Alzheimer Disease Cerebrospinal Fluid Biomarkers in a Tertiary Neurology Practice.

OBJECTIVE: To evaluate the performance of Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers in a tertiary neurology clinic setting with high frequency of non-AD cases, including normal pressure hydrocephalus (NPH). METHODS: There were 534 patients who underwent AD CSF biomarkers (Roche Elecsys Aß42, p-Tau181, total-Tau) from April 1, 2020, through April 23, 2021. A behavioral neurologist blinded to CSF results assigned a clinical diagnosis retrospectively on the basis of consensus criteria, and a neuroradiologist blinded to the diagnosis and CSF studies graded brain magnetic resonance images for indicators of CSF dynamics disorders. Associations between biomarkers, diagnoses, and imaging were assessed by χ2, analysis of covariance, and linear regression methods. RESULTS: Median age at time of testing was 67 years (range, 19 to 96 years), median symptom duration was 2 years (range, 0.4 to 28 years), and median Short Test of Mental Status score was 30 (range, 0 to 38). Clinical diagnoses significantly correlated with different CSF biomarker values (χ2=208.3; P=10e-4). p-Tau181/Aß42 ratios above 0.023 positively correlated with Alzheimer dementia (more than individual measures). This ratio also had the best performance for differentiating Alzheimer dementia from NPH (area under the curve, 0.869). Imaging markers supportive of CSF dynamics disorders correlated with low Aß42, p-Tau181, and total-Tau. CONCLUSION: In a heterogeneous clinical population, abnormal p-Tau181/Aß42 ratios (>0.023) have the strongest association with Alzheimer dementia and probably represent a comorbid AD pathologic component in persons clearly matching non-AD neurodegenerative syndromes. Altered CSF dynamics were associated with lower concentrations of AD CSF biomarkers regardless of clinical diagnosis, but the ratio compensates for these changes. In the appropriate clinical setting, an isolated abnormal Aß42 should prompt consideration of NPH.

Altered resting-state functional connectivity and dynamic network properties in cognitive impairment: an independent component and dominant-coactivation pattern analyses study.

Introduction: Cognitive impairment (CI) due to Alzheimer's disease (AD) encompasses a decline in cognitive abilities and can significantly impact an individual's quality of life. Early detection and intervention are crucial in managing CI, both in the preclinical and prodromal stages of AD prior to dementia. Methods: In this preliminary study, we investigated differences in resting-state functional connectivity and dynamic network properties between 23 individual with CI due to AD based on clinical assessment and 15 healthy controls (HC) using Independent Component Analysis (ICA) and Dominant-Coactivation Pattern (d-CAP) analysis. The cognitive status of the two groups was also compared, and correlations between cognitive scores and d-CAP switching probability were examined. Results: Results showed comparable numbers of d-CAPs in the Default Mode Network (DMN), Executive Control Network (ECN), and Frontoparietal Network (FPN) between HC and CI groups. However, the Visual Network (VN) exhibited fewer d-CAPs in the CI group, suggesting altered dynamic properties of this network for the CI group. Additionally, ICA revealed significant connectivity differences for all networks. Spatial maps and effect size analyses indicated increased coactivation and more synchronized activity within the DMN in HC compared to CI. Furthermore, reduced switching probabilities were observed for the CI group in DMN, VN, and FPN networks, indicating less dynamic and flexible functional interactions. Discussion: The findings highlight altered connectivity patterns within the DMN, VN, ECN, and FPN, suggesting the involvement of multiple functional networks in CI. Understanding these brain processes may contribute to developing targeted diagnostic and therapeutic strategies for CI due to AD.

Combining Blood-Based Biomarkers and Structural MRI Measurements to Distinguish Persons with and without Significant Amyloid Plaques.

Background: Amyloid-ß (Aß) plaques play a pivotal role in Alzheimer's disease. The current positron emission tomography (PET) is expensive and limited in availability. In contrast, blood-based biomarkers (BBBMs) show potential for characterizing Aß plaques more affordably. We have previously proposed an MRI-based hippocampal morphometry measure to be an indicator of Aß plaques. Objective: To develop and validate an integrated model to predict brain amyloid PET positivity combining MRI feature and plasma Aß42/40 ratio. Methods: We extracted hippocampal multivariate morphometry statistics from MR images and together with plasma Aß42/40 trained a random forest classifier to perform a binary classification of participant brain amyloid PET positivity. We evaluated the model performance using two distinct cohorts, one from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the other from the Banner Alzheimer's Institute (BAI), including prediction accuracy, precision, recall rate, F1 score, and AUC score. Results: Results from ADNI (mean age 72.6, Aß+ rate 49.5%) and BAI (mean age 66.2, Aß+ rate 36.9%) datasets revealed the integrated multimodal (IMM) model's superior performance over unimodal models. The IMM model achieved prediction accuracies of 0.86 in ADNI and 0.92 in BAI, surpassing unimodal models based solely on structural MRI (0.81 and 0.87) or plasma Aß42/40 (0.73 and 0.81) predictors. CONCLUSIONS: Our IMM model, combining MRI and BBBM data, offers a highly accurate approach to predict brain amyloid PET positivity. This innovative multiplex biomarker strategy presents an accessible and cost-effective avenue for advancing Alzheimer's disease diagnostics, leveraging diverse pathologic features related to Aß plaques and structural MRI.

Machine Learning Predicts Conversion from Normal Aging to Mild Cognitive Impairment Using Medical History, APOE Genotype, and Neuropsychological Assessment.

Background: Identifying individuals at risk for mild cognitive impairment (MCI) is of urgent clinical need. Objective: This study aimed to determine whether machine learning approaches could harness longitudinal neuropsychology measures, medical data, and APOEɛ4 genotype to identify individuals at risk of MCI 1 to 2 years prior to diagnosis. Methods: Data from 676 individuals who participated in the 'APOE in the Predisposition to, Protection from and Prevention of Alzheimer's Disease' longitudinal study (N = 66 who converted to MCI) were utilized in supervised machine learning algorithms to predict conversion to MCI. Results: A random forest algorithm predicted conversion 1-2 years prior to diagnosis with 97% accuracy (p = 0.0026). The global minima (each individual's lowest score) of memory measures from the 'Rey Auditory Verbal Learning Test' and the 'Selective Reminding Test' were the strongest predictors. Conclusions: This study demonstrates the feasibility of using machine learning to identify individuals likely to convert from normal cognition to MCI.

Correlation studies of Hippocampal Morphometry and Plasma NFL Levels in Cognitively Unimpaired Subjects.

Alzheimer's disease(AD) is being the burden of society and family. Applying computing-aided strategies to reveal its pathology is one of the research highlights. Plasma neurofilament light (NFL) is an emerging noninvasive and economic biomarker for AD molecular pathology. It is valuable to reveal the correlations between the plasma NFL levels and neurodegeneration, especially hippcampal deformations at the preclinical stage. The negative correlation between plasma NFL levels and hippocampal volumes has been documented. However, the relationship between the plasma NFL levels and the hippocampal morphometry details at the preclinical stage is still elusive. This study seeks to demonstrate the capacity of our proposed surface-based hippocampal morphometry system to discern the plasma NFL positive (NFL+>41.9 pg/L) level and plasma NFL negative (NFL-<41.9pg/L) level and illustrate its superiority to the hippocampal volume measurement by drawing the cohort of 154 CU middle aged and elderly adults. We also apply this morphometry measure and a proposed sparse coding based classification algorithm to classify CU individuals with NFL+ and NFL- levels. Experimental results show that the proposed hippocampal morphometry system offers stronger statistical power to discriminate CU subjects with NFL+ and NFL- levels, comparing with the hippocampal volume measure. Furthermore, this system can discriminate plasma NFL levels in CU individuals (Accuracy=0.86). Both the group level and individual level analysis results indicate that the association between plasma NFL levels and the hippocampal shapes can be mapped at the preclinical stage.

A Surface-Based Federated Chow Test Model for Integrating APOE Status, Tau Deposition Measure, and Hippocampal Surface Morphometry.

BACKGROUND: Alzheimer's disease (AD) is the most common type of age-related dementia, affecting 6.2 million people aged 65 or older according to CDC data. It is commonly agreed that discovering an effective AD diagnosis biomarker could have enormous public health benefits, potentially preventing or delaying up to 40% of dementia cases. Tau neurofibrillary tangles are the primary driver of downstream neurodegeneration and subsequent cognitive impairment in AD, resulting in structural deformations such as hippocampal atrophy that can be observed in magnetic resonance imaging (MRI) scans. OBJECTIVE: To build a surface-based model to 1) detect differences between APOE subgroups in patterns of tau deposition and hippocampal atrophy, and 2) use the extracted surface-based features to predict cognitive decline. METHODS: Using data obtained from different institutions, we develop a surface-based federated Chow test model to study the synergistic effects of APOE, a previously reported significant risk factor of AD, and tau on hippocampal surface morphometry. RESULTS: We illustrate that the APOE-specific morphometry features correlate with AD progression and better predict future AD conversion than other MRI biomarkers. For example, a strong association between atrophy and abnormal tau was identified in hippocampal subregion cornu ammonis 1 (CA1 subfield) and subiculum in e4 homozygote cohort. CONCLUSION: Our model allows for identifying MRI biomarkers for AD and cognitive decline prediction and may uncover a corner of the neural mechanism of the influence of APOE and tau deposition on hippocampal morphology.

Plasma NfL is associated with the APOE ε4 allele, brain imaging measurements of neurodegeneration, and lower recall memory scores in cognitively unimpaired late-middle-aged and older adults.

BACKGROUND: Plasma neurofilament light (NfL) is an indicator of neurodegeneration and/or neuroaxonal injury in persons with Alzheimer's disease (AD) and a wide range of other neurological disorders. Here, we characterized and compared plasma NfL concentrations in cognitively unimpaired (CU) late-middle-aged and older adults with two, one, or no copies of the APOE ε4 allele, the major genetic risk factor for AD. We then assessed plasma NfL associations with brain imaging measurements of AD-related neurodegeneration (hippocampal atrophy and a hypometabolic convergence index [HCI]), brain imaging measurements of amyloid-ß plaque burden, tau tangle burden and white matter hyperintensity volume (WMHV), and delayed and total recall memory scores. METHODS: Plasma NfL concentrations were measured in 543 CU 69 ± 9 year-old participants in the Arizona APOE Cohort Study, including 66 APOE ε4 homozygotes (HM), 165 heterozygotes (HT), and 312 non-carriers (NC). Robust regression models were used to characterize plasma NfL associations with APOE ε4 allelic dose before and after adjustment for age, sex, and education. They were also used to characterize plasma NfL associations with MRI-based hippocampal volume and WMHV measurements, an FDG PET-based HCI, mean cortical PiB PET measurements of amyloid-ß plaque burden and meta-region-of-interest (meta-ROI) flortaucipir PET measurements of tau tangle burden, and Auditory Verbal Learning Test (AVLT) Delayed and Total Recall Memory scores. RESULTS: After the adjustments noted above, plasma NfL levels were significantly greater in APOE ε4 homozygotes and heterozygotes than non-carriers and significantly associated with smaller hippocampal volumes (r = - 0.43), greater tangle burden in the entorhinal cortex and inferior temporal lobes (r = 0.49, r = 0.52, respectively), and lower delayed (r = - 0.27), and total (r = - 0.27) recall memory scores (p < 0.001). NfL levels were not significantly associated with PET measurements of amyloid-ß plaque or total tangle burden. CONCLUSIONS: Plasma NfL concentrations are associated with the APOE ε4 allele, brain imaging biomarkers of neurodegeneration, and less good recall memory in CU late-middle-aged and older adults, supporting its value as an indicator of neurodegeneration in the preclinical study of AD.

Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy.

Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as "small vessel disease" or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia.

Hippocampal connectivity and memory decline in cognitively intact APOE ε4 carriers.

INTRODUCTION: Resting-state functional magnetic resonance imaging (fMRI) graph theory may help detect subtle functional connectivity changes affecting memory prior to impairment. METHODS: Cognitively normal apolipoprotein E (APOE) ε4 carriers/noncarriers underwent longitudinal cognitive assessment and one-time MRI. The relationship of left/right hippocampal connectivity and memory trajectory were compared between carriers/noncarriers. RESULTS: Steepness of verbal memory decline correlated with decreased connectivity in the left hippocampus, only among APOE ε4 carriers. Right hippocampal metrics were not correlated with memory and there were no significant correlations in the noncarriers. Verbal memory decline correlated with left hippocampal volume loss for both carriers and noncarriers, with no other significant volumetric findings. DISCUSSION: Findings support early hippocampal dysfunction in intact carriers, the AD disconnection hypothesis, and left hippocampal dysfunction earlier than the right. Combining lateralized graph theoretical metrics with a sensitive measure of memory trajectory allowed for detection of early-stage changes in APOE ε4 carriers before symptoms of mild cognitive impairment are present. HIGHLIGHTS: Graph theory connectivity detects preclinical hippocampal changes in APOE ε4 carriers. The AD disconnection hypothesis was supported in unimpaired APOE ε4 carriers. Hippocampal dysfunction starts asymmetrically on the left.

Improved Prediction of Amyloid-ß and Tau Burden Using Hippocampal Surface Multivariate Morphometry Statistics and Sparse Coding.

BACKGROUND: Amyloid-ß (Aß) plaques and tau protein tangles in the brain are the defining 'A' and 'T' hallmarks of Alzheimer's disease (AD), and together with structural atrophy detectable on brain magnetic resonance imaging (MRI) scans as one of the neurodegenerative ('N') biomarkers comprise the "ATN framework" of AD. Current methods to detect Aß/tau pathology include cerebrospinal fluid (invasive), positron emission tomography (PET; costly and not widely available), and blood-based biomarkers (promising but mainly still in development). OBJECTIVE: To develop a non-invasive and widely available structural MRI-based framework to quantitatively predict the amyloid and tau measurements. METHODS: With MRI-based hippocampal multivariate morphometry statistics (MMS) features, we apply our Patch Analysis-based Surface Correntropy-induced Sparse coding and max-pooling (PASCS-MP) method combined with the ridge regression model to individual amyloid/tau measure prediction. RESULTS: We evaluate our framework on amyloid PET/MRI and tau PET/MRI datasets from the Alzheimer's Disease Neuroimaging Initiative. Each subject has one pair consisting of a PET image and MRI scan, collected at about the same time. Experimental results suggest that amyloid/tau measurements predicted with our PASCP-MP representations are closer to the real values than the measures derived from other approaches, such as hippocampal surface area, volume, and shape morphometry features based on spherical harmonics. CONCLUSION: The MMS-based PASCP-MP is an efficient tool that can bridge hippocampal atrophy with amyloid and tau pathology and thus help assess disease burden, progression, and treatment effects.

Cognition Before and After COVID-19 Disease in Older Adults: An Exploratory Study.

BACKGROUND: Older age is a major risk factor for severe COVID-19 disease which has been associated with a variety of neurologic complications, both acutely and chronically. OBJECTIVE: We sought to determine whether milder COVID-19 disease in older vulnerable individuals is also associated with cognitive and behavioral sequelae. METHODS: Neuropsychological, behavioral, and clinical outcomes before and after contracting COVID-19 disease, were compared in members of two ongoing longitudinal studies, the Arizona APOE Cohort and the national Alzheimer's Disease Research Center (ADRC). RESULTS: 152 APOE and 852 ADRC cohort members, mean age overall roughly 70 years, responded to a survey that indicated 21 APOE and 57 ADRC members had contracted COVID-19 before their ensuing (post-COVID) study visit. The mean interval between test sessions that preceded and followed COVID was 2.2 years and 1.2 years respectively for the APOE and ADRC cohorts. The magnitude of change between the pre and post COVID test sessions did not differ on any neuropsychological measure in either cohort. There was, however, a greater increase in informant (but not self) reported cognitive change in the APOE cohort (p = 0.018), but this became nonsignificant after correcting for multiple comparisons. CONCLUSION: Overall members of both cohorts recovered well despite their greater age-related vulnerability to more severe disease.

Feasibility and preliminary effects of exercise interventions on plasma biomarkers of Alzheimer's disease in the FIT-AD trial: a randomized pilot study in older adults with Alzheimer's dementia.

BACKGROUND: Alzheimer's disease (AD) biomarkers have provided a unique opportunity to understand AD pathogenesis and monitor treatment responses. However, exercise trials show mixed effects on imagining and cerebrospinal fluid biomarkers of AD. The feasibility and effects of exercise on plasma biomarkers remain unknown. The primary objective of this study was to examine the feasibility of recruitment, retention, and blood sample collection in community-dwelling older adults with mild-to-moderate AD dementia. Secondarily, it estimated the preliminary effects of 6-month aerobic and stretching exercise on plasma amyloid-ß42 and Aß40 (Aß42/40) ratio, phosphorylated tau (p-tau) 181, and total tau (t-tau). METHODS: This pilot study was implemented in year 2 of the 2-parallel group FIT-AD trial that randomized 96 participants on a 2:1 allocation ratio to moderate-intensity cycling or low-intensity stretching for 20-50 min, 3 times/week for 6 months with 6-month follow-up. Investigators (except for the statistician) and data collectors were blinded to group assignment. Fasting blood samples were collected from 26 participants at baseline and 3 and 6 months. Plasma Aß42, Aß40, p-tau181, and t-tau were measured using Simoa™ assays. Data were analyzed using intention-to-treat, Cohen's d, and linear mixed models. RESULTSS: The sample averaged 77.6±6.99 years old and 15.4±3.00 years of education with 65% being male and 96.2% being apolipoprotein epsilon 4 gene carriers. The recruitment rate was 76.5%. The retention rate was 100% at 3 months and 96.2% at 6 months. The rate of blood collection was 88.5% at 3 months and 96.2% at 6 months. Means (standard deviation) of within-group 6-month difference in the stretching and cycling group were 0.001 (0.012) and -0.001 (0.010) for Aß42/40 ratio, 0.609 (1.417) pg/mL and 0.101(1.579) pg/mL for p-tau181, and -0.020 (0.279) pg/mL and -0.075 (0.215) pg/mL for t-tau. Effect sizes for within-group 6-month difference were observed for p-tau181 in stretching (d=0.43 [-0.33, 1.19]) and t-tau in cycling (-0.35 [-0.87, 0.17]). CONCLUSIONS: Blood collections with fasting were well received by participants and feasible with high recruitment and retention rates. Plasma biomarkers of AD may be modifiable by exercise intervention. Important design considerations are provided for future Phase III trials. TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01954550 and posted on October 1, 2013.

Sex-Specific Multiparameter Blood Test for the Early Diagnosis of Alzheimer's Disease.

Blood-based biomarkers are needed for the early diagnosis of Alzheimer's disease (AD). We analyzed longitudinal human plasma samples from AD and control cases to identify biomarkers for the early diagnosis of AD. Plasma samples were grouped based on clinical diagnosis at the time of collection: AD, mild cognitive impairment (MCI), and pre-symptomatic (preMCI). Samples were analyzed by ELISA using a panel of reagents against nine different AD-related amyloid-ß (Aß), tau, or TDP-43 variants. Receiver operating characteristic (ROC) curves of different biomarker panels for different diagnostic sample groups were determined. Analysis of all of the samples gave a sensitivity of 92% and specificity of 76% for the diagnosis of AD. Early-stage diagnosis of AD, utilizing only the preMCI and MCI samples, identified 88% of AD cases. Using sex-biased biomarker panels, early diagnosis of AD cases improved to 96%. Using the sex-biased panels, we also identified 6 of the 25 control group cases as being at high risk of AD, which is consistent with what is expected given the advanced age of the control cases. Specific AD-associated protein variants are effective blood-based biomarkers for the early diagnosis of AD. Notably, significant differences were observed in biomarker profiles for the early detection of male and female AD cases.

INVESTIGATING THE EFFECT OF TAU DEPOSITION AND APOE ON HIPPOCAMPAL MORPHOMETRY IN ALZHEIMER'S DISEASE: A FEDERATED CHOW TEST MODEL.

Alzheimer's disease (AD) affects more than 1 in 9 people age 65 and older and becomes an urgent public health concern as the global population ages. Tau tangle is the specific protein pathological hallmark of AD and plays a crucial role in leading to dementia-related structural deformations observed in magnetic resonance imaging (MRI) scans. The volume loss of hippocampus is mainly related to the development of AD. Besides, apolipoprotein E (APOE) also has significant effects on the risk of developing AD. However, few studies focus on integrating genotypes, MRI, and tau deposition to infer multimodal relationships. In this paper, we proposed a federated chow test model to study the synergistic effects of APOE and tau on hippocampal morphometry. Our experimental results demonstrate our model can detect the difference of tau deposition and hippocampal atrophy among the cohorts with different genotypes and subiculum and cornu ammonis 1 (CA1 subfield) were identified as hippocampal subregions where atrophy is strongly associated with abnormal tau in the homozygote cohort. Our model will provide novel insight into the neural mechanisms about the individual impact of APOE and tau deposition on brain imaging.

SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19.

Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

Longitudinal Assessment of Intravoxel Incoherent Motion Diffusion-Weighted MRI Metrics in Cognitive Decline.

BACKGROUND: Advanced diffusion-based MRI biomarkers may provide insight into microstructural and perfusion changes associated with neurodegeneration and cognitive decline. PURPOSE: To assess longitudinal microstructural and perfusion changes using apparent diffusion coefficient (ADC) and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) parameters in cognitively impaired (CI) and healthy control (HC) groups. STUDY TYPE: Prospective/longitudinal. POPULATION: Twelve CI patients (75% female) and 13 HC subjects (69% female). FIELD STRENGTH/SEQUENCE: 3 T; Spin-Echo-IVIM-DWI. ASSESSMENT: Two MRI scans were performed with a 12-month interval. ADC and IVIM-DWI metrics (diffusion coefficient [D] and perfusion fraction [f]) were generated from monoexponential and biexponential fits, respectively. Additionally, voxel-based correlations were evaluated between change in Montreal Cognitive Assessment (ΔMoCA) and baseline imaging parameters. STATISTICAL TESTS: Analysis of covariance with sex and age as covariates was performed for main effects of group and time (false discovery rate [FDR] corrected) with post hoc comparisons using Bonferroni correction. Partial-η2 and Hedges' g were used for effect-size analysis. Spearman's correlations (FDR corrected) were used for the relationship between ΔMoCA score and imaging. P < 0.05 was considered statistically significant. RESULTS: Significant differences were found for the main effects of group (HC vs. CI) and time. For group effects, higher ADC, IVIM-D, and IVIM-f were observed in the CI group compared to HC (ADC: 1.23 ± 0.08. 10-3 vs. 1.09 ± 0.07. 10-3  mm2 /sec; IVIM-D: 0.82 ± 0.01. 10-3 vs. 0.73 ± 0.01. 10-3  mm2 /sec; and IVIM-f: 0.317 ± 0.008 vs. 0.253 ± 0.009). Significantly higher ADC, IVIM-D, and IVIM-f values were observed in the CI group after 12 months (ADC: 1.45 ± 0.05. 10-3 vs. 1.50 ± 0.07. 10-3  mm2 /sec; IVIM-D: 0.87 ± 0.01. 10-3 vs. 0.94 ± 0.02. 10-3  mm2 /sec; and IVIM-f: 0.303 ± 0.007 vs. 0.332 ± 0.008), but not in the HC group at large effect size. ADC, IVIM-D, and IVIM-f negatively correlated with ΔMoCA score (ρ = -0.49, -0.51, and -0.50, respectively). DATA CONCLUSION: These findings demonstrate that longitudinal differences between CI and HC cohorts can be measured using IVIM-based metrics. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Studying APOE ɛ4 Allele Dose Effects with a Univariate Morphometry Biomarker.

BACKGROUND: A univariate neurodegeneration biomarker (UNB) based on MRI with strong statistical discrimination power would be highly desirable for studying hippocampal surface morphological changes associated with APOE ɛ4 genetic risk for AD in the cognitively unimpaired (CU) population. However, existing UNB work either fails to model large group variances or does not capture AD induced changes. OBJECTIVE: We proposed a subspace decomposition method capable of exploiting a UNB to represent the hippocampal morphological changes related to the APOE ɛ4 dose effects among the longitudinal APOE ɛ4 homozygotes (HM, N = 30), heterozygotes (HT, N = 49) and non-carriers (NC, N = 61). METHODS: Rank minimization mechanism combined with sparse constraint considering the local continuity of the hippocampal atrophy regions is used to extract group common structures. Based on the group common structures of amyloid-ß (Aß) positive AD patients and Aß negative CU subjects, we identified the regions-of-interest (ROI), which reflect significant morphometry changes caused by the AD development. Then univariate morphometry index (UMI) is constructed from these ROIs. RESULTS: The proposed UMI demonstrates a more substantial statistical discrimination power to distinguish the longitudinal groups with different APOE ɛ4 genotypes than the hippocampal volume measurements. And different APOE ɛ4 allele load affects the shrinkage rate of the hippocampus, i.e., HM genotype will cause the largest atrophy rate, followed by HT, and the smallest is NC. CONCLUSION: The UMIs may capture the APOE ɛ4 risk allele-induced brain morphometry abnormalities and reveal the dose effects of APOE ɛ4 on the hippocampal morphology in cognitively normal individuals.

Federated Morphometry Feature Selection for Hippocampal Morphometry Associated Beta-Amyloid and Tau Pathology.

Amyloid-ß (Aß) plaques and tau protein tangles in the brain are now widely recognized as the defining hallmarks of Alzheimer's disease (AD), followed by structural atrophy detectable on brain magnetic resonance imaging (MRI) scans. One of the particular neurodegenerative regions is the hippocampus to which the influence of Aß/tau on has been one of the research focuses in the AD pathophysiological progress. This work proposes a novel framework, Federated Morphometry Feature Selection (FMFS) model, to examine subtle aspects of hippocampal morphometry that are associated with Aß/tau burden in the brain, measured using positron emission tomography (PET). FMFS is comprised of hippocampal surface-based feature calculation, patch-based feature selection, federated group LASSO regression, federated screening rule-based stability selection, and region of interest (ROI) identification. FMFS was tested on two Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts to understand hippocampal alterations that relate to Aß/tau depositions. Each cohort included pairs of MRI and PET for AD, mild cognitive impairment (MCI), and cognitively unimpaired (CU) subjects. Experimental results demonstrated that FMFS achieves an 89× speedup compared to other published state-of-the-art methods under five independent hypothetical institutions. In addition, the subiculum and cornu ammonis 1 (CA1 subfield) were identified as hippocampal subregions where atrophy is strongly associated with abnormal Aß/tau. As potential biomarkers for Aß/tau pathology, the features from the identified ROIs had greater power for predicting cognitive assessment and for survival analysis than five other imaging biomarkers. All the results indicate that FMFS is an efficient and effective tool to reveal associations between Aß/tau burden and hippocampal morphometry.

Predicting Tau Accumulation in Cerebral Cortex with Multivariate MRI Morphometry Measurements, Sparse Coding, and Correntropy.

Biomarker-assisted diagnosis and intervention in Alzheimer's disease (AD) may be the key to prevention breakthroughs. One of the hallmarks of AD is the accumulation of tau plaques in the human brain. However, current methods to detect tau pathology are either invasive (lumbar puncture) or quite costly and not widely available (Tau PET). In our previous work, structural MRI-based hippocampal multivariate morphometry statistics (MMS) showed superior performance as an effective neurodegenerative biomarker for preclinical AD and Patch Analysis-based Surface Correntropy-induced Sparse coding and max-pooling (PASCS-MP) has excellent ability to generate low-dimensional representations with strong statistical power for brain amyloid prediction. In this work, we apply this framework together with ridge regression models to predict Tau deposition in Braak12 and Braak34 brain regions separately. We evaluate our framework on 925 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Each subject has one pair consisting of a PET image and MRI scan which were collected at about the same times. Experimental results suggest that the representations from our MMS and PASCS-MP have stronger predictive power and their predicted Braak12 and Braak34 are closer to the real values compared to the measures derived from other approaches such as hippocampal surface area and volume, and shape morphometry features based on spherical harmonics (SPHARM).

Predicting Brain Amyloid Using Multivariate Morphometry Statistics, Sparse Coding, and Correntropy: Validation in 1,101 Individuals From the ADNI and OASIS Databases.

Biomarker assisted preclinical/early detection and intervention in Alzheimer's disease (AD) may be the key to therapeutic breakthroughs. One of the presymptomatic hallmarks of AD is the accumulation of beta-amyloid (Aß) plaques in the human brain. However, current methods to detect Aß pathology are either invasive (lumbar puncture) or quite costly and not widely available (amyloid PET). Our prior studies show that magnetic resonance imaging (MRI)-based hippocampal multivariate morphometry statistics (MMS) are an effective neurodegenerative biomarker for preclinical AD. Here we attempt to use MRI-MMS to make inferences regarding brain Aß burden at the individual subject level. As MMS data has a larger dimension than the sample size, we propose a sparse coding algorithm, Patch Analysis-based Surface Correntropy-induced Sparse-coding and Max-Pooling (PASCS-MP), to generate a low-dimensional representation of hippocampal morphometry for each individual subject. Then we apply these individual representations and a binary random forest classifier to predict brain Aß positivity for each person. We test our method in two independent cohorts, 841 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 260 subjects from the Open Access Series of Imaging Studies (OASIS). Experimental results suggest that our proposed PASCS-MP method and MMS can discriminate Aß positivity in people with mild cognitive impairment (MCI) [Accuracy (ACC) = 0.89 (ADNI)] and in cognitively unimpaired (CU) individuals [ACC = 0.79 (ADNI) and ACC = 0.81 (OASIS)]. These results compare favorably relative to measures derived from traditional algorithms, including hippocampal volume and surface area, shape measures based on spherical harmonics (SPHARM) and our prior Patch Analysis-based Surface Sparse-coding and Max-Pooling (PASS-MP) methods.