Journal of Alzheimer's Disease - Volume 97, issue 2

Authors: Fan, Xinxin | Li, Haining | Liu, Lin | Zhang, Kai | Zhang, Zhewei | Chen, Yi | Wang, Zhen | He, Xiaoli | Xu, Jinping | Hu, Qingmao

Article Type: Research Article

Abstract: Background: Structural magnetic resonance imaging (sMRI) is vital for early Alzheimer’s disease (AD) diagnosis, though confirming specific biomarkers remains challenging. Our proposed Multi-Scale Self-Attention Network (MUSAN) enhances classification of cognitively normal (CN) and AD individuals, distinguishing stable (sMCI) from progressive mild cognitive impairment (pMCI). Objective: This study leverages AD structural atrophy properties to achieve precise AD classification, combining different scales of brain region features. The ultimate goal is an interpretable algorithm for this method. Methods: The MUSAN takes whole-brain sMRI as input, enabling automatic extraction of brain region features and modeling of correlations …between different scales of brain regions, and achieves personalized disease interpretation of brain regions. Furthermore, we also employed an occlusion sensitivity algorithm to localize and visualize brain regions sensitive to disease. Results: Our method is applied to ADNI-1, ADNI-2, and ADNI-3, and achieves high performance on the classification of CN from AD with accuracy (0.93), specificity (0.82), sensitivity (0.96), and area under curve (AUC) (0.95), as well as notable performance on the distinguish of sMCI from pMCI with accuracy (0.85), specificity (0.84), sensitivity (0.74), and AUC (0.86). Our sensitivity masking algorithm identified key regions in distinguishing CN from AD: hippocampus, amygdala, and vermis. Moreover, cingulum, pallidum, and inferior frontal gyrus are crucial for sMCI and pMCI discrimination. These discoveries align with existing literature, confirming the dependability of our model in AD research. Conclusion: Our method provides an effective AD diagnostic and conversion prediction method. The occlusion sensitivity algorithm enhances deep learning interpretability, bolstering AD research reliability. Show more

Keywords: Alzheimer’s disease, deep learning, explainable deep learning, multilevel feature learning, structural MRI

DOI: 10.3233/JAD-230705

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 909-926, 2024

Authors: Gao, Ju | Leinonen, Henri | Wang, Evan J. | Ding, Mao | Perry, George | Palczewski, Krzysztof | Wang, Xinglong

Article Type: Research Article

Abstract: Background: Increasing evidence has highlighted retinal impairments in neurodegenerative diseases. Dominant mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the accumulation of TDP-43 in the cytoplasm is a pathological hallmark of ALS, frontotemporal dementia (FTD), and many other neurodegenerative diseases. Objective: While homozygous transgenic mice expressing the disease-causing human TDP-43 M337V mutant (TDP-43M337V mice) experience premature death, hemizygous TDP-43M337V mice do not suffer sudden death, but they exhibit age-dependent motor-coordinative and cognitive deficits. This study aims to leverage the hemizygous TDP-43M337V mice as a valuable ALS/FTD disease model for the …assessment also of retinal changes during the disease progression. Methods: We evaluated the retinal function of young TDP-43M337V mice by full field electroretinogram (ERG) recordings. Results: At 3–4 months of age, well before the onset of brain dysfunction at 8 months, the ERG responses were notably impaired in the retinas of young female TDP-43M337V mice in contrast to their male counterparts and age-matched non-transgenic mice. Mitochondria have been implicated as critical targets of TDP-43. Further investigation revealed that significant changes in the key regulators of mitochondrial dynamics and bioenergetics were only observed in the retinas of young female TDP-43M337V mice, while these alterations were not present in the brains of either gender. Conclusions: Together our findings suggest a sex-specific vulnerability within the retina in the early disease stage, and highlight the importance of retinal changes and mitochondrial markers as potential early diagnostic indicators for ALS, FTD, and other TDP-43 related neurodegenerative conditions. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, mitochondrial dynamics, OXPHOS, retina, sex differences, TDP-43

DOI: 10.3233/JAD-231102

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 927-937, 2024

Authors: Dingle, Sara E. | Milte, Catherine M. | Daly, Robin M. | Torres, Susan J.

Article Type: Research Article

Abstract: Background: Dementia, with the most common form being Alzheimer’s disease, is a global health issue and lifestyle-based strategies may reduce risk. Individuals with a family history of dementia are an important target group, but little is known about their attitudes and perceptions of dementia risk reduction. Objective: To elucidate the attitudes to and key considerations for multidomain lifestyle-based dementia prevention strategies in middle-aged Australians with a family history of dementia. Methods: Twenty participants (80% female; age range 47–65 years), undertook semi-structured phone-based interviews. Inductive thematic analysis of interview transcripts was conducted. Hierarchical coding …frames and illustrative quotes were compiled and critically challenged until a final set of themes was produced. Results: Some participants expressed a positive attitude toward lifestyle-based dementia prevention. Reasons related to wanting to future proof, believing that risk reduction is relevant at all life stages and/or that there is always room for improvement. Other participants had a negative attitude, expressing that they were already following a healthy lifestyle, did not feel it was relevant to them yet, and/or held a deterministic view that dementia is random. Important considerations congregated on the themes of being tailored/personalized, taking a holistic approach, and involving small, achievable steps. Conclusions: In individuals with a family history of dementia, a positive attitude to dementia prevention holds promise for intervention efforts, but in individuals expressing negative attitudes, further education and individual-level counselling may be warranted. Multidomain lifestyle-based preventive strategies also need to be tailored to the needs of key target groups to optimize appeal and effectiveness. Show more

Keywords: Alzheimer’s disease, dementia, lifestyle, prevention, qualitative study

DOI: 10.3233/JAD-230176

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 939-949, 2024

Authors: de la Perrelle, Lenore

Article Type: Article Commentary

Abstract: With an aging population, an increase in cases of Alzheimer’s disease and dementia worldwide poses a significant health burden. While we hope for a cure, preventing dementia by reducing risks is important for global population health. Prevention strategies are difficult to implement when facing inequality across the world for access to healthy lifestyles. An approach that centers on individual responsibility and health professional interventions for targeted groups may risk missing the policy and environmental drivers of change. Barriers and enablers need to be explored and interventions are needed at individual, structural and social levels to normalize mid-life risk reduction.

Keywords: Alzheimer’s disease, dementia risk reduction, family history, mid-life strategies, multidomain interventions

DOI: 10.3233/JAD-231348

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 951-952, 2024

Authors: Frentz, Ingeborg | van Arendonk, Joyce | Leeuwis, Anna E. | Vernooij, Meike W. | van der Flier, Wiesje M. | Bos, Daniel | De Deyn, Peter Paul | Wolters, Frank J. | Ikram, M. Arfan

Article Type: Research Article

Abstract: Background: Dementia is a multifactorial disease, with Alzheimer’s disease (AD) and vascular pathology often co-occurring in many individuals with dementia. Yet, the interplay between AD and vascular pathology in cognitive decline is largely undetermined. Objective: The aim of the present study was to examine the joint effect of arteriosclerosis and AD pathology on cognition in the general population without dementia. Methods: We determined the interaction between blood-based AD biomarkers and CT-defined arteriosclerosis on cognition in 2,229 dementia-free participants of the population-based Rotterdam Study (mean age: 68.9 years, 52% women) cross-sectionally. Results: Amyloid-β (Aβ)42 …and arterial calcification were associated with cognitive performance. After further adjustment for confounders in a model that combined all biomarkers, only arterial calcification remained independently associated with cognition. There was a significant interaction between arterial calcification and Aβ42 and between arterial calcification and the ratio of Aβ42/40 . Yet, estimates attenuated, and interactions were no longer statistically significant after adjustment for cardio metabolic risk factors. Conclusions: Arteriosclerosis and AD display additive interaction-effects on cognition in the general population, that are due in part to cardio metabolic risk factors. These findings suggest that joint assessment of arteriosclerosis and AD pathology is important for understanding of disease etiology in individuals with cognitive impairment. Show more

Keywords: Alzheimer’s disease, amyloid-β, arteriosclerosis, calcification, dementia, plasma biomarkers

DOI: 10.3233/JAD-230604

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 953-961, 2024

Authors: de Boer, Sterre C.M. | Riedl, Lina | Fenoglio, Chiara | Rue, Ishana | Landin-Romero, Ramon | Matis, Sophie | Chatterton, Zac | Galimberti, Daniela | Halliday, Glenda | Diehl-Schmid, Janine | Piguet, Olivier | Pijnenburg, Yolande A.L. | Ducharme, Simon

Article Type: Research Article

Abstract: Background: The behavioral variant of frontotemporal dementia (bvFTD) is very heterogeneous in pathology, genetics, and disease course. Unlike Alzheimer’s disease, reliable biomarkers are lacking and sporadic bvFTD is often misdiagnosed as a primary psychiatric disorder (PPD) due to overlapping clinical features. Current efforts to characterize and improve diagnostics are centered on the minority of genetic cases. Objective: The multi-center study DIPPA-FTD aims to develop diagnostic and prognostic algorithms to help distinguish sporadic bvFTD from late-onset PPD in its earliest stages. Methods: The prospective DIPPA-FTD study recruits participants with late-life behavioral changes, suspect for bvFTD or …late-onset PPD diagnosis with a negative family history for FTD and/or amyotrophic lateral sclerosis. Subjects are invited to participate after diagnostic screening at participating memory clinics or recruited by referrals from psychiatric departments. At baseline visit, participants undergo neurological and psychiatric examination, questionnaires, neuropsychological tests, and brain imaging. Blood is obtained to investigate biomarkers. Patients are informed about brain donation programs. Follow-up takes place 10-14 months after baseline visit where all examinations are repeated. Results from the DIPPA-FTD study will be integrated in a data-driven approach to develop diagnostic and prognostic models. Conclusions: DIPPA-FTD will make an important contribution to early sporadic bvFTD identification. By recruiting subjects with ambiguous or prodromal diagnoses, our research strategy will allow the characterization of early disease stages that are not covered in current sporadic FTD research. Results will hopefully increase the ability to diagnose sporadic bvFTD in the early stage and predict progression rate, which is pivotal for patient stratification and trial design. Show more

Keywords: Alzheimer’s disease, diagnostics, frontotemporal dementia, neurodegeneration, prognostics, psychiatric disorders

DOI: 10.3233/JAD-230829

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 963-973, 2024

Article Type: Correction

DOI: 10.3233/JAD-239014

Citation: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 975-976, 2024