Resting heart rate (variability) and cognition relationships reveal cognitively healthy individuals with pathological amyloid/tau ratio.

Introduction: Resting heart rate (HR) and heart rate variability (HRV) have been linked with cognition in the general population and in older individuals. The knowledge of this aspect of heart-brain relationship is relatively absent in older individuals with early Alzheimer's disease (AD) pathology. This study explores relationships of the HR, HRV, and cognition in cognitively healthy individuals with pathological amyloid/tau ratio (CH-PATs) in cerebral spinal fluid (CSF) compared to those with normal ratio (CH-NATs). Methods: We examined therelationshipsbetween1) resting HR and Mini-Mental State Examination (MMSE); 2) resting HR and brain processing during Stroop interference; and 3) resting vagally mediated HRV (vmHRV) and task switching performance. Results: Our studies showed that compared to CH-NATs, those CH-PATs with higher resting HR presented with lower MMSE, and less brain activation during interference processing. In addition, resting vmHRV was significantly correlated with task switching accuracy in CH-NATs, but not in CH-PATs. Discussion: Thesethreedifferenttestsindicatedysfunctionalheart-brainconnections in CH-PATs, suggesting a potential cardio-cerebral dysfunctional integration.

Biomarkers - Part 1.

BACKGROUND: The CSF amyloid to tau ratio can isolate cognitively healthy participants into normal Aß42/tau (CH-NAT) or a pathological Aß42/tau (CH-PAT) with a low or high risk of cognitive decline, respectively. We aim to determine if plasma Aß42/tau ratios can differentiate CH-NAT from CH-PAT participants. METHOD: Study participants (> 65 years of age) were recruited, and demographic, neurological, and neuropsychological data were obtained in an ongoing HMRI Brain Aging study. Overnight fasting plasma and CSF were collected within a month of examination, and the levels of Aß38, Aß40, Aß42 (MSD 6E10 kit), and total tau were quantified using the MSD electrochemiluminescence platform. Differences in fluid biomarker levels and the plasma ratios (n = 55) and CSF ratios (Aß42/Aß40, n = 41, Aß42/tau, n = 55) were determined using nonparametric student t-test and correlations using a Spearman test. RESULT: Aß40 and Aß42 levels were higher (15-18-fold, and 10-14-fold, respectively), while tau levels are 8-13-fold higher in CSF than in plasma. Plasma and CSF Aß40 were not distinct in CH-NAT compared with CH-PAT. In contrast, Aß42 levels were 30.9% lower in CH-PAT (16.3 ± 18.3 pg/ml) compared with CH-NAT plasma (23.6 ± 26.4 pg/mL) (p < 0.05). CSF Aß42 levels in CH-PAT (171.6 ± 124.6 pg/mL) were lower by 47.6% compared with CH-NAT (327.6 ± 182.6 pg/ml) (p < 0.0001). The Aß42/Aß40 ratio was significantly lower in both plasma and CSF (Table 1A). Similarly, the Aß42/tau ratio was significantly lower in plasma and CSF (Table 1B). Individually, plasma levels of Aß42 and tau did not correlate with CSF levels. However, the ratio of Aß42 to total tau in plasma significantly correlated with the CSF ratios (Spearman r = 0.36, p = 0.0071). Finally, CSF Aß42/Aß40 ratio correlated with Aß42/tau ratio for all samples, CH (n = 100) and MCI (n = 35) (Fig. 1). CONCLUSION: While not as robust as CSF ratios, plasma Aß42/Aß40 and Aß42/tau ratios can isolate cognitively healthy participants with lower risk from participants with a higher risk of cognitive decline. Thus, plasma represents a less invasive medium for the biomarker classification of aging participants.

Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial.

BACKGROUND: Past clinical trials of docosahexaenoic Acid (DHA) supplements for the prevention of Alzheimer's disease (AD) dementia have used lower doses and have been largely negative. We hypothesized that larger doses of DHA are needed for adequate brain bioavailability and that APOE4 is associated with reduced delivery of DHA and eicosapentaenoic acid (EPA) to the brain before the onset of cognitive impairment. METHODS: 33 individuals were provided with a vitamin B complex (1 mg vitamin B12, 100 mg of vitamin B6 and 800 mcg of folic acid per day) and randomized to 2,152 mg of DHA per day or placebo over 6 months. 26 individuals completed both lumbar punctures and MRIs, and 29 completed cognitive assessments at baseline and 6 months. The primary outcome was the change in CSF DHA. Secondary outcomes included changes in CSF EPA levels, MRI hippocampal volume and entorhinal thickness; exploratory outcomes were measures of cognition. FINDINGS: A 28% increase in CSF DHA and 43% increase in CSF EPA were observed in the DHA treatment arm compared to placebo (mean difference for DHA (95% CI): 0.08 µg/mL (0.05, 0.10), p<0.0001; mean difference for EPA: 0.008 µg/mL (0.004, 0.011), p<0.0001). The increase in CSF EPA in non-APOE4 carriers after supplementation was three times greater than APOE4 carriers. The change in brain volumes and cognitive scores did not differ between groups. INTERPRETATION: Dementia prevention trials using omega-3 supplementation doses equal or lower to 1 g per day may have reduced brain effects, particularly in APOE4 carriers. TRIAL REGISTRATION: NCT02541929. FUNDING: HNY was supported by R01AG055770, R01AG054434, R01AG067063 from the National Institute of Aging and NIRG-15-361854 from the Alzheimer's Association, and MGH by the L. K. Whittier Foundation. This work was also supported by P50AG05142 (HCC) from the National Institutes of Health. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.

Vascular contributions to dementia and Alzheimer's disease are increasingly recognized1-6. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer's disease5,8-10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease11-14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15-19, which maintain BBB integrity20-22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-ß or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRß7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-ß and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.

Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction.

Vascular contributions to cognitive impairment are increasingly recognized1-5 as shown by neuropathological6,7, neuroimaging4,8-11, and cerebrospinal fluid biomarker4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer's disease (AD)3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-ß (Aß)3,11,14, and more recently tau15. Animal studies suggest that Aß and tau lead to blood vessel abnormalities and blood-brain barrier (BBB) breakdown14-16. Although neurovascular dysfunction3,11 and BBB breakdown develop early in AD1,4,5,8-10,12,13, how they relate to changes in the AD classical biomarkers Aß and tau, which also develop before dementia17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-ß8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging8-10. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer's Aß and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aß and tau.