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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. 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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3. Generalizable deep learning model for early Alzheimer’s disease detection from structural MRIs

   https://doi.org/10.1038/s41598-022-20674-x  

   Liu, Sheng ; Masurkar, Arjun V. ; Rusinek, Henry ; Chen, Jingyun ; Zhang, Ben ; Zhu, Weicheng ; Fernandez-Granda, Carlos ; Razavian, Narges ( October 2022 , Scientific Reports)

   Early diagnosis of Alzheimer’s disease plays a pivotal role in patient care and clinical trials. In this study, we have developed a new approach based on 3D deep convolutional neural networks to accurately differentiate mild Alzheimer’s disease dementia from mild cognitive impairment and cognitively normal individuals using structural MRIs. For comparison, we have built a reference model based on the volumes and thickness of previously reported brain regions that are known to be implicated in disease progression. We validate both models on an internal held-out cohort from The Alzheimer's Disease Neuroimaging Initiative (ADNI) and on an external independent cohort from The National Alzheimer's Coordinating Center (NACC). The deep-learning model is accurate, achieved an area-under-the-curve (AUC) of 85.12 when distinguishing between cognitive normal subjects and subjects with either MCI or mild Alzheimer’s dementia. In the more challenging task of detecting MCI, it achieves an AUC of 62.45. It is also significantly faster than the volume/thickness model in which the volumes and thickness need to be extracted beforehand. The model can also be used to forecast progression: subjects with mild cognitive impairment misclassified as having mild Alzheimer’s disease dementia by the model were faster to progress to dementia over time. An analysis of the features learned by the proposed model shows that it relies on a wide range of regions associated with Alzheimer's disease. These findings suggest that deep neural networks can automatically learn to identify imaging biomarkers that are predictive of Alzheimer's disease, and leverage them to achieve accurate early detection of the disease.

    

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4. Novel methodology for detection and prediction of mild cognitive impairment using resting‐state EEG

   https://doi.org/10.1002/alz.13411  

   Deng, Jinxian ; Sun, Boxin ; Kavcic, Voyko ; Liu, Mingyan ; Giordani, Bruno ; Li, Tongtong ( July 2023 , Alzheimer's & Dementia)

   Early discrimination and prediction of cognitive decline are crucial for the study of neurodegenerative mechanisms and interventions to promote cognitive resiliency.

   Our research is based on resting‐state electroencephalography (EEG) and the current dataset includes 137 consensus‐diagnosed, community‐dwelling Black Americans (ages 60–90 years, 84 healthy controls [HC]; 53 mild cognitive impairment [MCI]) recruited through Wayne State University and Michigan Alzheimer's Disease Research Center. We conducted multiscale analysis on time‐varying brain functional connectivity and developed an innovative soft discrimination model in which each decision on HC or MCI also comes with a connectivity‐based score.

   The leave‐one‐out cross‐validation accuracy is 91.97% and 3‐fold accuracy is 91.17%. The 9 to 18 months’ progression trend prediction accuracy over an availability‐limited subset sample is 84.61%.

   The EEG‐based soft discrimination model demonstrates high sensitivity and reliability for MCI detection and shows promising capability in proactive prediction of people at risk of MCI before clinical symptoms may occur.

    

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5. Detection of dementia on voice recordings using deep learning: a Framingham Heart Study

   https://doi.org/10.1186/s13195-021-00888-3  

   Xue, Chonghua ; Karjadi, Cody ; Paschalidis, Ioannis Ch. ; Au, Rhoda ; Kolachalama, Vijaya B. ( December 2021 , Alzheimer's Research & Therapy)

   Abstract Background Identification of reliable, affordable, and easy-to-use strategies for detection of dementia is sorely needed. Digital technologies, such as individual voice recordings, offer an attractive modality to assess cognition but methods that could automatically analyze such data are not readily available. Methods and findings We used 1264 voice recordings of neuropsychological examinations administered to participants from the Framingham Heart Study (FHS), a community-based longitudinal observational study. The recordings were 73 min in duration, on average, and contained at least two speakers (participant and examiner). Of the total voice recordings, 483 were of participants with normal cognition (NC), 451 recordings were of participants with mild cognitive impairment (MCI), and 330 were of participants with dementia (DE). We developed two deep learning models (a two-level long short-term memory (LSTM) network and a convolutional neural network (CNN)), which used the audio recordings to classify if the recording included a participant with only NC or only DE and to differentiate between recordings corresponding to those that had DE from those who did not have DE (i.e., NDE (NC+MCI)). Based on 5-fold cross-validation, the LSTM model achieved a mean (±std) area under the receiver operating characteristic curve (AUC) of 0.740 ± 0.017, mean balanced accuracy of 0.647 ± 0.027, and mean weighted F1 score of 0.596 ± 0.047 in classifying cases with DE from those with NC. The CNN model achieved a mean AUC of 0.805 ± 0.027, mean balanced accuracy of 0.743 ± 0.015, and mean weighted F1 score of 0.742 ± 0.033 in classifying cases with DE from those with NC. For the task related to the classification of participants with DE from NDE, the LSTM model achieved a mean AUC of 0.734 ± 0.014, mean balanced accuracy of 0.675 ± 0.013, and mean weighted F1 score of 0.671 ± 0.015. The CNN model achieved a mean AUC of 0.746 ± 0.021, mean balanced accuracy of 0.652 ± 0.020, and mean weighted F1 score of 0.635 ± 0.031 in classifying cases with DE from those who were NDE. Conclusion This proof-of-concept study demonstrates that automated deep learning-driven processing of audio recordings of neuropsychological testing performed on individuals recruited within a community cohort setting can facilitate dementia screening. 

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