity during the COVID-19 pandemic may help alleviate some of the negative mental health impacts that older adults may be experiencing while isolated and adhering to SDG during the COVID-19 pandemic.

Episodic Memory and Hippocampal Volume Predict 5-Year Mild Cognitive Impairment Conversion in Healthy Apolipoprotein ε4 Carriers.

OBJECTIVE: The Apolipoprotein (APOE) ε4 allele increases the risk for mild cognitive impairment (MCI) and dementia, but not all carriers develop MCI/dementia. The purpose of this exploratory study was to determine if early and subtle preclinical signs of cognitive dysfunction and medial temporal lobe atrophy are observed in cognitively intact ε4 carriers who subsequently develop MCI. METHODS: Twenty-nine healthy, cognitively intact ε4 carriers (ε3/ε4 heterozygotes; ages 65-85) underwent neuropsychological testing and MRI-based measurements of medial temporal volumes over a 5-year follow-up interval; data were converted to z-scores based on a non-carrier group consisting of 17 ε3/ε3 homozygotes. RESULTS: At follow-up, 11 ε4 carriers (38%) converted to a diagnosis of MCI. At study entry, the MCI converters had significantly lower scores on the Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT) Trials 1-5, and RAVLT Immediate Recall compared to non-converters. MCI converters also had smaller MRI volumes in the left subiculum than non-converters. Follow-up logistic regressions revealed that left subiculum volumes and RAVLT Trials 1-5 scores were significant predictors of MCI conversion. CONCLUSIONS: Results from this exploratory study suggest that ε4 carriers who convert to MCI exhibit subtle cognitive and volumetric differences years prior to diagnosis.

The fear of Alzheimer's disease: mediating effects of anxiety on subjective memory complaints.

Objectives: To determine if the fear of developing Alzheimer's disease (FDAD) construct, in combination with similar psychoemotional factors, could help elucidate the nature of older adults' subjective memory complaints (SMCs) and subsequent objective memory performance.Methods: One hundred ninety-three healthy older adults (aged 65-93) were administered clinician and self-report measures of depression, worry, anxiety, illness attitudes, and memory, and each rated their concern with developing AD.Results: Self-reported FDAD was not associated with objective memory performance (p > .05). FDAD, trait anxiety, general anxiety, and general and illness-related worry were independently associated with subjective memory report (ps < .05). The relationship between FDAD and subjective memory report was mediated by measures of general trait and state anxiety, but not general worry or illness-specific worry.Conclusions: FDAD was not associated with objective memory functioning, suggesting AD concerns were not reflective of memory pathology. The mediating effect of anxiety on the relationship between FDAD and subjective memory report suggests that assessment of anxiety, beyond AD fear, may help identify older adults at risk for developing negative perceptions of memory and related distress.

Cardiovascular health and cognitive functioning among centenarians: a comparison between the Tokyo and Georgia centenarian studies.

ABSTRACTObjectives:Centenarians have survived into very late life, but whether they reach very old age in good health remains unclear. The purpose of this study was to compare the cardiovascular health status and cognitive functioning of centenarians in the United States with centenarians in Japan. DESIGN, SETTING, AND PARTICIPANTS: This cross-national design compared centenarians from the United States and Japan. The sample of U.S. centenarians was recruited from the Georgia Centenarian Study and included 287 centenarians. The sample of Japanese centenarians was recruited from the Tokyo Centenarian Study and included 304 centenarians. MEASUREMENTS: Cognitive functioning was assessed with a mental status questionnaire, and cardiovascular disease by a health history assessment, blood pressure, and selected blood parameters. RESULTS: The results suggest that Tokyo centenarians had lower disease experiences and BMI values, when compared to Georgia centenarians, but blood pressure was higher among Japanese centenarians. Lower levels of hemoglobin in Japanese centenarians and higher levels of C-reactive protein in Georgia were also found. The positive association of hypertension and albumin levels with cognitive functioning and the negative association of stroke occurrence with cognitive functioning were replicated in both countries. Differential effects were obtained for heart problems, BMI, and C-reactive protein (with positive effects for Tokyo centenarians, except for C-reactive protein). CONCLUSION: For extremely old individuals, some markers of cardiovascular disease are replicable across countries, whereas differential effects for cardiovascular health also need to be considered in cardiovascular health.

Duration of Fame and Extent of Semantic Knowledge of Famous Names in Cognitively Intact Older Adults.

OBJECTIVE: The greater resilience of older memories relative to recent memories has primarily been demonstrated in clinical groups, but this phenomenon has been less extensively examined in cognitively intact older adults. Additionally, most studies of person-identity have only examined recognition or familiarity of a famous face or name, and there has been less systematic study of access to more specific person-identity semantic knowledge. The current study examined the effect of both memory age and extent of semantic knowledge on famous name recognition and retrieval of person-identity biographical information in healthy older adults. METHOD: We examined recognition accuracy and response time of famous names at three time epochs (recent fame, transitory fame and enduring fame) in cognitively intact older adults. We also compared access to semantic knowledge that differed on the degree of specificity of biographical information: categorical, associative, and attribute knowledge. RESULTS: As predicted, participants recognized transitory famous names more quickly and accurately than recent famous names. Additionally, participants recognized enduring famous names more accurately than transitory famous names and recent names. We also found that categorical semantic knowledge was accessed more quickly and accurately than semantic knowledge for associative and attribute information. CONCLUSIONS: These findings provide data on the cognitive structure and retrieval of person-identity knowledge and memory age in older cognitively intact individuals.

Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis.

A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multiday SNAr arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We have devised an orthogonal approach using a Chan-Lam coupling between a halogenated aryl pinacol boronate ester and an aryl methanesulfonamide. This reaction is performed using a cationic Cu(I) precatalyst, which can be easily generated in situ using KPF6 as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penultimate borylation chemistry using simple monodentate phosphine ligands, with PCyPh2 identified as optimal. Reaction progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as the base. We have devised a K2CO3/pivalic acid system as an alternative, which dramatically outperforms the standard conditions. This new synthesis proceeds in eight stages with a 20% overall yield.

Physical, sensory, and cognitive functioning among centenarians: a comparison between the Tokyo and Georgia centenarian studies.

PURPOSE: The purpose of this study was to compare centenarians in the United States and Japan on sensory, cognitive, and physical functioning and to evaluate a model that tests the interrelationship between physical function, cognition, and sensory impairment in these two unique samples of the oldest old. METHODS: The sample of U. S. centenarians included 245 centenarians, the sample of Japanese centenarians included 304 centenarians. Sensory impairment was assessed by general assessments of vision and hearing, and physical function was assessed with six physical activities of daily living (i.e., eating, grooming, dressing, transporting, bathing, and walking). RESULTS: The results suggest that centenarians from the Georgia study showed higher levels of functioning in all domains when compared to the Tokyo sample. A structural equation model yielded stronger associations between cognitive and sensory function with physical function for the Tokyo sample. CONCLUSIONS: Functional differences may be due, in part, to different care patterns for the oldest old in the United States when compared to Japan.

Differential 5-year brain atrophy rates in cognitively declining and stable APOE-ε4 elders.

OBJECTIVE: The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for late-onset Alzheimer's disease. Many ε4 carriers, however, never develop Alzheimer's disease. The purpose of this study is to characterize the variability in phenotypic expression of the ε4 allele, as measured by the longitudinal trajectory of cognitive test scores and MRI brain volumes, in cognitively intact elders. METHOD: Healthy older adults, ages 65-85, participated in a 5-year longitudinal study that included structural MRI and cognitive testing administered at baseline and at 1.5 and 5 years postenrollment. Participants included 22 ε4 noncarriers, 15 ε4 carriers who experienced a decline in cognition over the 5-year interval, and 11 ε4 carriers who remained cognitively stable. RESULTS: No baseline cognitive or volumetric group differences were observed. Compared to noncarriers, declining ε4 carriers had significantly greater rates of atrophy in left (p = .001, Cohen's d = .691) and right (p = .003, d = .622) cortical gray matter, left (p = .003, d = .625) and right (p = .020, d = .492) hippocampi, and greater expansion of the right inferior lateral ventricle (p < .001, d = .751) over 5 years. CONCLUSIONS: This study illustrates the variability in phenotypic expression of the ε4 allele related to neurodegeneration. Specifically, only those individuals who exhibited longitudinal declines in cognitive function experienced concomitant changes in brain volume. Future research is needed to better understand the biological and lifestyle factors that may influence the expression of the ε4 allele. (PsycINFO Database Record

The recency ratio as predictor of early MCI.

ABSTRACTObjectives:Individuals with Alzheimer's disease (AD) present poor immediate primacy recall accompanied by intact or exaggerated recency, which then tends to decline after a delay. Bruno et al. (Journal of Clinical and Experimental Neuropsychology, Vol. 38, 2016, pp. 967-973) have shown that higher ratio scores between immediate and delayed recency (i.e. the recency ratio; Rr) are associated with cognitive decline in high-functioning older individuals. We tested whether Rr predicted conversion to early mild cognitive impairment (early MCI) from a cognitively healthy baseline. DESIGN: Data were analyzed longitudinally with binomial regression. Baseline scores were used to predict conversion to early MCI after approximately nine years. SETTING: Data were collected at the Wisconsin Registry of Alzheimer's Prevention, in Madison, Wisconsin. PARTICIPANTS: For the study, 427 individuals were included in the analysis; all participants were 50 years of age or older and cognitively intact at baseline, and were native English speakers. MEASUREMENTS: Memory data were collected using the Rey's Auditory Verbal Learning Test, and the early MCI diagnosis was obtained via consensus conference. RESULTS: Our results showed that higher Rr scores are correlated with greater risk of later early MCI diagnosis, and this association is independent of total recall performance. CONCLUSIONS: Rr is an emerging cognitive marker of cognitive decline.