Kidney Disease, Intensive Hypertension Treatment, and Risk for Dementia and Mild Cognitive Impairment: The Systolic Blood Pressure Intervention Trial.

BACKGROUND: Intensively treating hypertension may benefit cardiovascular disease and cognitive function, but at the short-term expense of reduced kidney function. METHODS: We investigated markers of kidney function and the effect of intensive hypertension treatment on incidence of dementia and mild cognitive impairment (MCI) in 9361 participants in the randomized Systolic Blood Pressure Intervention Trial, which compared intensive versus standard systolic BP lowering (targeting <120 mm Hg versus <140 mm Hg, respectively). We categorized participants according to baseline and longitudinal changes in eGFR and urinary albumin-to-creatinine ratio. Primary outcomes were occurrence of adjudicated probable dementia and MCI. RESULTS: Among 8563 participants who completed at least one cognitive assessment during follow-up (median 5.1 years), probable dementia occurred in 325 (3.8%) and MCI in 640 (7.6%) participants. In multivariable adjusted analyses, there was no significant association between baseline eGFR <60 ml/min per 1.73 m2 and risk for dementia or MCI. In time-varying analyses, eGFR decline ≥30% was associated with a higher risk for probable dementia. Incident eGFR <60 ml/min per 1.73 m2 was associated with a higher risk for MCI and a composite of dementia or MCI. Although these kidney events occurred more frequently in the intensive treatment group, there was no evidence that they modified or attenuated the effect of intensive treatment on dementia and MCI incidence. Baseline and incident urinary ACR ≥30 mg/g were not associated with probable dementia or MCI, nor did the urinary ACR modify the effect of intensive treatment on cognitive outcomes. CONCLUSIONS: Among hypertensive adults, declining kidney function measured by eGFR is associated with increased risk for probable dementia and MCI, independent of the intensity of hypertension treatment.

Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial.

Importance: There are currently no proven treatments to reduce the risk of mild cognitive impairment and dementia. Objective: To evaluate the effect of intensive blood pressure control on risk of dementia. Design, Setting, and Participants: Randomized clinical trial conducted at 102 sites in the United States and Puerto Rico among adults aged 50 years or older with hypertension but without diabetes or history of stroke. Randomization began on November 8, 2010. The trial was stopped early for benefit on its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. The final date for follow-up of cognitive outcomes was July 22, 2018. Interventions: Participants were randomized to a systolic blood pressure goal of either less than 120 mm Hg (intensive treatment group; n = 4678) or less than 140 mm Hg (standard treatment group; n = 4683). Main Outcomes and Measures: The primary cognitive outcome was occurrence of adjudicated probable dementia. Secondary cognitive outcomes included adjudicated mild cognitive impairment and a composite outcome of mild cognitive impairment or probable dementia. Results: Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 8563 (91.5%) completed at least 1 follow-up cognitive assessment. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1000 person-years; hazard ratio [HR], 0.83; 95% CI, 0.67-1.04). Intensive BP control significantly reduced the risk of mild cognitive impairment (14.6 vs 18.3 cases per 1000 person-years; HR, 0.81; 95% CI, 0.69-0.95) and the combined rate of mild cognitive impairment or probable dementia (20.2 vs 24.1 cases per 1000 person-years; HR, 0.85; 95% CI, 0.74-0.97). Conclusions and Relevance: Among ambulatory adults with hypertension, treating to a systolic blood pressure goal of less than 120 mm Hg compared with a goal of less than 140 mm Hg did not result in a significant reduction in the risk of probable dementia. Because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this end point. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Association of Intensive vs Standard Blood Pressure Control With Cerebral White Matter Lesions.

Importance: The effect of intensive blood pressure lowering on brain health remains uncertain. Objective: To evaluate the association of intensive blood pressure treatment with cerebral white matter lesion and brain volumes. Design, Setting, and Participants: A substudy of a multicenter randomized clinical trial of hypertensive adults 50 years or older without a history of diabetes or stroke at 27 sites in the United States. Randomization began on November 8, 2010. The overall trial was stopped early because of benefit for its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. Brain magnetic resonance imaging (MRI) was performed on a subset of participants at baseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up date was July 1, 2016. Interventions: Participants were randomized to a systolic blood pressure (SBP) goal of either less than 120 mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standard treatment, n = 315). Main Outcomes and Measures: The primary outcome was change in total white matter lesion volume from baseline. Change in total brain volume was a secondary outcome. Results: Among 670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years; 40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 years after randomization, after a median intervention period of 3.40 years. In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm3 (difference, 0.92 cm3 [95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3 [95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, -0.54 cm3 [95% CI, -0.87 to -0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm3 (difference, -30.6 cm3 [95% CI, -32.3 to -28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3 (difference, -26.9 cm3 [95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, -3.7 cm3 [95% CI, -6.3 to -1.1]). Conclusions and Relevance: Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Cognitive Function and Kidney Disease: Baseline Data From the Systolic Blood Pressure Intervention Trial (SPRINT).

BACKGROUND: Chronic kidney disease is common and is associated with cardiovascular disease, cerebrovascular disease, and cognitive function, although the nature of this relationship remains uncertain. STUDY DESIGN: Cross-sectional cohort using baseline data from the Systolic Blood Pressure Intervention Trial (SPRINT). SETTING & PARTICIPANTS: Participants in SPRINT, a randomized clinical trial of blood pressure targets in older community-dwelling adults with cardiovascular disease, chronic kidney disease, or high cardiovascular disease risk and without diabetes or known stroke, who underwent detailed neurocognitive testing in the cognition substudy, SPRINT-Memory and Cognition in Decreased Hypertension (SPRINT-MIND). PREDICTORS: Urine albumin-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). OUTCOMES: Cognitive function, a priori defined as 5 cognitive domains based on 11 cognitive tests using z scores, and abnormal white matter volume quantified by brain magnetic resonance imaging. RESULTS: Of 9,361 SPRINT participants, 2,800 participated in SPRINT-MIND and 2,707 had complete data; 637 had brain imaging. Mean age was 68 years, 37% were women, 30% were black, and 20% had known cardiovascular disease. Mean eGFR was 70.8±20.9mL/min/1.73m2 and median urine ACR was 9.7 (IQR, 5.7-22.5) mg/g. In adjusted analyses, higher ACR was associated with worse global cognitive function, executive function, memory, and attention, such that each doubling of urine ACR had the same association with cognitive performance as being 7, 10, 6, and 14 months older, respectively. Lower eGFR was independently associated with worse global cognitive function and memory. In adjusted models, higher ACR, but not eGFR, was associated with larger abnormal white matter volume. LIMITATIONS: Cross-sectional only, no patients with diabetes were included. CONCLUSIONS: In older adults, higher urine ACR and lower eGFR have independent associations with global cognitive performance with different affected domains. Albuminuria concurrently identifies a higher burden of abnormal brain white matter disease, suggesting that vascular disease may mediate these relationships.

Neuropsychological Practice Effects in the Context of Cognitive Decline: Contributions from Learning and Task Novelty.

Although cognitive decline is typically associated with decreasing practice effects (PEs) (presumably due to declining memory), some studies show increased PEs with declines in cognition. One explanation for these inconsistencies is that PEs reflect not only memory, but also rebounds from adapting to task novelty (i.e., novelty effect), leading to increased PEs. We examined a theoretical model of relationships among novelty effects, memory, cognitive decline, and within-session PEs. Sixty-six older adults ranging from normal to severely impaired completed measures of memory, novelty effects, and two trials each of Wechsler Adult Intelligence Scale, 4 th Edition Symbol Search and Coding. Interrelationships among variables were examined using regression analyses. PEs for Symbol Search and Coding (a) were related to different proposed PE components (i.e., memory and novelty effects), such that novelty effect predicted Symbol Search PE (R2 =.239, p<.001) and memory predicted Coding PE (R2 =.089, p=.015), and (b) showed different patterns across stages of cognitive decline, such that the greatest cognitive decline was associated with smallest Coding PE (R2 =.125, p=.004), whereas intermediate cognitive decline was associated with the greatest Symbol Search PE (R2 =.097, p=.040). The relationship between cognitive decline and PE for Symbol Search was partially mediated by novelty effect among older adults with abnormal cognitive decline (model R2 =.286, p<.001). These findings (a) suggest that PE is not a unitary construct, (b) offer an explanation for contradictory findings in the literature, and (c) highlight the need for a better understanding of component processes of PE across different neuropsychological measures.

Sociolinguistic reflection on neuropsychological assessment: an insight into selected culturally adapted battery of Lebanese Arabic cognitive testing.

Neuropsychological tests (NPTs) are highly dependent on education, culture differences as well as age and sex. It is therefore essential to take these factors into consideration when translating NPTs to be used in screening for cognitive impairment. Translations into Arabic must respect the principles of linguistic relativity and cultural specificity of the population under study. The objective is to assess feasibility and outcome of translating neuropsychological tests to Arabic. A team of Lebanese professionals selected a battery of screening NPTs. These tests were translated into Arabic and independently back translated by a team of sociolinguists and cultural specialists. The translations were adapted to suit the Lebanese culture. The final NPT translated versions were reached by consensus of an expert panel and tested on a group of independently living community-dwelling elderly. Translated items had to be modified when: (1) terms could not be translated using one word as required by the test; (2) Concepts were foreign to the culture; (3) Translated words carried multiple meanings; (4) Words were rarely used in Lebanon; (5) Sentences did not have an equivalent; and (6) Words had letters pronounced differently by subgroups in Lebanon. Despite all measures to maintain cultural sensitivity in translations, non-linguistic challenges remained. A battery of cognitive screening tests were translated into Arabic and adapted for the Lebanese population. These adaptations allow for a better assessment of cognitive abilities since they reflect the thought patterns of the population. The challenge is to establish local normative data.

A prospective randomized wait list control trial of intravenous iron sucrose in older adults with unexplained anemia and serum ferritin 20-200 ng/mL.

Anemia is common in older persons and is associated with substantial morbidity and mortality. One third of anemic older adults have unexplained anemia of the elderly (UAE). We carried out a randomized, wait list control trial in outpatients with UAE and serum ferritin levels between 20 and 200 ng/mL. Intravenous iron sucrose was given as a 200-mg weekly dose for 5 weeks either immediately after enrollment (immediate intervention group) or following a 12-week wait list period (wait list control group). The primary outcome measure was changed in 6-minute walk test (6MWT) distances from baseline to 12 weeks between the two groups. Hematologic, physical, cognitive, and quality of life parameters were also assessed. The study was terminated early after 19 subjects enrolled. The distance walked in the 6MWT increased a mean 8.05±55.48 m in the immediate intervention group and decreased a mean 11.45±49.46 m in the wait list control group (p=0.443). The hemoglobin increased a mean 0.39±0.46 g/dL in the immediate intervention group and declined a mean 0.39±0.85 g/dL in the wait list control group (p=0.026). Thus, a subgroup of adults with UAE may respond to intravenous iron. Enrollment of subjects into this type of study remains challenging.

Functional architecture of the cortico-basal ganglia circuitry during motor task execution: correlations of strength of functional connectivity with neuropsychological task performance among female subjects.

The primary aim of this study was to enhance our understanding of the functional architecture of the cortico-basal ganglia circuitry during motor task execution. Twenty right-handed female subjects without any history of neuropsychiatric illness underwent fMRI at 3 T. The activation paradigm was a complex motor task completed with the nondominant hand. Analyses of functional connectivity strength were conducted for pairs of structures in input, intrinsic, and output segments of the circuitry. Next, connectivity strengths were correlated with results of neurocognitive testing conducted outside of the scanner, which provided information about both motor and cognitive processes. For input pathways, results indicate that SMA-striatum interactions are particularly relevant for motor behavior and disruptions may impact both motor and cognitive functions. For intrinsic pathways, results indicate that thalamus (VA nucleus) to striatum feedback pathway appears to have an important role during task execution and carries information relevant for motor planning. Together, these findings add to accumulating evidence that the GPe may play a role in higher order basal ganglia processing. A potentially controversial finding was that strong functional connectivity appears to occur across intrinsic inhibitory pathways. Finally, output (thalamus to cortex) feedback was only correlated with motor planning. This result suggests circuit processes may be more relevant for future behaviors than the execution of the current task.

Neuropsychological outcome after deep brain stimulation in the ventral capsule/ventral striatum for highly refractory obsessive-compulsive disorder or major depression.

BACKGROUND: Deep brain stimulation (DBS) has shown promise as a treatment for severe, highly treatment-refractory obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). We describe the neuropsychological outcome in 21 patients (10 OCD and 11 MDD) who received DBS in the anterior limb of the internal capsule/ventral striatum (VC/VS). METHODS: All patients completed a preoperative and postoperative neuropsychological battery. Average duration of DBS stimulation was 8.91 months (SD = 4.63) at the time of follow-up testing. Data were analyzed using practice-effect-corrected change scores. RESULTS: No significant cognitive declines were seen. There were significant improvements in prose passage recall after chronic DBS. The cognitive improvements were not related to change in severity of OCD, depression or global impairment. CONCLUSIONS: This preliminary study suggests that VC/VS DBS does not result in cognitive declines. The observations that verbal memory improved are consistent with current theories on the role of the VS in the memory, but require replication in larger studies.

Within-session practice effects in patients referred for suspected dementia.

BACKGROUND: Practice effects are improvements in cognitive test performance associated with repeated administrations of same or similar measures and are traditionally seen as error variance. However, there is growing evidence that practice effects provide clinically useful information. METHODS: Within-session practice effects (WISPE) across 2 h were collected from 61 non-consecutive patients referred for suspected dementia and compared to the Mini Mental Status Examination (MMSE), a screening measure of dementia severity. RESULTS: In all patients, WISPE on two cognitive measures were significantly correlated with MMSE, even after controlling for baseline cognitive scores (partial r = 0.47, p < 0.001; partial r = 0.26, p = 0.046). In patients diagnosed with probable Alzheimer's disease, the trend was even stronger (partial r = 0.72, p < 0.01; partial r = 0.58, p = 0.046). In both groups, lower WISPE were associated with lower MMSE scores (i.e. greater dementia severity), even after controlling for initial cognitive scores. CONCLUSION: If future research validates these findings with longitudinal studies, then WISPE may have important clinical applications in dementia evaluations.

Robust demographically-adjusted normative data for the Montreal Cognitive Assessment (MoCA): Results from the systolic blood pressure intervention trial.

To generate robust, demographically-adjusted regression-based norms for the Montreal Cognitive Assessment (MoCA) using a large sample of diverse older US adults.Baseline MoCA scores were examined for participants in the Systolic Blood Pressure Intervention Trial (SPRINT). A robust, cognitively-normal sample was drawn from individuals not subsequently adjudicated with cognitive impairment through 4 years of follow-up. Multivariable Beta-Binomial regression was used to model the association of demographic variables with MoCA performance and to create demographically-stratified normative tables.Participants' (N = 5,338) mean age was 66.9 ± 8.8 years, with 35.7% female, 63.1% White, 27.4% Black, 9.5% Hispanic, and 44.5% with a college or graduate education. A large proportion scored below published MoCA cutoffs: 61.4% scored below 26 and 29.2% scored below 23. A disproportionate number falling below these cutoffs were Black, Hispanic, did not graduate from college, or were ≥75 years of age. Multivariable modeling identified education, race/ethnicity, age, and sex as significant predictors of MoCA scores (p<.001), with the best fitting model explaining 24.4% of the variance. Model-based predictions of median MoCA scores were generally 1 to 2 points lower for Black and Hispanic participants across combinations of age, sex, and education. Demographically-stratified norm-tables based on regression modeling are provided to facilitate clinical use, along with our raw data.By using regression-based strategies that more fully account for demographic variables, we provide robust, demographically-adjusted metrics to improve cognitive screening with the MoCA in diverse older adults.

Effect of intensive blood pressure control on subtypes of mild cognitive impairment and risk of progression from SPRINT study.

BACKGROUND: To examine the effect of intensive blood pressure control on the occurrence of subtypes of mild cognitive impairment (MCI) and determine the risk of progression to dementia or death. METHODS: Secondary analysis of a randomized trial of community-dwelling adults (≥50 years) with hypertension. Participants were randomized to a systolic blood pressure (SBP) goal of <120 mm Hg (intensive treatment; n = 4678) or <140 mm Hg (Standard treatment; n = 4683). Outcomes included adjudicated MCI, MCI subtype (amnestic, non-amnestic, multi-domain, single domain), and probable dementia. Multistate survival models were used to examine transitions in cognitive status accounting for the competing risk of death. RESULTS: Among 9361 randomized participants (mean age, 67.9 years; 3332 women [35.6%]), 640 participants met the protocol definition for MCI, with intensive treatment reducing the risk of MCI overall (hazard ratio [HR], 0.81 [95% confidence interval {CI}, 0.69-0.94]), as previously reported. This effect was largely reflected in amnestic subtypes (HR, 0.78 [95% CI, 0.66-0.92]) and multi-domain subtypes (HR, 0.78 [95% CI, 0.65-0.93]). An adjudication of MCI, as compared with normal cognitive function, substantially increased the probability of progressing to probable dementia (5.9% [95% CI: 4.5%-7.7%] vs. 0.6% [95% CI: 0.3%-0.9%]) and to death (10.0% [95% CI: 8.3%-11.9%] vs. 2.3% [95% CI: 2.0%-2.7%]) within 2 years. CONCLUSIONS: Intensive treatment reduced the risk for amnestic and multi-domain subtypes of MCI. An adjudication of MCI was associated with increased risk of progression to dementia and death, highlighting the relevance of MCI as a primary outcome in clinical and research settings.

Age-related changes of the functional architecture of the cortico-basal ganglia circuitry during motor task execution.

Normal human aging is associated with declining motor control and function. It is thought that dysfunction of the cortico-basal ganglia circuitry may contribute to age-related sensorimotor impairment, however the underlying mechanisms are poorly characterized. The aim of this study was to enhance our understanding of age-related changes in the functional architecture of these circuits. Fifty-nine subjects, consisting of a young, middle and old group, were studied using functional MRI and a motor activation paradigm. Functional connectivity analyses and examination of correlations of connectivity strength with performance on the activation task as well as neurocognitive tasks completed outside of magnet were conducted. Results indicated that increasing age is associated with changes in the functional architecture of the cortico-basal ganglia circuitry. Connectivity strength increased between subcortical nuclei and cortical motor and sensory regions but no changes were found between subcortical components of the circuitry. Further, increased connectivity was correlated with poorer performance on a neurocognitive task independently of age. This result suggests that increased connectivity reflects a decline in brain function rather than a compensatory process. These findings advance our understanding of the normal aging process. Further, the methods employed will likely be useful for future studies aimed at disambiguating age-related versus illness progression changes associated with neuropsychiatric disorders that involve the cortico-basal ganglia circuitry.

Practice effects predict cognitive outcome in amnestic mild cognitive impairment.

OBJECTIVE: Practice effects on cognitive tests have been shown to further characterize patients with amnestic mild cognitive impairment (aMCI) and may provide predictive information about cognitive change across time. We tested the hypothesis that a loss of practice effects would portend a worse prognosis in aMCI. DESIGN: Longitudinal, observational design following participants across 1 year. SETTING: Community-based cohort. PARTICIPANTS: Three groups of older adults: 1) cognitively intact (n = 57), 2) aMCI with large practice effects across 1 week (MCI + PE, n = 25), and 3) aMCI with minimal practice effects across 1 week (MCI - PE, n = 26). MEASUREMENTS: Neuropsychological tests. RESULTS: After controlling for age and baseline cognitive differences, the MCI - PE group performed significantly worse than the other groups after 1 year on measures of immediate memory, delayed memory, language, and overall cognition. CONCLUSIONS: Although these results need to be replicated in larger samples, the loss of short-term practice effects portends a worse prognosis in patients with aMCI.

Cognitive decline in the elderly: an analysis of population heterogeneity.

BACKGROUND: studies of cognitive ageing at the group level suggest that age is associated with cognitive decline; however, there may be individual differences such that not all older adults will experience cognitive decline. OBJECTIVE: to evaluate patterns of cognitive decline in a cohort of older adults initially free of dementia. DESIGN, SETTING AND SUBJECTS: elderly Catholic clergy members participating in the Religious Orders Study were followed for up to 15 years. Cognitive performance was assessed annually. METHODS: performance on a composite global measure of cognition was analysed using random effects models for baseline performance and change over time. A profile mixture component was used to identify subgroups with different cognitive trajectories over the study period. RESULTS: from a sample of 1,049 participants (mean age 75 years), three subgroups were identified based on the distribution of baseline performance and change over time. The majority (65%) of participants belonged to a slow decline class that did not experience substantial cognitive decline over the observation period [-0.04 baseline total sample standard deviation (SD) units/year]. About 27% experienced moderate decline (-0.19 SD/year), and 8% belonged to a class experiencing rapid decline (-0.57 SD/year). A subsample analysis revealed that when substantial cognitive decline does occur, the magnitude and rate of decline is correlated with neuropathological processes. CONCLUSIONS: in this sample, the most common pattern of cognitive decline is extremely slow, perceptible on a time scale measured by decades, not years. While in need of cross validation, these findings suggest that cognitive changes associated with ageing may be minimal and emphasise the importance of understanding the full range of age-related pathologies that may diminish brain function.

Differential patterns of cognitive decline in anterior and posterior white matter hyperintensity progression.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) found on brain MRI in elderly individuals are largely thought to be due to microvascular disease, and its progression has been associated with cognitive decline. The present study sought to determine patterns of cognitive decline associated with anterior and posterior WMH progression. METHODS: Subjects included 110 normal controls, aged >or=60 years, who were participants in the Duke Neurocognitive Outcomes of Depression in the Elderly study. All subjects had comprehensive cognitive evaluations and MRI scans at baseline and after 2 years. Cognitive composites were created in 5 domains: complex processing speed, working memory, general memory, visual-constructional skills, and language. Change in cognition was calculated using standard regression-based models accounting for variables known to impact serial testing. A semiautomated segmentation method was used to measure WMH extent in anterior and posterior brain regions. Hierarchical multiple linear regression models were used to evaluate which of the 5 measured cognitive domains was most strongly associated with regional (anterior and posterior) and total WMH progression after adjusting for demographics (age, sex, and education). RESULTS: Decline in complex processing speed was independently associated with both anterior (r(2)=0.06, P=0.02) and total WMH progression (r(2)=0.05, P=0.04). In contrast, decline in visual-constructional skills was uniquely associated with posterior progression (r(2)=0.05, P<0.05). CONCLUSIONS: Distinct cognitive profiles are associated with anterior and posterior WMH progression among normal elders. These differing profiles need to be considered when evaluating the cognitive correlates of WMHs.

Reliable change indices for the 37-item version of the MMSE in Spanish older adults.

OBJECTIVE: The aim of this study was to establish reliable change and regression-based change score norms on the 37-item version of MMSE in older Spanish adults at the three-year follow-up. METHOD: All subjects of this research were selected from the Neurological Disorders in Central Spain (NEDICES), a prospective population-based cohort study of older adults (65 years and over). Of the 4208 individuals free from neurological disorders in this cohort, 2073 participants completed the MMSE-37 at baseline and at the three-year follow-up. Reliable Change Indices were computed for the 80, 90% and 95 confidence intervals (CIs). Multiple regression analyses were used to derive equations for predicting MMSE-37 post-test scores taking into account baseline scores, time to follow-up and sociodemographic factors. RESULTS: The MMSE-37 obtained a marginal test-retest reliability (.70). The results showed significant effects of education, age, and sex on the MMSE-37 change scores. After correcting for regression to the mean, at least a 6-point change on MMSE-37 (three-years follow-up) is required to be classified as reliable (90% CI). CONCLUSIONS: These findings demonstrate that the MMSE-37 is a reliable test-retest measure whose change scores are significantly influenced by sociodemographic factors. Importantly, small changes on this measure require a cautious interpretation.

Consensus Parameter: Research Methodologies to Evaluate Neurodevelopmental Effects of Pubertal Suppression in Transgender Youth.

Purpose: Pubertal suppression is standard of care for early pubertal transgender youth to prevent the development of undesired and distressing secondary sex characteristics incongruent with gender identity. Preliminary evidence suggests pubertal suppression improves mental health functioning. Given the widespread changes in brain and cognition that occur during puberty, a critical question is whether this treatment impacts neurodevelopment. Methods: A Delphi consensus procedure engaged 24 international experts in neurodevelopment, gender development, puberty/adolescence, neuroendocrinology, and statistics/psychometrics to identify priority research methodologies to address the empirical question: is pubertal suppression treatment associated with real-world neurocognitive sequelae? Recommended study approaches reaching 80% consensus were included in the consensus parameter. Results: The Delphi procedure identified 160 initial expert recommendations, 44 of which ultimately achieved consensus. Consensus study design elements include the following: a minimum of three measurement time points, pubertal staging at baseline, statistical modeling of sex in analyses, use of analytic approaches that account for heterogeneity, and use of multiple comparison groups to minimize the limitations of any one group. Consensus study comparison groups include untreated transgender youth matched on pubertal stage, cisgender (i.e., gender congruent) youth matched on pubertal stage, and an independent sample from a large-scale youth development database. The consensus domains for assessment includes: mental health, executive function/cognitive control, and social awareness/functioning. Conclusion: An international interdisciplinary team of experts achieved consensus around primary methods and domains for assessing neurodevelopmental effects (i.e., benefits and/or difficulties) of pubertal suppression treatment in transgender youth.

Effects of intensive versus standard blood pressure control on domain-specific cognitive function: a substudy of the SPRINT randomised controlled trial.

BACKGROUND: Results from the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive control of systolic blood pressure significantly reduced the occurrence of mild cognitive impairment, but not probable dementia. We investigated the effects of intensive lowering of systolic blood pressure on specific cognitive functions in a preplanned substudy of participants from SPRINT. METHODS: SPRINT was an open-label, multicentre, randomised controlled trial undertaken at 102 sites, including academic medical centres, Veterans Affairs medical centres, hospitals, and independent clinics, in the USA and Puerto Rico. Participants were adults aged 50 years or older with systolic blood pressure higher than 130 mm Hg, but without diabetes, history of stroke, or dementia. Participants were randomly assigned (1:1) to a systolic blood pressure goal of less than 120 mm Hg (intensive treatment) versus less than 140 mm Hg (standard treatment). All major classes of antihypertensive agents were included. A subgroup of randomly assigned participants including, but not limited to, participants enrolled in an MRI substudy was then selected for a concurrent substudy of cognitive function (target 2800 participants). Each individual was assessed with a screening cognitive test battery and an extended cognitive test battery at baseline and biennially during the planned 4-year follow-up. The primary outcomes for this substudy were standardised composite scores for memory (Logical Memory I and II, Modified Rey-Osterrieth Complex Figure [immediate recall], and Hopkins Verbal Learning Test-Revised [delayed recall]) and processing speed (Trail Making Test and Digit Symbol Coding). SPRINT was registered with ClinicalTrials.gov, NCT01206062. FINDINGS: From Nov 23, 2010, to Dec 28, 2012, 2921 participants (mean age 68·4 years [SD 8·6], 1080 [37%] women) who had been randomly assigned in SPRINT were enrolled in the substudy (1448 received intensive treatment and 1473 received standard treatment). SPRINT was terminated early due to benefit observed in the primary outcome (composite of cardiovascular events). After a median follow-up of 4·1 years (IQR 3·7-5·8), there was no between-group difference in memory, with an annual decline in mean standardised domain score of -0·005 (95% CI -0·010 to 0·001) in the intensive treatment group and -0·001 (-0·006 to 0·005) in the standard treatment group (between-group difference -0·004, 95% CI -0·012 to 0·004; p=0·33). Mean standardised processing speed domain scores declined more in the intensive treatment group (between-group difference -0·010, 95% CI -0·017 to -0·002; p=0·02), with an annual decline of -0·025 (-0·030 to -0·019) for the intensive treatment group and -0·015 (-0·021 to 0·009) for the standard treatment group. INTERPRETATION: Intensive treatment to lower systolic blood pressure did not result in a clinically relevant difference compared with standard treatment in memory or processing speed in a subgroup of participants from SPRINT. The effect of blood pressure lowering might not be evident in specific domains of cognitive function, but instead distributed across multiple domains. FUNDING: National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Alzheimer's Association.

The Association between the Montreal Cognitive Assessment and Functional Activity Questionnaire in the Systolic Blood Pressure Intervention Trial (SPRINT).

OBJECTIVE: To examine the association of global cognitive function assessed via the Montreal Cognitive Assessment (MoCA) and deficiencies in instrumental activities of daily living (IADL) on the Functional Activity Questionnaire (FAQ) in hypertensive older adults in the Systolic Blood Pressure Intervention Trial (SPRINT). METHODS: In cross-sectional analysis, 9,296 SPRINT participants completed the MoCA at baseline. The FAQ was obtained from 2,705 informants for SPRINT participants scoring <21 or <22 on the MoCA, depending on education. FAQ severity ranged from no dysfunction (Score = 0) to moderate/severe dysfunction (Score = 5+). RESULTS: Participants who triggered FAQ administration were older, less educated, and more likely to be Black or Hispanic (p < 0.001). Sixty-one percent (n = 1,661) of participants' informants reported no functional difficulties in IADLs. An informant report, however, of any difficulty on the FAQ was associated with lower MoCA scores after controlling for age, sex, race/ethnicity, and education (p < 0.05). Partial proportional odds regression indicates that participants scoring lower on the MoCA (in the 10th to <25th, fifth to <10th, and