Cognitively Normal Subjects Research Articles

Longitudinal Assessment of Amyloid-β Deposition by [18F]-Flutemetamol PET Imaging Compared With [11C]-PIB Across the Spectrum of Alzheimer's Disease.

This study evaluates the longitudinal changes in the amyloid-β (Aβ) deposition with [18F]-flutemetamol (FMM) PET imaging across the spectrum of Alzheimer’s disease (AD), compared with [11C]-Pittsburgh Compound-B (PIB) PET. Eleven AD, 17 mild cognitive impairment (MCI) and 13 cognitively normal (CN) subjects underwent neuropsychological assessment and amyloid PET imaging using [18F]-FMM and [11C]-PIB during a follow-up period. Regions of interest were defined on co-registered MRI, and the FMM and PIB standardized uptake value ratio (SUVR) was used in the same cortical regions. The annual rate of change in FMM and PIB SUVRs was calculated. Cortical FMM SUVR in amyloid-positive subjects increased over a follow-up of 3.1 ± 0.5 years. An individual FMM SUVR was significantly correlated with PIB SUVR at baseline and at follow-up in the same AD, MCI, and CN subjects. The annual rate of increase in FMM SUVR was significantly greater in typical amyloid-positive (0.033 ± 0.023, n = 7), focal positive MCI (0.076 ± 0.034, n = 4) and positive CN (0.039 ± 0.027, n = 4) while that in AD (0.020 ± 0.018, n = 11) was smaller. Among amyloid-positive patients, the baseline FMM SUVR was inversely related with the increased rate in FMM SUVR (r=−0.44, n = 26, p < 0.05). An individual annual rate in change of cortical FMM SUVR was significantly correlated with that in cortical PIB SUVR. Our results suggest that the [18F]-FMM PET imaging can clarify the longitudinal assessment of Aβ deposition across the AD spectrum, similarly to [11C]-PIB PET. The Increase in Aβ deposition is faster in the predementia stage but not at a constant rate across the clinical stages of the AD spectrum.

OLFACTORY DEFICITS AND FUNCTIONAL CONNECTIVITY DISRUPTIONS IN PATIENTS WITH SUBJECTIVE COGNITIVE DECLINE (SCD)

Patients with subjective cognitive decline (SCD) are the high risk group for developing Alzheimer's disease (AD). Olfactory fMRI)was used to investigate olfactory activation and connectivity in SCD and cognitively normal (CN) adults, and to explore early functional markers for AD. Twenty SCD participants and 20 age-, education-level-matched CN elderly were recruited. Full set of neurocognitive tests, olfactory threshold and identification battery tests (Osmic Enterprise, LLC), and olfactory fMRI were administered to each participant. The differences in olfactory behavior scores, neuropsychological scales, and task-fMRI brain activation maps between the two groups were analyzed, and the correlation between brain activation and olfactory behavior scores was evaluated. Brain regions, which had significant different activations were used as seeds for resting-state functional connection analysis. There was no statistically significant difference in olfactory threshold between SCD and CN subjects, but SCD showed a significant decrease in olfactory identification ability (p < 0.05). There was also a significant decrease (p < 0.05) in the SCD self-rating scale, the immediate and delayed test of Philadelphia verbal learning, while the remaining neuropsychological scales were within normal range. In the olfactory fMRI, activation in bilateral primary olfactory cortex was significantly reduced in SCD patients, including bilateral entorhinal cortex, amygdala, piriform cortex, anterior olfactory nucleus, and head of the hippocampus (Fig. 1). The resting-state functional connectivity with the bilateral primary olfactory cortex (POC) showed that the functional connections between the POC and frontal cortex and the default mode network (DMN) were significantly weakened in the SCD patients (Fig. 2 and 3, AlphaSim correction with voxel level p<0.01 and cluster level p<0.05).

P1‐271: CSF GLUCOSE TRACKS BRAAK STAGE TAU DEPOSITION

Type 2 diabetes is a known risk factor for Alzheimer's disease (AD). Tau hyperphosphorylation, a marker of neurodegeneration, occurs in the brain of both type 2 diabetes and AD patients. Furthermore, CSF glucose is strongly associated with CSF total tau protein levels in AD patients. It is not known if CSF glucose is associated with regional tau deposition, however, and if such associations regionally vary depending on AD genetic risk factors, baseline diagnosis, or sex. Data from 142 aged adults was downloaded from the Alzheimer's Disease Neuroimaging Initiative (ADNI). CSF glucose levels were derived from standard lab assays. Fully preprocessed F18-AV-1451 positron emission tomography scans where coregistered to the subject's T1-weighted image in native space. Mean regional uptake in FreeSurfer defined regions was divided by mean uptake in the inferior cerebellum reference region to derive Standardized Uptake Value Ratios (SUVRs). Multiple linear regression regressed CSF glucose against regional AV-1451 SUVR in regions of interest. Due to the large number of cognitive normal subjects scanned (n=103), analyses were restricted to Braak stages 1/2 and 3/4. Interactions between CSF glucose and gender, family history of AD, and beta-amyloid (Aβ) status were also explored. Higher CSF glucose was significantly associated with lower tau deposition in the caudal anterior cingulate gyrus (Braak 4). Moderation analyses showed that only Mild Cognitive Impairment (MCI) and AD participants drove this association. A gender x CSF glucose interaction showed that higher CSF glucose was related to lower hippocampal tau deposition (Braak 2) in women but not men. Finally, for subjects with AD parental history, higher CSF glucose was linked to less regional tau deposition in all Braak stage 3 and 4 regions, particularly the lingual gyrus, fusiform gyrus, and isthmus of cingulate gyrus. Taken together, these results suggest that higher CSF glucose levels may be protective against early tau deposition among women, as well as later tau deposition among subjects with cognitive impairment or a parental history of AD. Future work will examine similar associations with peripheral insulin resistance and moderation by regional amyloid deposition.

Increased cerebral blood flow with increased amyloid burden in the preclinical phase of alzheimer's disease.

Arterial spin labeling (ASL) is an emerging MRI technique for noninvasive measurement of cerebral blood flow (CBF) that has been used to show hemodynamic changes in the brains of people with Alzheimer's disease (AD). CBF changes have been measured using positron emission tomography (PET) across the AD spectrum, but ASL showed limited success in measuring CBF variations in the preclinical phase of AD, where amyloid β (Aβ) plaques accumulate in the decades prior to symptom onset. To investigate the relationship between CBF measured by multiphase-pseudocontinuous-ASL (MP-PCASL) and Aβ burden as measured by 11 C-PiB PET imaging in a study of cognitively normal (CN) subjects age over 65. Cross-sectional. Forty-six CN subjects including 33 with low levels of Aβ burden and 13 with high levels of Aβ. 3T/3D MP-PCASL. The MP-PCASL method was chosen because it has a high signal-to-noise ratio. Furthermore, the data were analyzed using an efficient processing pipeline consisting of motion correction, ASL motion correction imprecision removal, temporal and spatial filtering, and partial volume effect correction. General Linear Model. In CN subjects positive for Aβ burden (n = 13), we observed a positive correlation between CBF and Aβ burden in the hippocampus, amygdala, caudate (P < 0.01), frontal, temporal, and insula (P < 0.05). To the best of our knowledge, this is the first study using MP-PCASL in the study of AD, and the results suggest a potential compensatory hemodynamic mechanism that protects against pathology in the early stages of AD. 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:505-513.

Diagnostic performance of new and classic CSF biomarkers in age-related dementias.

The identification of diagnostic-prognostic biomarkers of dementia has become a global priority due to the prevalence of neurodegenerative diseases in aging populations. The objective of this study was to assess the diagnostic performance of cerebrospinal fluid (CSF) biomarkers across patients affected by either Alzheimer’s disease (AD), tauopathies other than AD (TP), or vascular dementia (VD), and cognitively normal subjects (CNS). One hundred fifty-three patients were recruited and tested for classical AD CSF biomarkers- Amyloid-ß42 and tau proteins - and novel candidate biomarkers - neurofilament (NF-) light and microRNA (miR) -21, -125b, -146a, and -222.All dementia patients had significantly higher concentrations of NF-light compared to CNS, with the TP group displaying the highest NF-light values. A significant inverse correlation was also observed between NF-light and cognitive impairment. Of the four miRNAs analyzed, miR-222 levels were significantly increased in VD patients compared to both CNS and AD. In addition, while NF-light showed a better diagnostic performance than miR-222 and classical AD biomarkers in differentiating TP and VD from CNS, classical AD biomarkers revealed higher performance in discriminating AD from non-AD disorders.Overall, our results suggest that CSF NF-light and miR-222 are promising biomarkers that may help to diagnose non-AD disorders.

¹⁸F]THK5351 PET Imaging in Patients with Mild Cognitive Impairment.

Background and PurposeMild cognitive impairment (MCI) is a condition with diverse clinical outcomes and subgroups. Here we investigated the topographic distribution of tau in vivo using the positron emission tomography (PET) tracer [18F]THK5351 in MCI subgroups.MethodsThis study included 96 participants comprising 38 with amnestic MCI (aMCI), 21 with nonamnestic MCI (naMCI), and 37 with normal cognition (NC) who underwent 3.0-T MRI, [18F]THK5351 PET, and detailed neuropsychological tests. [18F]flutemetamol PET was also performed in 62 participants. The aMCI patients were further divided into three groups: 1) verbal-aMCI, only verbal memory impairment; 2) visual-aMCI, only visual memory impairment; and 3) both-aMCI, both visual and verbal memory impairment. Voxel-wise statistical analysis and region-of-interest -based analyses were performed to evaluate the retention of [18F]THK5351 in the MCI subgroups. Subgroup analysis of amyloid-positive and -negative MCI patients was also performed. Correlations between [18F]THK5351 retention and different neuropsychological tests were evaluated using statistical parametric mapping analyses.Results[18F]THK5351 retention in the lateral temporal, mesial temporal, parietal, frontal, posterior cingulate cortices and precuneus was significantly greater in aMCI patients than in NC subjects, whereas it did not differ significantly between naMCI and NC participants. [18F] THK5351 retention was greater in the both-aMCI group than in the verbal-aMCI and visualaMCI groups, and greater in amyloid-positive than amyloid-negative MCI patients. The cognitive function scores were significantly correlated with cortical [18F]THK5351 retention.Conclusions[18F]THK5351 PET might be useful for identifying distinct topographic patterns of [18F]THK5351 retention in subgroups of MCI patients who are at greater risk of the progression to Alzheimer's dementia.

Pattern of Altered Plasma Elemental Phosphorus, Calcium, Zinc, and Iron in Alzheimer\u2019s Disease

Metal/mineral dyshomeostasis has been implicated in the development of Alzheimer’s disease (AD). The aim of the study was to investigate the difference in absolute and percentage levels of plasma phosphorus, calcium, iron, zinc, copper, selenium in cognitively normal (CN) and AD subjects. Total reflection X-ray fluorescence (TXRF) spectroscopy was used to detect plasma metals/minerals in CN and AD subjects (n = 44 per group). TXRF detected significantly increased plasma levels of phosphorus (p = 1.33 × 10−12) and calcium (p = 0.025) in AD compared to CN subjects, with higher phosphorus/calcium (p = 2.55 × 10−14) ratio in the former. Percentage concentrations calculated for phosphorus, calcium, iron, zinc, copper, selenium by dividing the concentration of each element by the total concentration of these elements and multiplying by 100%, demonstrated phosphorus was higher in AD compared to CN subjects, while calcium, iron, zinc, copper and selenium were lower in AD subjects, with area under the curves as high as 0.937 (p = 6 × 10−5) computed from receiver operating curves. With exclusion of high levels of phosphorus and calcium from percentage calculations, iron levels remained low in AD whereas zinc was higher in AD, and copper and selenium levels were similar. We demonstrate altered distribution of elements in the plasma of AD subjects with high interdependencies between elemental levels and propose the potential of TXRF measurements for disease monitoring.

Cerebrospinal Fluid Levels of β-Amyloid 40 and β-Amyloid 42 are Proportionately Decreased in Amyloid Positron-Emission Tomography Negative Idiopathic Normal-Pressure Hydrocephalus Patients.

Background and PurposeCerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) could be misleading in idiopathic normal-pressure hydrocephalus (iNPH). We therefore investigated the CSF biomarkers in 18F-florbetaben amyloid-negative positron-emission tomography (PET) [amyloid PET(−)] iNPH, amyloid-positive PET [amyloid PET(+)] AD, and cognitively normal (CN) subjects.MethodsTen amyloid PET(+) AD patients (56.7±5.6 years old, mean±standard deviation), 10 amyloid PET(−) iNPH patients (72.8±4.5 years old), and 8 CN subjects (61.2±6.5 years old) were included. We measured the levels of β-amyloid (Aβ)40, Aβ42, total tau (t-tau) protein, and phosphorylated tau (p-tau) protein in the CSF using enzyme-linked immunosorbent assays.ResultsThe level of Aβ42 and the Aβ42/Aβ40 ratio in the CSF were significantly lower in AD than in iNPH or CN subjects. The Aβ40 level did not differ significantly between AD and iNPH (p=1.000), but it did between AD and CN subjects (p=0.032). The levels of both t-tau and p-tau were higher in AD than in iNPH or CN subjects. The levels of Aβ42, Aβ40, t-tau, and p-tau were lower in iNPH than in CN subjects, but there was no significant difference after controlling for age.ConclusionsOur results suggest that the mechanism underlying low CSF Aβ levels differs between amyloid PET(−) iNPH and amyloid PET(+) AD subjects. The lower levels of all CSF biomarkers in iNPH patients might be due to reduced clearances from extracellular fluid and decreased brain metabolism of the periventricular zone in iNPH resulting from glymphatic dysfunction.

Modified Mediterranean-Ketogenic Diet Modulates Gut Microbiome and Short-Chain Fatty Acids in Association with Alzheimer's Disease Markers in Subjects with Mild Cognitive Impairment

Background: Alzheimer's disease (AD) prevalence is increasing, but its etiology remains elusive. Gut microbes can contribute to AD pathology and may help identifying novel markers and therapies against AD. Methods: A randomized crossover pilot study of modified Mediterranean-ketogenic diet (MMKD) and American Heart Association Diet (AHAD) intervention is performed on 17 subjects (age: 63.4±3.7yr), of which 11 have mild cognitive impairment (MCI), while 6 are cognitively normal (CN). Subjects undergo MMKD and AHAD intervention for 6-weeks separated by 6-weeks washout periods. Gut microbiome, fecal short-chain fatty acids (SCFAs), and markers of AD in cerebrospinal fluid (CSF) including amyloid β (Aβ)-40 and As-42, total tau, and phosphorylated tau-181 (tau-p181) are measured at before and after diet interventions. Findings: At baseline, MCI and CN subjects show no notable difference in microbiome diversity but several unique microbial signatures are detected in MCI subjects. Proteobacteria correlate positively with Aβ-42: Aβ-40 while fecal propionate and butyrate correlates negatively with Aβ-42 in MCI subjects. Several bacteria are differently affected by the two diets with distinct patterns between CN and MCI subjects. Notably, the abundance of Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae and Erysipelotriaceae increases while that of Bifidobacterium and Lachnobacterium reduces on MMKD, while AHAD increases Mollicutes. MMKD slightly reduces fecal lactate and acetate while increasing propionate and butyrate. Conversely, AHAD increases acetate and propionate while reducing butyrate. Interpretation: The data suggest that specific gut microbial signatures may predict the MCI and that the MMKD can modulate the gut microbiome and metabolites in association with improved AD biomarkers. Funding Statement: The work was supported by National Institutes of Health grant P30AG049638; R01AG055122 (SC), the Department of Defense funding W81XWH-18-1-0118 (HY), as well as the funds and services provided from Center for Diabetes, Obesity and Metabolism, Wake Forest Baptist Medical Center and National Center for Advancing Translational Sciences (NCATS), National Institutes of Health funded Wake Forest Clinical and Translational Science Institute (WF CTSI) through Grant Award Number UL1TR001420. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study was approved by the Institutional Review Boards of the Wake Forest School of Medicine and was conducted in the Wake Forest Clinical Research Units. All protocols related to the cohorts involved in the study have been reviewed and approved by the Institutional Review Board of the Wake Forest School of Medicine. All experiments and samplings were carried out in accordance with ethical and biosafety protocols approved by the Institutional guidelines.

Correlation between visual association memory test and structural changes in patients with Alzheimer's disease and amnestic mild cognitive impairment

Visual association memory test (VAMT) is a brief 6-point cognition test that has been shown to be effective in differentiating Alzheimer's disease (AD) from other types of dementia. This study aimed to investigate the correlation of the VAMT performance with amyloid plaque burden and hippocampal atrophy. Fourteen patients with AD, 29 with amnestic mild cognitive impairment (aMCI), and 11 normal cognition (NC) subjects were recruited. Brain magnetic resonance imaging (MRI) and [18F]AV-45 positron emission tomography (PET) were performed to evaluate hippocampal atrophy and amyloid plaque burden. The VAMT median score and interquartile range of the NC, aMCI and AD groups were 6 (6-6), 2 (0-4), and 0 (0-1), respectively (p<0.001). The hippocampal atrophy was correlated with VAMT results across each group. The VAMT score was correlated with the occipital and parietal cortical [18F]AV-45 uptake in the NC group, and with the frontal, parietal and precuneus uptake in the aMCI group. However, no correlation between VAMT score and [18F]AV-45 uptake was found in the AD group. The VAMT can be an adjunctive cognitive test to identify patients with AD, and the early amyloid plaque accumulation is correlated with VAMT scores in patients with aMCI and even NC subjects.

Subjective memory complaint as a useful tool for the early detection of Alzheimer's disease.

PurposeDespite their high prevalence in Alzheimer’s disease (AD), and the increasing level of concern they have generated, subjective memory complaints (SMCs) are poorly understood. This study investigated the accuracy with which SMC can separate mild cognitive impairment (MCI) and early AD from cognitive normal (CN), and explored whether the discrimination ability is similar to or better than that of the Mini-Mental State Exam (MMSE).Patients and methodsThis study recruited 175 CN subjects, 52 with MCI, and 66 with probable AD aged 60 years or older. To test the independent contributions of SMC and MMSE scores to the classification of cognitive status (CN vs MCI or early AD), logistic regression analyses were performed, adjusting for the following potential confounding variables: age, gender, Frontal Assessment Battery score, modified Hachinski Ischemic Scale score, and apolipoprotein E ε4 status. Receiver operating characteristic (ROC) curve analyses were used to determine the discrimination accuracy of SMC and MMSE scores, and area under the ROC curve (AUROC) was also calculated.ResultsIn the highly educated (≥7 years), nondepressed (Geriatric Depression Scale ≤15) subgroup, SMC showed good accuracy in discriminating cognitively impaired subjects from CN after adjusting for potential confounding variables (the AUROC of the adjusted SMC was 0.841 for MCI discrimination, and it was 0.858 for MCI plus early AD discrimination). Both SMC and MMSE scores significantly contributed to differentiating between CN and MCI (OR=2.372, 95% CI=1.086–5.177; OR=0.730, 95% CI=0.566–0.941, respectively) after adjusting for the same covariates. However, in the highly educated and nondepressed subgroups, SMC showed significant predictive power for MCI from CN (OR=3.119, 95% CI=1.190–8.176; OR=3.328, 95% CI=1.320–8.396, respectively), whereas MMSE scores did not.ConclusionOur findings support the usefulness of SMC, which was comparable or even superior to MMSE scores, for detecting MCI or early AD.

Retinal tissue hypoperfusion in patients with clinical Alzheimer\u2019s disease

BackgroundIt remains unknow whether retinal tissue perfusion occurs in patients with Alzheimer’s disease. The goal was to determine retinal tissue perfusion in patients with clinical Alzheimer’s disease (CAD).MethodsTwenty-four CAD patients and 19 cognitively normal (CN) age-matched controls were recruited. A retinal function imager (RFI, Optical Imaging Ltd., Rehovot, Israel) was used to measure the retinal blood flow supplying the macular area of a diameter of 2.5 mm centered on the fovea. Blood flow volumes of arterioles (entering the macular region) and venules (exiting the macular region) of the supplied area were calculated. Macular blood flow was calculated as the average of arteriolar and venular flow volumes. Custom ultra-high-resolution optical coherence tomography (UHR–OCT) was used to calculate macular tissue volume. Automated segmentation software (Orion, Voxeleron LLC, Pleasanton, CA) was used to segment six intra-retinal layers in the 2.5 mm (diameter) area centered on the fovea. The inner retina (containing vessel network), including retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer (INL) and outer plexiform layer (OPL), was segmented and tissue volume was calculated. Perfusion was calculated as the flow divided by the tissue volume.ResultsThe tissue perfusion in CAD patients was 2.58 ± 0.79 nl/s/mm3 (mean ± standard deviation) and was significantly lower than in CN subjects (3.62 ± 0.44 nl/s/mm3, P < 0.01), reflecting a decrease of 29%. The flow volume was 2.82 ± 0.92 nl/s in CAD patients, which was 31% lower than in CN subjects (4.09 ± 0.46 nl/s, P < 0.01). GCIPL tissue volume was 0.47 ± 0.04 mm3 in CAD patients and 6% lower than CN subjects (0.50 ± 0.05 mm3, P < 0.05). No other significant alterations were found in the intra-retinal layers between CAD and CN participants.ConclusionsThis study is the first to show decreased retinal tissue perfusion that may be indicative of diminished tissue metabolic activity in patients with clinical Alzheimer’s disease.

Magnitude Squared Coherence Method based on Weighted Canonical Correlation Analysis for EEG Synchronization Analysis in Amnesic Mild Cognitive Impairment of Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) increases the risk of amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). aMCI is the transitory stage from normal cognition to AD, which seriously impacts the quality of human life, especially for old people. Electroencephalography (EEG) coherence can assess the functional connectivity between different brain regions, which is an effective way to research the pathogenesis of aMCI and distinguish aMCI patients from normal cognitive subjects. In this paper, we propose a new EEG coherence approach named magnitude squared coherence based on weighted canonical correlation analysis (WCCA-MSC) which improves the accuracy in coherence estimation by the means of weighting. In comparison to the magnitude squared coherence based on canonical correlation analysis (CCA-MSC) and magnitude squared coherence based on reduced-rank canonical correlation analysis (RCCA-MSC), the proposed WCCA-MSC behaves better in the influence of noise and relative amplitude of frequency components and provides more accuracy at non-coherent frequencies. The application of the new method to EEG signals showed increased coherence in Delta and Theta frequency bands decreased coherence in an Alpha frequency band in aMCI patients. Considering its property of better performance, the proposed coherence method is of great advantage in analyzing the pathogenesis of aMCI with T2DM.

Neuroimaging Characteristics of Small-Vessel Disease in Older Adults with Normal Cognition, Mild Cognitive Impairment, and Alzheimer Disease

Introduction: Cerebral small-vessel disease (SVD) represents the most frequent type of vascular brain lesions, often coexisting with Alzheimer disease (AD). By quantifying white matter hyperintensities (WMH) and hippocampal and parietal atrophy, we aimed to describe the prevalence and severity of SVD among older adults with normal cognition (NC), mild cognitive impairment (MCI), and probable AD and to describe associated risk factors. Methods: This study included 105 older adults evaluated with magnetic resonance imaging and clinical and neuropsychological tests. We used the Fazekas scale (FS) for quantification of WMH, the Scheltens scale (SS) for hippocampal atrophy, and the Koedam scale (KS) for parietal atrophy. Logistic regression models were performed to determine the association between FS, SS, and KS scores and the presence of NC, MCI, or probable AD. Results: Compared to NC subjects, SVD was more prevalent in MCI and probable AD subjects. After adjusting for confounding factors, logistic regression showed a positive association between higher scores on the FS and probable AD (OR = 7.6, 95% CI 2.7–20, p < 0.001). With the use of the SS and KS (OR = 4.5, 95% CI 3.5–58, p = 0.003 and OR = 8.9, 95% CI 1–72, p = 0.04, respectively), the risk also remained significant for probable AD. Conclusions: These results suggest an association between severity of vascular brain lesions and neurodegeneration.

Disrupted reward and cognitive control networks contribute to anhedonia in depression

Neuroimaging studies have identified that anhedonia, a core feature of major depressive disorder (MDD), is associated with dysfunction in reward and cognitive control processing. However, it is still not clear how the reward network (β-network) and the cognitive control network (δ-network) are linked to biased anhedonia in MDD patients. Sixty-eight MDD patients and 64 cognitively normal (CN) subjects underwent a resting-state functional magnetic resonance imaging scan. A 2*2 ANCOVA analysis was used to explore the differences in the nucleus accumbens-based, voxelwise functional connectivity (FC) between the groups. Then, the β- and δ-networks were constructed, and the FC intensities were compared within and between theβ- and δ-networks across all subjects. Multiple linear regression analyses were also employed to investigate the relationships between the neural features of the β- and δ-networks and anhedonia in MDD patients. Compared to the CN subjects, the MDD patients showed synergistic functional decoupling in both the β- and δ-networks, as well as decreased FC intensities in the intra- and inter- β- and δ-networks. In addition, the FC in both the β- and δ-networks was significantly correlated with anhedonia severity in the MDD patients. Importantly, the integrated neural features of the β- and δ-networks could more precisely predict anhedonic symptoms. These findings initially demonstrated that the imbalance between β- and δ-network activity successfully predicted anhedonia severity and suggested that the neural features of both the β- and δ-networks could represent a fundamental mechanism that underlies anhedonia in MDD patients.

Classifying Alzheimer's disease with brain imaging and genetic data using a neural network framework.

A long-standing question is how to best use brain morphometric and genetic data to distinguish Alzheimer's disease (AD) patients from cognitively normal (CN) subjects and to predict those who will progress from mild cognitive impairment (MCI) to AD. Here, we use a neural network (NN) framework on both magnetic resonance imaging-derived quantitative structural brain measures and genetic data to address this question. We tested the effectiveness of NN models in classifying and predicting AD. We further performed a novel analysis of the NN model to gain insight into the most predictive imaging and genetics features and to identify possible interactions between features that affect AD risk. Data were obtained from the AD Neuroimaging Initiative cohort and included baseline structural MRI data and single nucleotide polymorphism (SNP) data for 138 AD patients, 225 CN subjects, and 358 MCI patients. We found that NN models with both brain and SNP features as predictors perform significantly better than models with either alone in classifying AD and CN subjects, with an area under the receiver operating characteristic curve (AUC) of 0.992, and in predicting the progression from MCI to AD (AUC=0.835). The most important predictors in the NN model were the left middle temporal gyrus volume, the left hippocampus volume, the right entorhinal cortex volume, and the APOE (a gene that encodes apolipoprotein E) ɛ4 risk allele. Furthermore, we identified interactions between the right parahippocampal gyrus and the right lateral occipital gyrus, the right banks of the superior temporal sulcus and the left posterior cingulate, and SNP rs10838725 and the left lateral occipital gyrus. Our work shows the ability of NN models to not only classify and predict AD occurrence but also to identify important AD risk factors and interactions among them.

Activated forms of astrocytes with higher GLT-1 expression are associated with cognitive normal subjects with Alzheimer pathology in human brain

Although the cognitive impairment in Alzheimer’s disease (AD) is believed to be caused by amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), several postmortem studies have reported cognitive normal subjects with AD brain pathology. As the mechanism underlying these discrepancies has not been clarified, we focused the neuroprotective role of astrocytes. After examining 47 donated brains, we classified brains into 3 groups, no AD pathology with no dementia (N-N), AD pathology with no dementia (AD-N), and AD pathology with dementia (AD-D), which represented 41%, 21%, and 38% of brains, respectively. No differences were found in the accumulation of Aβ plaques or NFTs in the entorhinal cortex (EC) between AD-N and AD-D. Number of neurons and synaptic density were increased in AD-N compared to those in AD-D. The astrocytes in AD-N possessed longer or thicker processes, while those in AD-D possessed shorter or thinner processes in layer I/II of the EC. Astrocytes in all layers of the EC in AD-N showed enhanced GLT-1 expression in comparison to those in AD-D. Therefore these activated forms of astrocytes with increased GLT-1 expression may exert beneficial roles in preserving cognitive function, even in the presence of Aβ and NFTs.

Abstract WP416: Comparison of Ex-vivo Human Leptomeningeal Arteriole Function in Cognitively Normal and Dementia Disorders From Rapid Autopsy Brain Donors

Vascular dysfunction is increasingly recognized in the pathophysiology of dementia disorders such as Alzheimer’s disease (AD). We showed that exposure to β-amyloid (Aβ) and medin (aging-associated amyloid) cause cerebrovascular endothelial dysfunction which may be involved with cognitive dysfunction. We aim to test the hypotheses that patients with AD, mild cognitive impairment (MCI) and vascular dementia (VD) differ in cerebrovascular arteriole function and have worse vascular response to amyloid proteins when compared to cognitively normal (CN) patients. Methods: Under a Brain Donation Rapid Autopsy Program, leptomeningeal arterioles were isolated from 44 donors (89.6±1.4 years), cannulated, pressurized and baseline endothelium-dependent dilation (EDD, acetylcholine max 10 -4 M) and smooth muscle dilation (SMD, papaverine or DETA-Nonoate) were measured and compared among CN, MCI, AD and VD subjects. % change from baseline responses were also measured following 1 hour exposure to Aβ42 (0.5 or 2 μM) or medin (5 μM). Results: There was no difference in baseline EDD and SMD among the groups (Fig. A,B). Overall, Aβ caused reduction in EDD (46.2±3.8 vs. 75.3±3.5% baseline, p&lt;0.001) and SMD (83.6±2.8 vs. 90.7±2.6% baseline, p=0.02). Medin caused similar reduction in EDD (35.7±4.7 vs. 77.5±4% baseline, p&lt;0.001) and SMD (70.9±5.4 vs. 89.3±3% baseline, p=0.006). Dilator responses to Aβ and medin did not differ among the groups (Fig. C-F). Conclusions: Contrary to our hypotheses, leptomeningeal arteriole function did not differ among CN, MCI, AD and VD patients. Aβ and medin caused endothelium and smooth muscle dysfunction, but the degree of dysfunction was not different among the groups. The results may point to the importance of duration/degree of exposure to vasculogenic amyloid proteins (the ‘milieu’) rather than intrinsic differences in arteriole properties in accounting for vascular dysfunction leading to cognitive dysfunction in dementia disorders.

Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages

IntroductionGenetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated. MethodsWe conducted genome-wide association studies for AD-related endophenotypes including hippocampal volume, logical memory scores, and cerebrospinal fluid Aβ42 and total/phosphorylated tau in cognitively normal (CN), mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative study. ResultsIn CN subjects, study-wide significant (P < 8.3 × 10−9) loci were identified for total tau near SRRM4 and C14orf79 and for hippocampal volume near MTUS1. In mild cognitive impairment subjects, study-wide significant association was found with single nucleotide polymorphisms (SNPs) near ZNF804B for logical memory test of delayed recall scores. We found consistent expression patterns of C14orf40 and MTUS1 in carriers with risk alleles of expression SNPs and in brains of AD patients, compared with in the noncarriers and in brains of controls. DiscussionOur findings for AD-related brain changes before AD provide insight about early AD-related biological processes.

Mediating Role of the Reward Network in the Relationship between the Dopamine Multilocus Genetic Profile and Depression.

Multiple genetic loci in the dopamine (DA) pathway have been associated with depression symptoms in patients with major depressive disorder (MDD). However, the neural mechanisms underlying the polygenic effects of the DA pathway on depression remain unclear. We used an imaging genetic approach to investigate the polygenic effects of the DA pathway on the reward network in MDD. Fifty-three patients and 37 cognitively normal (CN) subjects were recruited and underwent resting-state functional magnetic resonance imaging (R-fMRI) scans. Multivariate linear regression analysis was employed to measure the effects of disease and multilocus genetic profile scores (MGPS) on the reward network, which was constructed using the nucleus accumbens (NAc) functional connectivity (NAFC) network. DA-MGPS was widely associated within the NAFC network, mainly in the inferior frontal cortex, insula, hypothalamus, superior temporal gyrus, and occipital cortex. The pattern of DA-MGPS effects on the fronto-striatal pathway differed in MDD patients compared with CN subjects. More importantly, NAc-putamen connectivity mediates the association between DA MGPS and anxious depression traits in MDD patients. Our findings suggest that the DA multilocus genetic profile makes a considerable contribution to the reward network and anxious depression in MDD patients. These results expand our understanding of the pathophysiology of polygenic effects underlying brain network abnormalities in MDD.