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IntroductionLate-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.MethodsWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.ResultsWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DiscussionMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.HighlightsLong-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

Alzheimers disease (AD) is influenced by a variety of modifiable risk factors, including a persons dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KDs metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean Ketogenic Diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.

BACKGROUND: Frontotemporal dementia (FTD) represents a collection of neurobehavioral and neurocognitive syndromes that are associated with a significant degree of clinical, pathological, and genetic heterogeneity. Such heterogeneity hinders the identification of effective biomarkers, preventing effective targeted recruitment of participants in clinical trials for developing potential interventions and treatments. In the present study, we aim to automatically differentiate patients with three clinical phenotypes of FTD, behavioral-variant FTD (bvFTD), semantic variant PPA (svPPA), and nonfluent variant PPA (nfvPPA), based on their structural MRI by training a deep neural network (DNN). METHODS: Data from 277 FTD patients (173 bvFTD, 63 nfvPPA, and 41 svPPA) recruited from two multi-site neuroimaging datasets: the Frontotemporal Lobar Degeneration Neuroimaging Initiative and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration databases. Raw T1-weighted MRI data were preprocessed and parcellated into patch-based ROIs, with cortical thickness and volume features extracted and harmonized to control the confounding effects of sex, age, total intracranial volume, cohort, and scanner difference. A multi-type parallel feature embedding framework was trained to classify three FTD subtypes with a weighted cross-entropy loss function used to account for unbalanced sample sizes. Feature visualization was achieved through post-hoc analysis using an integrated gradient approach. RESULTS: The proposed differential diagnosis framework achieved a mean balanced accuracy of 0.80 for bvFTD, 0.82 for nfvPPA, 0.89 for svPPA, and an overall balanced accuracy of 0.84. Feature importance maps showed more localized differential patterns among different FTD subtypes compared to groupwise statistical mapping. CONCLUSION: In this study, we demonstrated the efficiency and effectiveness of using explainable deep-learning-based parallel feature embedding and visualization framework on MRI-derived multi-type structural patterns to differentiate three clinically defined subphenotypes of FTD: bvFTD, nfvPPA, and svPPA, which could help with the identification of at-risk populations for early and precise diagnosis for intervention planning.

PurposeTo reduce the total scan time of multiple postlabeling delay (multi-PLD) pseudo-continuous arterial spin labeling (pCASL) by developing a hierarchically structured 3D convolutional neural network (H-CNN) that estimates the arterial transit time (ATT) and cerebral blow flow (CBF) maps from the reduced number of PLDs as well as averages.MethodsA total of 48 subjects (38 females and 10 males), aged 56-80 years, compromising a training group (n = 45) and a validation group (n = 3) underwent MRI including multi-PLD pCASL. We proposed an H-CNN to estimate the ATT and CBF maps using a reduced number of PLDs and a separately reduced number of averages. The proposed method was compared with a conventional nonlinear model fitting method using the mean absolute error (MAE).ResultsThe H-CNN provided the MAEs of 32.69 ms for ATT and 3.32 mL/100 g/min for CBF estimations using a full data set that contains six PLDs and six averages in the 3 test subjects. The H-CNN also showed that the smaller number of PLDs can be used to estimate both ATT and CBF without significant discrepancy from the reference (MAEs of 231.45 ms for ATT and 9.80 mL/100 g/min for CBF using three of six PLDs).ConclusionThe proposed machine learning-based ATT and CBF mapping offers substantially reduced scan time of multi-PLD pCASL.

IntroductionLittle is known about how antecedent vascular risk factor (VRF) profiles impact late-life brain health.MethodsWe examined baseline VRFs, and cognitive testing and neuroimaging measures (β-amyloid [Aβ] PET, MRI) in a diverse longitudinal cohort (N = 159; 50% African-American, 50% White) from Wake Forest's Multi-Ethnic Study of Atherosclerosis Core.ResultsAfrican-Americans exhibited greater baseline Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke risk profile (FSRP), and atherosclerotic cardiovascular disease risk estimate (ASCVD) scores than Whites. We observed no significant racial differences in Aβ positivity, cortical thickness, or white matter hyperintensity (WMH) volume. Higher baseline VRF scores were associated with lower cortical thickness and greater WMH volume, and FSRP and CAIDE were associated with Aβ. Aβ was cross-sectionally associated with cognition, and all imaging biomarkers were associated with greater 6-year cognitive decline.DiscussionResults suggest the convergence of multiple vascular and Alzheimer's processes underlying neurodegeneration and cognitive decline.

INTRODUCTION: Mid-life dietary patterns are associated with Alzheimers 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 (Aβ)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 Aβ42 /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.

BACKGROUND: Cardiometabolic disorders (hypertension, diabetes) are key modifiable risk factors for Alzheimers disease and related disorders. They often co-occur; yet, the extent to which they independently affect brain structure and function is unclear. OBJECTIVE: We hypothesized their combined effect is greater in associations with cognitive function and neuroimaging biomarkers of white matter (WM) health and cerebral perfusion in a diverse older adult cohort. METHODS: Participants aged 50-85 years received: clinical evaluation, oral glucose tolerance testing, neuroimaging, cognitive testing, and adjudication. Neuroimaging included: T1 (gray [GM]/WM segmentation, regional volumes/thicknesses); FLAIR (WM hyperintensity volume [WMHv]; arterial spin labeling (cerebral blood flow); diffusion tensor imaging (fractional anisotropy [FA]); and neurite orientation dispersion and density imaging (Free Water). Hypertension (HTN) and impaired glucose tolerance (IGT) were staged and cardiometabolic status was categorized (HTN only, IGT only, IGT+HTN, neither). Multivariable linear regression modeled associations with cognitive and neuroimaging measures (covariates: age, gender, race). RESULTS: MRI was available for 478 participants (35% mild cognitive impairment, 10% dementia) with mean age 70±8 years, 74% with HTN, 61% with IGT, and 15% self-identified as Black/African-American. IGT+HTN was significantly associated with cognitive impairment, higher WM Free Water and WMHv, lower FA, and lower GM perfusion compared to neither factor. HTN alone was associated with poorer cognition and lower GM perfusion. Cardiometabolic factors were not associated with GM macrostructure (volumes, temporal lobe cortical thickness) or cognitive status. CONCLUSION: HTN and its co-occurrence with IGT (HTN+IGT) were associated with lower global cognitive performance and reduced GM perfusion and impaired WM microstructure.

[This corrects the article DOI: 10.3389/fphys.2021.645342.].

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.

Vascular risk factors (e.g., obesity and hypertension) are associated with cerebral small vessel disease, Alzheimers disease (AD) pathology, and dementia. Reduced perfusion may reflect the impaired ability of blood vessels to regulate blood flow in reaction to varying circumstances such as hypercapnia (increased end-tidal partial pressures of CO2). It has been shown that cerebrovascular reactivity (CVR) measured with blood-oxygen-level-dependent (BOLD) MRI is correlated with cognitive performance and alterations of CVR may be an indicator of vascular disfunction leading to cognitive decline. However, the underlying mechanism of CVR alterations in BOLD signal may not be straight-forward because BOLD signal is affected by multiple physiological parameters, such as cerebral blood flow (CBF), cerebral blood volume, and oxygen metabolism. Arterial spin labeling (ASL) MRI quantitatively measures blood flow in the brain providing images of local CBF. Therefore, in this study, we measured CBF and its changes using a dynamic ASL technique during a hypercapnia challenge and tested if CBF or CVR was related to cognitive performance using the Mini-mental state examination (MMSE) score. Seventy-eight participants underwent cognitive testing and MRI including ASL during a hypercapnia challenge with a RespirAct computer-controlled gas blender, targeting 10 mmHg higher end-tidal CO2 level than the baseline while end-tidal O2 level was maintained. Pseudo-continuous ASL (PCASL) was collected during a 2-min baseline and a 2-min hypercapnic period. CVR was obtained by calculating a percent change of CBF per the end-tidal CO2 elevation in mmHg between the baseline and the hypercapnic challenge. Multivariate regression analyses demonstrated that baseline resting CBF has no significant relationship with MMSE, while lower CVR in the whole brain gray matter (β = 0.689, p = 0.005) and white matter (β = 0.578, p = 0.016) are related to lower MMSE score. In addition, region of interest (ROI) based analysis showed positive relationships between MMSE score and CVR in 26 out of 122 gray matter ROIs.

BackgroundIntranasally administered insulin has shown promise in both rodent and human studies in Alzheimer's disease; however, both effects and mechanisms require elucidation.ObjectiveWe assessed the effects of intranasally administered insulin on white matter health and its association with cognition and cerebral spinal fluid biomarker profiles in adults with mild cognitive impairment or Alzheimer's disease in secondary analyses from a prior phase 2 clinical trial (NCT01767909).DesignA randomized (1:1) double-blind clinical trial.SettingTwelve sites across the United States.ParticipantsAdults with mild cognitive impairment or Alzheimer's disease.InterventionParticipants received either twice daily placebo or insulin (20 IU Humulin R U-100 b.i.d.) intranasally for 12 months. Seventy-eight participants were screened, of whom 49 (32 men) were enrolled.MeasurementsChanges from baseline in global and regional white matter hyperintensity volume and gray matter volume were analyzed and related to changes in cerebral spinal fluid biomarkers, Alzheimer's Disease Assessment Scale-Cognition, Clinical Disease Rating-Sum of Boxes, Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale, and a memory composite.ResultsThe insulin-treated group demonstrated significantly reduced changes in white matter hyperintensity volume in deep and frontal regions after 12 months, with a similar trend for global volume. White matter hyperintensity volume progression correlated with worsened Alzheimer's disease cerebral spinal fluid biomarker profile and cognitive function; however, patterns of correlations differed by treatment group.ConclusionIntranasal insulin treatment for 12 months reduced white matter hyperintensity volume progression and supports insulin's potential as a therapeutic option for Alzheimer's disease.

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 Aβ42 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.

Background: Intranasal insulin (INI) is being explored as a treatment for Alzheimer's disease (AD). Improved memory, functional ability, and cerebrospinal fluid (CSF) AD biomarker profiles have been observed following INI administration. However, the method of intranasal delivery may significantly affect outcomes. Objective: To show reliable delivery of insulin to the brain using the Aptar Cartridge Pump System (CPS) intranasal delivery system. Methods: To visualize INI biodistribution, we developed a novel PET radiotracer, Gallium 68-radiolabeled (NOTA-conjugated) insulin, [68Ga]Ga-NOTA-insulin. We used the Aptar CPS to administer [68Ga]Ga-NOTA-insulin to anesthetized healthy adult vervet monkeys and measured brain regional activity and whole-body dosimetry following PET/CT scans. Results: We observed brain penetration of [68Ga]Ga-NOTA-insulin following intranasal administration with the Aptar CPS. Radioactive uptake was seen in multiple regions, including the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus. A safety profile and whole-body dosimetry were also established in a second cohort of vervets. Safety was confirmed: vitals remained stable, blood glucose levels were unchanged, and no organ was exposed to more than 2.5 mSv of radioactivity. Extrapolations from vervet organ distribution allowed for estimation of the [68Ga]Ga-NOTA-insulin absorbed dose in humans, and the maximum dose of [68Ga]Ga-NOTA-insulin that can be safely administered to humans was determined to be 185 MBq. Conclusions: The use of [68Ga]Ga-NOTA-insulin as a PET radiotracer is safe and effective for observing brain uptake in vervet monkeys. Further, the Aptar CPS successfully targets [68Ga]Ga-NOTA-insulin to the brain. The data will be essential in guiding future studies of intranasal [68Ga]Ga-NOTA-insulin administration in humans. [ABSTRACT FROM AUTHOR]

Objective Assess the feasibility and concurrent validity of a modified Uniform Data Set version 3 (UDSv3) for remote administration for individuals with normal cognition (NC), mild cognitive impairment (MCI), and early dementia. Method Participants (N =  93) (age: 72.8 [8.9] years; education: 15.6 [2.5] years; 72% female; 84% White) were enrolled from the Wake Forest ADRC. Portions of the UDSv3 cognitive battery, plus the Rey Auditory Verbal Learning Test, were completed by telephone or video within ~6 months of participant's in-person visit. Adaptations for phone administration (e.g. Oral Trails for Trail Making Test [TMT] and Blind Montreal Cognitive Assessment [MoCA] for MoCA) were made. Participants reported on the pleasantness, difficulty, and preference for each modality. Staff provided validity ratings for assessments. Participants' remote data were adjudicated by cognitive experts blinded to the in person-diagnosis (NC [ N =  44], MCI [ N =  35], Dementia [ N =  11], or other [ N =  3]). Results Remote assessments were rated as pleasant as in-person assessments by 74% of participants and equally difficult by 75%. Staff validity rating (video = 92%; phone = 87.5%) was good. Concordance between remote/in-person scores was generally moderate to good (r  = .3 −.8; p  < .05) except for TMT-A/OTMT-A (r  = .3; p  > .05). Agreement between remote/in-person adjudicated cognitive status was good (k  = .61–.64). Conclusions We found preliminary evidence that older adults, including those with cognitive impairment, can be assessed remotely using a modified UDSv3 research battery. Adjudication of cognitive status that relies on remotely collected data is comparable to classifications using in-person assessments. [ABSTRACT FROM AUTHOR]

Blood-based bioenergetic profiling provides a minimally invasive assessment of mitochondrial health shown to be related to key features of aging. Previous studies show that blood cells recapitulate mitochondrial alterations in the central nervous system under pathological conditions, including the development of Alzheimer's disease. In this study of nonhuman primates, we focus on mitochondrial function and bioenergetic capacity assessed by the respirometric profiling of monocytes, platelets, and frontal cortex mitochondria. Our data indicate that differences in the maximal respiratory capacity of brain mitochondria are reflected by CD14+ monocyte maximal respiratory capacity and platelet and monocyte bioenergetic health index. A subset of nonhuman primates also underwent [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to assess brain glucose metabolism. Our results indicate that platelet respiratory capacity positively correlates to measures of glucose metabolism in multiple brain regions. Altogether, the results of this study provide early evidence that blood-based bioenergetic profiling is related to brain mitochondrial metabolism. While these measures cannot substitute for direct measures of brain metabolism, provided by measures such as FDG-PET, they may have utility as a metabolic biomarker and screening tool to identify individuals exhibiting systemic bioenergetic decline who may therefore be at risk for the development of neurodegenerative diseases.

BackgroundLong acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers.ObjectiveThe present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD.MethodsThis randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n = 12), 40 IU of insulin detemir (n = 12), or 40 IU of regular insulin (n = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer's Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers.ResultsThe regular insulin treated group had better memory after two and four months compared with placebo (p

More than 5 million Americans are living with Alzheimer's disease (AD) today, and nearly two-thirds of Americans with AD are women. This sex difference may be due to the higher longevity women generally experience; however, increasing evidence suggests that longevity alone is not a sufficient explanation and there may be other factors at play. The Alzheimer's Association convened an expert think tank to focus on the state of the science and level of evidence around gender and biological sex differences for AD, including the knowledge gaps and areas of science that need to be more fully addressed. This article summarizes the think tank discussion, moving forward a research agenda and funding program to better understand the biological underpinnings of sex- and gender-related disparities of risk for AD.