KATP channels are necessary for glucose-dependent increases in amyloid-ß and Alzheimer's disease-related pathology.

Elevated blood glucose levels, or hyperglycemia, can increase brain excitability and amyloid-ß (Aß) release, offering a mechanistic link between type 2 diabetes and Alzheimer's disease (AD). Since the cellular mechanisms governing this relationship are poorly understood, we explored whether ATP-sensitive potassium (KATP) channels, which couple changes in energy availability with cellular excitability, play a role in AD pathogenesis. First, we demonstrate that KATP channel subunits Kir6.2/KCNJ11 and SUR1/ABCC8 were expressed on excitatory and inhibitory neurons in the human brain, and cortical expression of KCNJ11 and ABCC8 changed with AD pathology in humans and mice. Next, we explored whether eliminating neuronal KATP channel activity uncoupled the relationship between metabolism, excitability, and Aß pathology in a potentially novel mouse model of cerebral amyloidosis and neuronal KATP channel ablation (i.e., amyloid precursor protein [APP]/PS1 Kir6.2-/- mouse). Using both acute and chronic paradigms, we demonstrate that Kir6.2-KATP channels are metabolic sensors that regulate hyperglycemia-dependent increases in interstitial fluid levels of Aß, amyloidogenic processing of APP, and amyloid plaque formation, which may be dependent on lactate release. These studies identify a potentially new role for Kir6.2-KATP channels in AD and suggest that pharmacological manipulation of Kir6.2-KATP channels holds therapeutic promise in reducing Aß pathology in patients with diabetes or prediabetes.

Intranasal insulin modulates cerebrospinal fluid markers of neuroinflammation in mild cognitive impairment and Alzheimer's disease: a randomized trial.

Intranasal insulin (INI) has shown promise as a treatment for Alzheimer's disease (AD) in pilot clinical trials. In a recent phase 2 trial, participants with mild cognitive impairment (MCI) or AD who were treated with INI with one of two delivery devices showed improved cerebral spinal fluid (CSF) biomarker profiles and slower symptom progression compared with placebo. In the cohort which showed benefit, we measured changes in CSF markers of inflammation, immune function and vascular integrity and assessed their relationship with changes in cognition, brain volume, and CSF amyloid and tau concentrations. The insulin-treated group had increased CSF interferon-γ (p = 0.032) and eotaxin (p = 0.049), and reduced interleukin-6 (p = 0.048) over the 12 month trial compared to placebo. Trends were observed for increased CSF macrophage-derived chemokine for the placebo group (p = 0.083), and increased interleukin-2 in the insulin-treated group (p = 0.093). Insulin-treated and placebo groups showed strikingly different patterns of associations between changes in CSF immune/inflammatory/vascular markers and changes in cognition, brain volume, and amyloid and tau concentrations. In summary, INI treatment altered the typical progression of markers of inflammation and immune function seen in AD, suggesting that INI may promote a compensatory immune response associated with therapeutic benefit.

Mediterranean and Western diet effects on Alzheimer's disease biomarkers, cerebral perfusion, and cognition in mid-life: A randomized trial.

INTRODUCTION: Mid-life dietary patterns are associated with Alzheimer's disease (AD) risk, although few controlled trials have been conducted. METHODS: Eighty-seven participants (age range: 45 to 65) with normal cognition (NC, n = 56) or mild cognitive impairment (MCI, n = 31) received isocaloric diets high or low in saturated fat, glycemic index, and sodium (Western-like/West-diet vs. Mediterranean-like/Med-diet) for 4 weeks. Diet effects on cerebrospinal fluid (CSF) biomarkers, cognition, and cerebral perfusion were assessed to determine whether responses differed by cognitive status. RESULTS: CSF amyloid beta (Aß)42/40 ratios increased following the Med-diet, and decreased after West-diet for NC adults, whereas the MCI group showed the reverse pattern. For the MCI group, the West-diet reduced and the Med-diet increased total tau (t-tau), whereas CSF Aß42 /t-tau ratios increased following the West-diet and decreased following the Med-diet. For NC participants, the Med-diet increased and the West-diet decreased cerebral perfusion. DISCUSSION: Diet response during middle age may highlight early pathophysiological processes that increase AD risk.

Collegiate athlete brain data for white matter mapping and network neuroscience.

We describe a dataset of processed data with associated reproducible preprocessing pipeline collected from two collegiate athlete groups and one non-athlete group. The dataset shares minimally processed diffusion-weighted magnetic resonance imaging (dMRI) data, three models of the diffusion signal in the voxel, full-brain tractograms, segmentation of the major white matter tracts as well as structural connectivity matrices. There is currently a paucity of similar datasets openly shared. Furthermore, major challenges are associated with collecting this type of data. The data and derivatives shared here can be used as a reference to study the effects of long-term exposure to collegiate athletics, such as the effects of repetitive head impacts. We use advanced anatomical and dMRI data processing methods publicly available as reproducible web services at brainlife.io.

Brain insulin resistance in Alzheimer's disease and related disorders: mechanisms and therapeutic approaches.

Insulin is a peptide secreted by the pancreas and plays an important role in the regulation of glucose metabolism in peripheral tissues. Although the role of insulin in the periphery is well understood, less is known about its multifactorial role in the brain. However, emerging evidence from human and animal studies indicate that insulin influences cerebral bioenergetics, enhances synaptic viability and dendritic spine formation, and increases turnover of neurotransmitters, such as dopamine. Insulin also has a role in proteostasis, influencing clearance of the amyloid ß peptide and phosphorylation of tau, which are hallmarks of Alzheimer's disease. Insulin also modulates vascular function through effects on vasoreactivity, lipid metabolism, and inflammation. Through these multiple pathways, insulin dysregulation could contribute to neurodegeneration. Thus, new approaches to restore cerebral insulin function that could offer therapeutic benefit to adults with Alzheimer's disease, vascular cognitive impairment, or related disorders are being investigated.

Modified ketogenic diet is associated with improved cerebrospinal fluid biomarker profile, cerebral perfusion, and cerebral ketone body uptake in older adults at risk for Alzheimer's disease: a pilot study.

There is currently no established therapy to treat or prevent Alzheimer's disease. The ketogenic diet supplies an alternative cerebral metabolic fuel, with potential neuroprotective effects. Our goal was to compare the effects of a modified Mediterranean-ketogenic diet (MMKD) and an American Heart Association Diet (AHAD) on cerebrospinal fluid Alzheimer's biomarkers, neuroimaging measures, peripheral metabolism, and cognition in older adults at risk for Alzheimer's. Twenty participants with subjective memory complaints (n = 11) or mild cognitive impairment (n = 9) completed both diets, with 3 participants discontinuing early. Mean compliance rates were 90% for MMKD and 95% for AHAD. All participants had improved metabolic indices following MMKD. MMKD was associated with increased cerebrospinal fluid Aß42 and decreased tau. There was increased cerebral perfusion and increased cerebral ketone body uptake (11C-acetoacetate PET, in subsample) following MMKD. Memory performance improved after both diets, which may be due to practice effects. Our results suggest that a ketogenic intervention targeted toward adults at risk for Alzheimer's may prove beneficial in the prevention of cognitive decline.

Comparing fMRI activation during smooth pursuit eye movements among contact sport athletes, non-contact sport athletes, and non-athletes.

Objectives: Though sub-concussive impacts are common during contact sports, there is little consensus whether repeat blows affect brain function. Using a "lifetime exposure" rather than acute exposure approach, we examined oculomotor performance and brain activation among collegiate football players and two control groups. Our analysis examined whether there are group differences in eye movement behavioral performance and in brain activation during smooth pursuit. Methods: Data from 21 off-season Division I football "starters" were compared with a) 19 collegiate cross-country runners, and b) 11 non-athlete college students who were SES matched to the football player group (total N = 51). Visual smooth pursuit was performed while undergoing fMRI imaging via a 3 Tesla scanner. Smooth pursuit eye movements to three stimulus difficulty levels were measured with regard to RMS error, gain, and lag. Results: No meaningful differences were found for any of the standard analyses used to assess smooth pursuit eye movements. For fMRI, greater activation was seen in the oculomotor region of the cerebellar vermis and areas of the FEF for football players as compared to either control group, who did not differ on any measure. Conclusion: Greater cerebellar activity among football players while performing an oculomotor task could indicate that they are working harder to compensate for some subtle, long-term subconcussive deficits. Alternatively, top athletes in a sport requiring high visual motor skill could have more of their cerebellum and FEF devoted to oculomotor task performance regardless of subconcussive history. Overall, these results provide little firm support for an effect of accumulated subconcussion exposure on brain function.

Effects of Alcohol Cues on MRS Glutamate Levels in the Anterior Cingulate.

Growing evidence suggests that glutamate neurotransmission plays a critical role in alcohol addiction. Cue-induced change of glutamate has been observed in animal studies but never been investigated in humans. This work investigates cue-induced change in forebrain glutamate in individuals with alcohol use disorder (AUD). A total of 35 subjects (17 individuals with AUD and 18 healthy controls) participated in this study. The glutamate concentration was measured with single-voxel 1H-MR spectroscopy at the dorsal anterior cingulate. Two MRS sessions were performed in succession, the first to establish basal glutamate levels and the second to measure the change in response to alcohol cues. The changes in glutamate were quantified for both AUD subjects and controls. A mixed model ANOVA and t-tests were performed for statistical analysis. ANOVA revealed a main effect of cue-induced decrease of glutamate level in the anterior cingulate cortex (ACC). A significant interaction revealed that only AUD subjects showed significant decrease of glutamate in the ACC. There were no significant group differences in the level of basal glutamate. However, a negative correlation was found between the basal glutamate level and the number of drinking days in the past 2 weeks for the AUD subjects. Collectively, our results indicate that glutamate in key areas of the forebrain reward circuit is modulated by alcohol cues in early alcohol dependence.