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1. Brain structure and allelic associations in Alzheimer's disease

   https://doi.org/10.1111/cns.14073  

   Moon, Seok Woo ; Zhao, Lu ; Matloff, William ; Hobel, Sam ; Berger, Ryan ; Kwon, Daehong ; Kim, Jaebum ; Toga, Arthur W. ; Dinov, Ivo D. ; for the Alzheimer's Disease Neuroimaging Initiative ( December 2022 , CNS Neuroscience & Therapeutics)

   Alzheimer's disease (AD), the most prevalent form of dementia, affects 6.5 million Americans and over 50 million people globally. Clinical, genetic, and phenotypic studies of dementia provide some insights of the observed progressive neurodegenerative processes, however, the mechanisms underlying AD onset remain enigmatic.

   This paper examines late‐onset dementia‐related cognitive impairment utilizing neuroimaging‐genetics biomarker associations.

   The participants, ages 65–85, included 266 healthy controls (HC), 572 volunteers with mild cognitive impairment (MCI), and 188 Alzheimer's disease (AD) patients. Genotype dosage data for AD‐associated single nucleotide polymorphisms (SNPs) were extracted from the imputed ADNI genetics archive using sample‐major additive coding. Such 29 SNPs were selected, representing a subset of independent SNPs reported to be highly associated with AD in a recent AD meta‐GWAS study by Jansen and colleagues.

   We identified the significant correlations between the 29 genomic markers (GMs) and the 200 neuroimaging markers (NIMs). The odds ratios and relative risks for AD and MCI (relative to HC) were predicted using multinomial linear models.

   In the HC and MCI cohorts, mainly cortical thickness measures were associated with GMs, whereas the AD cohort exhibited different GM‐NIM relations. Network patterns within the HC and AD groups were distinct in cortical thickness, volume, and proportion of White to Gray Matter (pct), but not in the MCI cohort. Multinomial linear models of clinical diagnosis showed precisely the specific NIMs and GMs that were most impactful in discriminating between AD and HC, and between MCI and HC.

   This study suggests that advanced analytics provide mechanisms for exploring the interrelations between morphometric indicators and GMs. The findings may facilitate further clinical investigations of phenotypic associations that support deep systematic understanding of AD pathogenesis.

    

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2. An Artificial Intelligence-Assisted Method for Dementia Detection Using Images from the Clock Drawing Test

   https://doi.org/10.3233/JAD-210299  

   Amini, Samad ; Zhang, Lifu ; Hao, Boran ; Gupta, Aman ; Song, Mengting ; Karjadi, Cody ; Lin, Honghuang ; Kolachalama, Vijaya B. ; Au, Rhoda ; Paschalidis, Ioannis Ch. ( September 2021 , Journal of Alzheimer's Disease)

   Background: Widespread dementia detection could increase clinical trial candidates and enable appropriate interventions. Since the Clock Drawing Test (CDT) can be potentially used for diagnosing dementia-related disorders, it can be leveraged to develop a computer-aided screening tool. Objective: To evaluate if a machine learning model that uses images from the CDT can predict mild cognitive impairment or dementia. Methods: Images of an analog clock drawn by 3,263 cognitively intact and 160 impaired subjects were collected during in-person dementia evaluations by the Framingham Heart Study. We processed the CDT images, participant’s age, and education level using a deep learning algorithm to predict dementia status. Results: When only the CDT images were used, the deep learning model predicted dementia status with an area under the receiver operating characteristic curve (AUC) of 81.3% ± 4.3%. A composite logistic regression model using age, level of education, and the predictions from the CDT-only model, yielded an average AUC and average F1 score of 91.9% ±1.1% and 94.6% ±0.4%, respectively. Conclusion: Our modeling framework establishes a proof-of-principle that deep learning can be applied on images derived from the CDT to predict dementia status. When fully validated, this approach can offer a cost-effective and easily deployable mechanism for detecting cognitive impairment. 

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3. Linking brain structure, cognition, and sleep: insights from clinical data

   https://doi.org/10.1093/sleep/zsad294  

   Wei, Ruoqi ; Ganglberger, Wolfgang ; Sun, Haoqi ; Hadar, Peter N. ; Gollub, Randy L. ; Pieper, Steve ; Billot, Benjamin ; Au, Rhoda ; Eugenio Iglesias, Juan ; Cash, Sydney S. ; et al ( November 2023 , SLEEP)

   To use relatively noisy routinely collected clinical data (brain magnetic resonance imaging (MRI) data, clinical polysomnography (PSG) recordings, and neuropsychological testing), to investigate hypothesis-driven and data-driven relationships between brain physiology, structure, and cognition.

   We analyzed data from patients with clinical PSG, brain MRI, and neuropsychological evaluations. SynthSeg, a neural network-based tool, provided high-quality segmentations despite noise. A priori hypotheses explored associations between brain function (measured by PSG) and brain structure (measured by MRI). Associations with cognitive scores and dementia status were studied. An exploratory data-driven approach investigated age-structure-physiology-cognition links.

   Six hundred and twenty-three patients with sleep PSG and brain MRI data were included in this study; 160 with cognitive evaluations. Three hundred and forty-two participants (55%) were female, and age interquartile range was 52 to 69 years. Thirty-six individuals were diagnosed with dementia, 71 with mild cognitive impairment, and 326 with major depression. One hundred and fifteen individuals were evaluated for insomnia and 138 participants had an apnea–hypopnea index equal to or greater than 15. Total PSG delta power correlated positively with frontal lobe/thalamic volumes, and sleep spindle density with thalamic volume. rapid eye movement (REM) duration and amygdala volume were positively associated with cognition. Patients with dementia showed significant differences in five brain structure volumes. REM duration, spindle, and slow-oscillation features had strong associations with cognition and brain structure volumes. PSG and MRI features in combination predicted chronological age (R2 = 0.67) and cognition (R2 = 0.40).

   Routine clinical data holds extended value in understanding and even clinically using brain-sleep-cognition relationships.

    

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4. Predicting 5‐year dementia conversion in veterans with mild cognitive impairment

   https://doi.org/10.1002/dad2.12572  

   Irwin, Chase ; Tjandra, Donna ; Hu, Chengcheng ; Aggarwal, Vinod ; Lienau, Amanda ; Giordani, Bruno ; Wiens, Jenna ; Migrino, Raymond Q. ( March 2024 , Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring)

   Identifying mild cognitive impairment (MCI) patients at risk for dementia could facilitate early interventions. Using electronic health records (EHRs), we developed a model to predict MCI to all‐cause dementia (ACD) conversion at 5 years.

   Cox proportional hazards model was used to identify predictors of ACD conversion from EHR data in veterans with MCI. Model performance (area under the receiver operating characteristic curve [AUC] and Brier score) was evaluated on a held‐out data subset.

   Of 59,782 MCI patients, 15,420 (25.8%) converted to ACD. The model had good discriminative performance (AUC 0.73 [95% confidence interval (CI) 0.72–0.74]), and calibration (Brier score 0.18 [95% CI 0.17–0.18]). Age, stroke, cerebrovascular disease, myocardial infarction, hypertension, and diabetes were risk factors, while body mass index, alcohol abuse, and sleep apnea were protective factors.

   EHR‐based prediction model had good performance in identifying 5‐year MCI to ACD conversion and has potential to assist triaging of at‐risk patients.

   Of 59,782 veterans with mild cognitive impairment (MCI), 15,420 (25.8%) converted to all‐cause dementia within 5 years.

   Electronic health record prediction models demonstrated good performance (area under the receiver operating characteristic curve 0.73; Brier 0.18).

   Age and vascular‐related morbidities were predictors of dementia conversion.

   Synthetic data was comparable to real data in modeling MCI to dementia conversion.

   An electronic health record–based model using demographic and co‐morbidity data had good performance in identifying veterans who convert from mild cognitive impairment (MCI) to all‐cause dementia (ACD) within 5 years.

   Increased age, stroke, cerebrovascular disease, myocardial infarction, hypertension, and diabetes were risk factors for 5‐year conversion from MCI to ACD.

   High body mass index, alcohol abuse, and sleep apnea were protective factors for 5‐year conversion from MCI to ACD.

   Models using synthetic data, analogs of real patient data that retain the distribution, density, and covariance between variables of real patient data but are not attributable to any specific patient, performed just as well as models using real patient data. This could have significant implications in facilitating widely distributed computing of health‐care data with minimized patient privacy concern that could accelerate scientific discoveries.

    

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5. Association of Cognitive Impairment With Free Water in the Nucleus Basalis of Meynert and Locus Coeruleus to Transentorhinal Cortex Tract

   https://doi.org/10.1212/WNL.0000000000013206  

   Chu, Winston Thomas ; Wang, Wei-en ; Zaborszky, Laszlo ; Golde, Todd Eliot ; DeKosky, Steven ; Duara, Ranjan ; Loewenstein, David A. ; Adjouadi, Malek ; Coombes, Stephen A. ; Vaillancourt, David E. ( February 2022 , Neurology)

   Background and Objectives The goal of this work was to determine the relationship between diffusion microstructure and early changes in Alzheimer disease (AD) severity as assessed by clinical diagnosis, cognitive performance, dementia severity, and plasma concentrations of neurofilament light chain. Methods Diffusion MRI scans were collected on cognitively normal participants (CN) and patients with early mild cognitive impairment (EMCI), late mild cognitive impairment, and AD. Free water (FW) and FW-corrected fractional anisotropy were calculated in the locus coeruleus to transentorhinal cortex tract, 4 magnocellular regions of the basal forebrain (e.g., nucleus basalis of Meynert), entorhinal cortex, and hippocampus. All patients underwent a battery of cognitive assessments; neurofilament light chain levels were measured in plasma samples. Results FW was significantly higher in patients with EMCI compared to CN in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus (mean Cohen d = 0.54; p fdr < 0.05). FW was significantly higher in those with AD compared to CN in all the examined regions (mean Cohen d = 1.41; p fdr < 0.01). In addition, FW in the hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus coeruleus to transentorhinal cortex tract positively correlated with all 5 cognitive impairment metrics and neurofilament light chain levels (mean r 2 = 0.10; p fdr < 0.05). Discussion These results show that higher FW is associated with greater clinical diagnosis severity, cognitive impairment, and neurofilament light chain. They also suggest that FW elevation occurs in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus in the transition from CN to EMCI, while other basal forebrain regions and the entorhinal cortex are not affected until a later stage of AD. FW is a clinically relevant and noninvasive early marker of structural changes related to cognitive impairment. 

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