Changes in Cognitive Function After Kidney Transplantation: A Longitudinal Cohort Study.

RATIONALE & OBJECTIVE: Kidney disease negatively affects cognition. We assessed the effect of kidney transplantation (KT) on different cognitive domains. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We examined pre- versus post-KT cognition in patients waitlisted for KT at an academic center. PREDICTORS: Transplant status. We measured cognitive function before KT (n=101), 3 months after KT (n=78), and 1 year after KT (n = 83). OUTCOMES: Our primary outcome was change in cognitive function before versus after KT. We used standard neuropsychological tests to assess global cognition (Mini-Mental State Exam [MMSE]), episodic/declarative memory (Logical Memory), psychomotor speed/visuospatial function (Digit Symbol Substitution Test [DSST], Trail Making Test [TMT] A), working memory/attention (Digit Span), executive function (TMT B), and semantic memory/verbal fluency/language (Category Fluency). ANALYTICAL APPROACH: Using linear mixed model analysis, we evaluated the changes in neuropsychological test scores adjusted for age, sex, race, education, and number of assessments. RESULTS: Before KT, Logical Memory I and II, DSST, MMSE, Category Fluency (animal naming), and Digit Span backward scores were low compared with normative values from the National Alzheimer's Coordinating Center data. Logical Memory I and II scores improved after KT (pre- vs post-KT, estimated group difference [d]=3.3, P<0.001 for Logical Memory I; d=4.27, P<0.001 for Logical Memory II), such that post-KT scores were similar to normative values (post-KT vs normative values, d = -0.37, P=0.06 for Logical Memory I; d = -0.89, P=0.08 for Logical Memory II). Category Fluency (animal naming; d=2.4, P<0.001) and DSST (d=3.12, P=0.01) scores also improved with KT, but post-KT DSST scores remained lower than normative values (post-KT vs normative values, d = -5.17, P<0.001). MMSE, Digit Span, and TMT A and B scores did not change after KT. LIMITATIONS: Single-center study. CONCLUSIONS: Episodic and verbal declarative memory normalize after KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function show partial improvement. Cognitive impairment in kidney disease is therefore at least partly reversible with KT. PLAIN-LANGUAGE SUMMARY: Cognitive impairment in kidney disease affects self-esteem, vocational abilities, quality of life, health care costs, and mortality. It is not clear whether kidney transplantation (KT) improves cognition and whether the improvement is uniform across cognitive domains. The distinction between reversible and irreversible cognitive impairment has important implications in the clinical care of patients before and after KT. We assessed cognition before KT and 3 months and 12 months after KT and discovered that episodic and verbal declarative memory normalized with KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function also improved with KT but did not reach normal levels. Cognitive impairment in kidney disease is therefore at least partly reversible.

Implementing a home-based virtual hypertension programme-a pilot feasibility study.

INTRODUCTION: Implementing a health system-based hypertension programme may lower blood pressure (BP). METHODS: We performed a randomized, controlled pilot study to assess feasibility, acceptability, and safety of a home-based virtual hypertension programme integrating evidence-based strategies to overcome current barriers to BP control. Trained clinical pharmacists staffed the virtual collaborative care clinic (vCCC) to remotely manage hypertension using a BP dashboard and phone "visits" to monitor BP, adherence, side effects of medications, and prescribe anti-hypertensives. Patients with uncontrolled hypertension were identified via electronic health records. Enrolled patients were randomized to either vCCC or usual care for 3 months. We assessed patients' home BP monitoring behaviour, and patients', physicians', and pharmacists' perspectives on feasibility and acceptability of individual programme components. RESULTS: Thirty-one patients (vCCC = 17, usual care = 14) from six physician clinics completed the pilot study. After 3 months, average BP decreased in the vCCC arm (P = 0.01), but not in the control arm (P = 0.45). The vCCC participants measured BP more (9.9 vs. 1.2 per week, P < 0.001). There were no intervention-related adverse events. Participating physicians (n = 6), pharmacists (n = 5), and patients (n = 31) rated all programme components with average scores of >4.0, a pre-specified benchmark. Nine adaptations in vCCC design and delivery were made based on potential barriers to implementing the programme and suggestions. CONCLUSION: A home-based virtual hypertension programme using team-based care, technology, and a logical integration of evidence-based strategies is safe, acceptable, and feasible to intended users. These pilot data support studies to assess the effectiveness of this programme at a larger scale.

Driving Automation for Older Adults with Preclinical Alzheimer's Disease.

INTRODUCTION: Older adults with preclinical Alzheimer's disease (AD) show changes in on-road driving performance. The impact of preclinical AD on using automated vehicle (AV) technology is unknown. The aim was to evaluate safety and cognitive workload while operating AV technology in drivers with preclinical AD. INTRODUCTION: This cross-sectional study included 40 participants: 19 older adults (age 74.16 ± 4.78; MOCA scores 26.42 ± 2.52) with preclinical AD, evidenced by elevated cortical beta-amyloid; and 21 controls (age 73.81 ± 5.62; MOCA scores 28.24 ± 1.67). All participants completed two scenarios in a driving simulator. Scenario 1 included conditional automation with an emergency event that required a manual take-over maneuver. Scenario 2 was identical but with a cognitive distractor task. Emergency response time was the main safety outcome measure. Cognitive workload was calculated using moment-to-moment changes in pupillary size and converted into an Index of Cognitive Activity (ICA). Mann-Whitney U and independent t tests were used to compare group differences. RESULTS: Emergency response times were similar between drivers with preclinical AD and controls in scenario 1 (20.85 s ± 1.08 vs. 20.52 s ± 3.18; p = 0.83) and scenario 2 (14.83 s ± 7.37 vs. 13.45 s ± 10.43; p = 0.92). Likewise, no differences were found in ICA between drivers with preclinical AD and controls in scenario 1 (0.34 ± 0.08 vs. 0.33 ± 0.17; p = 0.74) or scenario 2 (0.30 ± 0.07 vs. 0.29 ± 0.17; p = 0.93). CONCLUSIONS: Older drivers with preclinical AD may safely operate AV technology, without increased response times or cognitive workload. Future on-road studies with AV technology should confirm these preliminary results in drivers with preclinical AD.

Association between the Estimated Glomerular Filtration Rate and Brain Atrophy in Older Adults.

End-stage kidney disease has been associated with cognitive impairment and brain atrophy. It remains unclear if mild to moderate kidney dysfunction is associated with brain atrophy, especially in older adults. We used cross-sectional data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), an NIH-funded multicenter longitudinal cohort study, to better understand the association between estimated glomerular filtration rate (eGFR) and brain volumes. We included all ADNI participants with both baseline serum creatinine values and MRI brain volume assessments. We used multiple linear regression modeling to assess cross-sectional associations between eGFR and whole-brain gray matter, hippocampus, entorhinal, fusiform, and middle temporal brain volumes. Participants (n = 1,596) were 74 ± 7 years old with a mean eGFR of 69.4 ± 14.8 mL/min/1.73 m2; 53% had mild cognitive impairment, and 19% had dementia. Unadjusted analysis showed an association between lower eGFR and smaller brain volumes. After adjusting for age, sex, and education, there was no association between eGFR brain volumes (p > 0.05 for all). These results remained consistent after subgroup analysis by age stratification and baseline cognitive status. Age was a confounding variable in the unadjusted association between the eGFR and brain volumes. Thus, a mild to moderately reduced eGFR was not associated with brain atrophy in ADNI participants.

Mild to moderate decrease in eGFR and cognitive decline in older adults.

BACKGROUND: Whether mild to moderately low estimated glomerular filtration rate (eGFR) is associated with cognitive decline in older adults is not clear. We evaluated changes in cognition in relation to baseline eGFR in older adults participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI). METHODS: This is a longitudinal secondary analysis of an established observational cohort. We used data from the ADNI, an National Institutes of Health-funded, multicenter longitudinal observational study that includes participants with and without cognitive impairment who were administered a comprehensive battery of neuropsychological tests every 6 months. We related the Chronic Kidney Disease Epidemiology Collaboration eGFR with previously validated cognition composite scores for memory (ADNI-Mem) and executive function (ADNI-EF) in multivariable linear regression analysis adjusted for age, sex, race and level of education. RESULTS: A total of 1127 ADNI participants (mean age 74 ± 7 years, 57% men, 97% Caucasian, mean follow-up 6 ± 2.6 years) were included in the analysis. The mean baseline eGFR was 76 ± 19 mL/min/1.73 m2, with 6% with eGFR <45, 22% with eGFR 45-<60, 51% with eGFR 60-90 and 21% with eGFR >90 mL/min/1.73 m2 at baseline. Both ADNI-Mem and ADNI-EF scores declined over time. In the multivariable linear regression model, older age (ß = -0.117, P = 0.01), female sex (ß = 0.312, P < 0.001) and lower education (ß = 0.079, P < 0.001) were associated with a decline in ADNI-Mem scores, whereas baseline eGFR (each 10 mL/min/1.73 m2 change) was not {ß = -0.03 [confidence interval (CI) -0.06-0.001], P = 0.11}. Similarly, older age (ß = -0.278, P < 0.001) and lower education (ß = 0.099, P < 0.001) were associated with a decline in ADNI-EF scores, whereas baseline eGFR was not [ß = 0.004 (95% CI -0.04-0.04), P = 0.84]. CONCLUSIONS: In this cohort from the ADNI study, there was no association between baseline eGFR and cognitive decline in older adults with mild to moderately low eGFR.

Statin contribution to middle cerebral artery blood flow velocity in older adults at risk for dementia.

PURPOSE: It is plausible that statins could improve cerebral blood flow through pleiotropic mechanisms. The purpose of this investigation was to assess the contribution of statins to cerebrovascular variables in older adults with dyslipidemia and familial history of dementia. Furthermore, we explored the interaction between statin use and sex due to prevalent bias in statin trials. METHODS: Middle cerebral artery blood flow velocity (MCAv) was measured using transcranial Doppler ultrasound. Continuous supine rest recordings lasted 8 min. Participants included in analyses were statin (n = 100) or non-statin users (n = 112). RESULTS: MCAv and cerebrovascular conductance were significantly higher in statin users (p = 0.047; p = 0.04), and pulsatility index (PI) was significantly lower in statin users (p < 0.01). An interaction effect between statin use and sex was present for PI (p = 0.02); female statin users had significantly lower cerebrovascular resistance than the other three groups. CONCLUSION: In this cross-sectional analysis, statin use was positively associated with cerebrovascular variables in older adults at risk for dementia. Female statin users had significantly higher resting MCAv and cerebrovascular conductance than female non-statin users. The greatest contribution of statin use was the association with reduced cerebrovascular resistance. Given that cerebrovascular dysregulation is one of the earliest changes in Alzheimer's disease and related dementia pathology, targeting the cerebrovasculature with statins may be a promising prevention strategy.

Normalization of Cerebral Blood Flow, Neurochemicals, and White Matter Integrity after Kidney Transplantation.

BACKGROUND: CKD is associated with abnormalities in cerebral blood flow, cerebral neurochemical concentrations, and white matter integrity. Each of these is associated with adverse clinical consequences in the non-CKD population, which may explain the high prevalence of dementia and stroke in ESKD. Because cognition improves after kidney transplantation, comparing these brain abnormalities before and after kidney transplantation may identify potential reversibility in ESKD-associated brain abnormalities. METHODS: In this study of patients with ESKD and age-matched healthy controls, we used arterial spin labeling to assess the effects of kidney transplantation on cerebral blood flow and magnetic resonance spectroscopic imaging to measure cerebral neurochemical concentrations (N-acetylaspartate, choline, glutamate, glutamine, myo-inositol, and total creatine). We also assessed white matter integrity measured by fractional anisotropy (FA) and mean diffusivity (MD) with diffusion tensor imaging. We used a linear mixed model analysis to compare longitudinal, repeated brain magnetic resonance imaging measurements before, 3 months after, and 12 months after transplantation and compared these findings with those of healthy controls. RESULTS: Study participants included 29 patients with ESKD and 19 controls; 22 patients completed post-transplant magnetic resonance imaging. Cerebral blood flow, which was higher in patients pretransplant compared with controls (P=0.003), decreased post-transplant (P<0.001) to values in controls. Concentrations of neurochemicals choline and myo-inositol that were higher pretransplant compared with controls (P=0.001 and P<0.001, respectively) also normalized post-transplant (P<0.001 and P<0.001, respectively). FA increased (P=0.001) and MD decreased (P<0.001) post-transplant. CONCLUSIONS: Certain brain abnormalities in CKD are reversible and normalize with kidney transplantation. Further studies are needed to understand the mechanisms underlying these brain abnormalities and to explore interventions to mitigate them even in patients who cannot be transplanted. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Cognitive Impairment and Imaging Correlates in End Stage Renal Disease, NCT01883349.

Apolipoprotein E4 Moderates the Association Between Vascular Risk Factors and Brain Pathology.

BACKGROUND: The strongest genetic risk factor for late-onset Alzheimer disease (AD), Apolipoprotein E4 (APOE4), increases cardiovascular disease risk and may also act synergistically with vascular risk factors to contribute to AD pathogenesis. Here, we assess the interaction between APOE4 and vascular risk on cerebrovascular dysfunction and brain pathology. METHODS: This is an observational study of cognitively normal older adults, which included positron emission tomography imaging and vascular risk factors. We measured beat-to-beat blood pressure and middle cerebral artery velocity at rest and during moderate-intensity exercise. Cerebrovascular measures included cerebrovascular conductance index and the cerebrovascular response to exercise. RESULTS: There was a significant interaction between resting cerebrovascular conductance index and APOE4 carrier status on ß-amyloid deposition (P=0.026), with poor conductance in the cerebrovasculature associated with elevated ß-amyloid for the APOE4 carriers only. There was a significant interaction between non-high-density lipoprotein cholesterol and APOE4 carrier status (P=0.014), with elevated non-high-density lipoprotein cholesterol predicting a blunted cerebrovascular response to exercise in APOE4 carriers and the opposite relationship in noncarriers. CONCLUSIONS: Both cerebral and peripheral vascular risk factors are preferentially associated with brain pathology in APOE4 carriers. These findings provide insight into pathogenic vascular risk mechanisms and target strategies to potentially delay AD onset.

Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients.

INTRODUCTION: Brain bioenergetics are defective in Alzheimer's disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement data are lacking. METHODS: We orally administered 500 or 1000 mg OAA, twice daily for 1 month, to AD participants (n = 15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, we performed fluorodeoxyglucose positron emission tomography (FDG PET) and magnetic resonance spectroscopy before and after the intervention. We also assessed pharmacokinetics and cognitive performance. RESULTS: Both doses were safe and tolerated. Compared to the lower dose, the higher dose benefited FDG PET glucose uptake across multiple brain regions (P < .05), and the higher dose increased parietal and frontoparietal glutathione (P < .05). We did not demonstrate consistent blood level changes and cognitive scores did not improve. CONCLUSIONS: 1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.

Exploratory analysis of mtDNA haplogroups in two Alzheimer's longitudinal cohorts.

INTRODUCTION: Inherited mitochondrial DNA (mtDNA) variants may influence Alzheimer's disease (AD) risk. METHODS: We sequenced mtDNA from 146 AD and 265 cognitively normal (CN) subjects from the University of Kansas AD Center (KUADC) and assigned haplogroups. We further considered 244 AD and 242 CN AD Neuroimaging Initiative (ADNI) subjects with equivalent data. RESULTS: Without applying multiple comparisons corrections, KUADC haplogroup J AD and CN frequencies were 16.4% versus 7.6% (P = .007), and haplogroup K AD and CN frequencies were 4.8% versus 10.2% (P = .063). ADNI haplogroup J AD and CN frequencies were 10.7% versus 7.0% (P = .20), and haplogroup K frequencies were 4.9% versus 8.7% (P = .11). For the combined 390 AD and 507 CN cases haplogroup J frequencies were 12.8% versus 7.3% (P = .006), odds ratio (OR) = 1.87, and haplogroup K frequencies were 4.9% versus 9.5% (P = .010), OR = 0.49. Associations remained significant after adjusting for apolipoprotein E, age, and sex. CONCLUSION: This exploratory analysis suggests inherited mtDNA variants influence AD risk.

Retention of Alzheimer Disease Research Participants.

INTRODUCTION: Participant retention is important to maintaining statistical power, minimizing bias, and preventing scientific error in Alzheimer disease and related dementias research. METHODS: We surveyed representative investigators from NIH-funded Alzheimer's Disease Research Centers (ADRC), querying their use of retention tactics across 12 strategies. We compared survey results to data from the National Alzheimer's Coordinating Center for each center. We used a generalized estimating equation with independent working covariance model and empirical standard errors to assess relationships between survey results and rates of retention, controlling for participant characteristics. RESULTS: Twenty-five (83%) responding ADRCs employed an average 42 (SD=7) retention tactics. In a multivariable model that accounted for participant characteristics, the number of retention tactics used by a center was associated with participant retention (odds ratio=1.68, 95% confidence interval: 1.42, 1.98; P<0.001 for the middle compared with the lowest tertile survey scores; odds ratio=1.59, 95% confidence interval: 1.30, 1.94; P<0.001 for the highest compared with the lowest tertile survey scores) at the first follow-up visit. Participant characteristics such as normal cognition diagnosis, older age, higher education, and Caucasian race were also associated with higher retention. CONCLUSIONS: Retention in clinical research is more likely to be achieved by employing a variety of tactics.

The Relationship Between Apolipoprotein ε4 Carrier Status and Sleep Characteristics in Cognitively Normal Older Adults.

The apolipoprotein (APOE) ε4 allele, a well-described genetic risk factor for late-onset Alzheimer disease (AD), is associated with sleep disturbances even in cognitively normal older adults, although it is not clear whether this association is independent of sleep apnea. We sought to extend previous studies by examining whether cognitively normal older adults without self-reported sleep apnea who carry the APOE ε4 allele have altered sleep characteristics compared to noncarriers. Data from N = 36 (APOE ε4 carriers [n = 9], noncarriers [n = 27]) cognitively normal older adults (Clinical Dementia Rating [CDR] scale = 0) without self-reported sleep apnea were used for these analyses. Participants wore an actigraph for 7 days to determine sleep characteristics. The Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) were used to assess sleep quality and daytime sleepiness, respectively. The APOE ε4 carriers had a higher number of awakenings compared to the noncarriers ( P = .02). There was no significant difference in the PSQI global score and the ESS; however, the PSQI subcomponent of daily disturbances was significantly higher in APOE ε4 carriers ( P = .03), indicating increased daytime dysfunction is related to disrupted sleep. This study provides evidence that individuals who are cognitively normal and genetically at risk of AD may have disrupted sleep. These findings are consistent with prior studies and suggest that sleep disruption may be present in the presymptomatic stages of AD.

Prevalence and correlates of cognitive impairment in kidney transplant recipients.

BACKGROUND: There is a high prevalence of cognitive impairment in dialysis patients. The prevalence of cognitive impairment after kidney transplantation is unknown. METHODS: Study Design: Cross-sectional study. SETTING AND PARTICIPANTS: Single center study of prevalent kidney transplant recipients from a transplant clinic in a large academic center. INTERVENTION: Assessment of cognition using the Montreal Cognitive Assessment (MoCA). Demographic and clinical variables associated with cognitive impairment were also examined. Outcomes and Measurements: a) Prevalence of cognitive impairment defined by a MoCA score of <26. b) Multivariable linear and logistic regression to examine the association of demographic and clinical factors with cognitive impairment. RESULTS: Data from 226 patients were analyzed. Mean (SD) age was 54 (13.4) years, 73% were white, 60% were male, 37% had diabetes, 58% had an education level of college or above, and the mean (SD) time since kidney transplant was 3.4 (4.1) years. The prevalence of cognitive impairment was 58.0%. Multivariable linear regression demonstrated that older age, male gender and absence of diabetes were associated with lower MoCA scores (p < 0.01 for all). Estimated glomerular filtration rate (eGFR) was not associated with level of cognition. The logistic regression analysis confirmed the association of older age with cognitive impairment. CONCLUSION: Cognitive impairment is common in prevalent kidney transplant recipients, at a younger age compared to general population, and is associated with certain demographic variables, but not level of eGFR.

Safety of disclosing amyloid status in cognitively normal older adults.

INTRODUCTION: Disclosing amyloid status to cognitively normal individuals remains controversial given our lack of understanding the test's clinical significance and unknown psychological risk. METHODS: We assessed the effect of amyloid status disclosure on anxiety and depression before disclosure, at disclosure, and 6 weeks and 6 months postdisclosure and test-related distress after disclosure. RESULTS: Clinicians disclosed amyloid status to 97 cognitively normal older adults (27 had elevated cerebral amyloid). There was no difference in depressive symptoms across groups over time. There was a significant group by time interaction in anxiety, although post hoc analyses revealed no group differences at any time point, suggesting a minimal nonsustained increase in anxiety symptoms immediately postdisclosure in the elevated group. Slight but measureable increases in test-related distress were present after disclosure and were related to greater baseline levels of anxiety and depression. DISCUSSION: Disclosing amyloid imaging results to cognitively normal adults in the clinical research setting with pre- and postdisclosure counseling has a low risk of psychological harm.

Exercise Test Performance Reveals Evidence of the Cardiorespiratory Fitness Hypothesis.

Positive physiologic and cognitive responses to aerobic exercise have resulted in a proposed cardiorespiratory (CR) fitness hypothesis in which fitness gains drive changes leading to cognitive benefit. The purpose of this study was to directly assess the CR fitness hypothesis. Using data from an aerobic exercise trial, we examined individuals who completed cardiopulmonary and cognitive testing at baseline and 26 weeks. Change in cognitive test performance was not related to CR fitness change (r2 = .06, p = .06). However, in the subset of individuals who gave excellent effort during exercise testing, change in cognitive test performance was related to CR fitness change (r2 = .33, p < .01). This was largely due to change in the cognitive domain of attention (r2 = .36, p < .01). The magnitude of change was not explained by duration of exercise. Our findings support further investigation of the CR fitness hypothesis and mechanisms by which physiologic adaptation may drive cognitive change.

Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.

Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis.

Cognitive Function and White Matter Changes Associated with Renal Transplantation.

BACKGROUND: End-stage renal disease (ESRD) is a disease with an aging population and a high prevalence of cognitive impairment affecting quality of life, health care costs and mortality. Structural changes in the brain with decreased white matter integrity have been observed in ESRD. Understanding the changes in cognition and associated changes in brain structure after renal transplantation can help define the mechanisms underlying cognitive impairment in ESRD. METHODS: We conducted a prospective, observational cohort study in ESRD patients listed for renal transplantation and followed them post-transplantation. We assessed their cognitive function with a battery of neuropsychological tests and brain white matter integrity with diffusion tensor imaging (DTI) both before transplant and 3 months after transplant. RESULTS: Eleven patients, aged 56.5 ± 10.7 years, completed the study. Cognitive measures of memory and executive function improved after the transplant, specifically on tests of logical memory I (p = 0.004), logical memory II (p = 0.003) and digit symbol (p < 0.0001). DTI metrics also improved post the transplant with an increase in fractional anisotropy (p = 0.01) and decrease in mean diffusivity (p = 0.004). These changes were more prominent in tracts associated with memory and executive function. CONCLUSIONS: Cognitive function, particularly memory and executive function, improve post the transplant with concurrent improvements in white matter integrity in tracts associated with memory and executive function. These data suggest that abnormalities in cognition and brain structure seen in the ESRD population are at least partially reversible.

Cerebral ß-Amyloid Angiopathy Is Associated with Earlier Dementia Onset in Alzheimer's Disease.

BACKGROUND: Cerebral ß-amyloid angiopathy (CAA) occurs when ß-amyloid (Aß) is deposited in the vascular media and adventitia. It is a common pathology in the brains of older individuals and has been linked to cognitive decline, but relatively little is known about the influence that CAA has on the clinical manifestation of Alzheimer's disease (AD). The aim of this retrospective analysis was to quantify the effect that CAA had on the manifestation of initial AD-related cognitive change and subsequent progression of dementia. METHODS: We analyzed neuropathological data from the National Alzheimer's Coordinating Center's data set, performing parametric analyses to assess differences in age of progression to moderate-stage dementia. RESULTS: We found that individuals with both CAA burden and Aß neuritic plaque burden at death had the greatest risk of earlier conversion to very mild and moderate-stage dementia, but not necessarily faster progression. CONCLUSIONS: Our results suggest that CAA contributes to changes in early AD pathogenesis. This supports the idea that vascular change and neuritic plaque deposition are not just parallel processes but reflect additive pathological cascades that influence the course of clinical AD manifestation. Further inquiry into the role of CAA and its contribution to early cognitive change in AD is suggested.

The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives.

Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aß) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aß at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it.