From Age-Related Cognitive Decline to Alzheimer’s Disease: A Translational Overview of the Potential Role for Phosphodiesterases

Heckman, Pim R. A.; Blokland, Arjan; Prickaerts, Jos

doi:10.1007/978-3-319-58811-7_6

Cited by 25 publications

(34 citation statements)

References 163 publications

(210 reference statements)

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“…Propentofylline would be superior to other PDE2 inhibitors primarily because 300 mg of it taken thrice daily one hour before meals has been tested and found to be safe and effective in mild to moderate AD patients in 5 phase III clinical trials [158][159][160][161][162][163][164]. Intriguingly, a recent review by Heckman and colleagues opined that, based on the preclinical evidence, inhibition of PDE2, PDE4, and PDE5 seemed to hold the most promise for the treatment of AD [165], and sildenafil and propentofylline administered together would potently inhibit these three therapeutic targets simultaneously [157].…”

Section: Discussionmentioning

confidence: 99%

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Sanders

2020

Journal of Alzheimer's Disease Reports

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Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer's disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is upregulated. Sildenafil inhibits PDE5 and increases cGMP levels. Integrating previous findings, we determine that most doses of sildenafil (especially low doses) likely activate peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC1␣) via protein kinase G-mediated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation and/or Sirtuin-1 activation and PGC1␣ deacetylation. Via PGC1␣ signaling, low-dose sildenafil likely suppresses ␤-secretase 1 expression and amyloid-␤ (A␤) generation, upregulates antioxidant enzymes, and induces mitochondrial biogenesis. Plus, sildenafil should increase brain perfusion, insulin sensitivity, long-term potentiation, and neurogenesis while suppressing neural apoptosis and inflammation. A systematic review of sildenafil in AD was undertaken. In vitro, sildenafil protected neural mitochondria from A␤ and advanced glycation end products. In transgenic AD mice, sildenafil was found to rescue deficits in CREB phosphorylation and memory, upregulate brain-derived neurotrophic factor, reduce reactive astrocytes and microglia, decrease interleukin-1␤, interleukin-6, and tumor necrosis factor-␣, decrease neural apoptosis, increase neurogenesis, and reduce tau hyperphosphorylation. All studies that tested A␤ levels reported significant improvements except the two that used the highest dosage, consistent with the doselimiting effect of cGMP-induced phosphodiesterase 2 (PDE2) activation and cAMP depletion on PGC1␣ signaling. In AD patients, a single dose of sildenafil decreased spontaneous neural activity, increased cerebral blood flow, and increased the cerebral metabolic rate of oxygen. A randomized control trial of sildenafil (ideally with a PDE2 inhibitor) in AD patients is warranted.

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Section: Discussionmentioning

confidence: 99%

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Sanders

2020

Journal of Alzheimer's Disease Reports

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“…We have selected four biomarkers previously inspired by medical community choices [20,21,22,23,24], as reviewed next:…”

Section: Ovbm Ad Sensory Stream Biomarkersmentioning

confidence: 99%

“…Significant research in AD such as [20] has proven that the disease impacts motor neurons. In other diseases, like Parkinson's, where motor neurons are affected, vocal cords have proven to be one of the first muscles affected [28].…”

Section: Biomarker 2 (Vocal Cords)mentioning

confidence: 99%

“…A: Saliency map to study the explainable AD evolution for all the patients in the study based on the predictions of individual biomarker models. BrainOS (2,8,14,20) show the model prediction at different chunk sizes. This map could be used to longitudinally monitor subjects where a lower score on the biomarkers could indicate a more progressed AD subject.…”

Section: Symbolic Compositional Modelsmentioning

confidence: 99%

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Longitudinal Speech Biomarkers for Automated Alzheimer's Detection

Laguarta

Hueto

Rajasekaran

et al. 2020

Preprint

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Background: We introduce a novel speech processing framework, the MIT CBMM Open Voice Brain Model (OVBM), combining implementations of the 4 modules of intelligence: The brain OS chunks and overlaps audio samples and transfers CNN features from the sensory stream and cognitive core creating a multi-modal graph neural network of symbolic compositional models for the target task.Methods: Our approach consists of pre-training models to extract acoustic features from selected biomarkers and then leverage transfer learning to combine the biomarker feature extractors into a graph neural network to provide an explainable diagnsotic for Alzheimer's Dementia (AD) using speech recordings.Results: We apply OVBM to the automated diagnostic of Alzheimer's Dementia patients, achieving above state-of-the-art accuracy of 93.8% using only raw audio, while extracting a personalized subject saliency map to track relative disease progression of 16 explainable biomarkers.Conclusion: By using independent biomarker models, OVBM lets health experts explore biomarker features and whether there are common biomarkers features between AD and other diseases like COVID-19. We present a novel lungs and respiratory tract biomarker created using 200.000+ cough samples to pre-train a model discriminating English from Catalan coughs. Transfer Learning is subsequently used to transfer features from this model with various other biomarker OVBM models. This strategy yielded consistent improvements in ADdetection, no matter the combination used. This cough dataset sets a new benchmark as largest audio health dataset with 30.000+ subjects participating in April 2020, demonstrating for the rst time cough cultural bias.

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“…L'avancée dans l'âge s'accompagne inexorablement d'un déclin cognitif considéré comme « normal ». Ce dernier s'échelonne d'un simple dysfonctionnement cognitif dû à l'âge au développement de la démence (Heckman et al, 2017). Il est reconnu que les séniors atteints de démence risquent fortement de perdre du poids, de la masse musculaire et des capacités fonctionnelles.…”

Section: L'impact Des Lipides Sur Le Cognitifunclassified

La place des lipides dans les compléments nutritionnels oraux (CNO)

Bonhomme

2019

OCL

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La dénutrition touche 2 millions de personnes en France et a pour conséquence une augmentation des complications, des infections et du risque de mortalité ; en découle une qualité de vie fortement impactée, des capacités fonctionnelles diminuées et un risque de dépendance. Les compléments nutritionnels oraux (CNO), considérés comme des DADFMS, sont une des premières étapes de la re-nutrition, et restent une solution physiologique et non invasive à la dénutrition protéino-énergétique. Les CNO hypercaloriques et hyperprotéinés comblent le manque d’apport alimentaire, sans augmenter grandement les volumes d’aliments consommés. La formulation des CNO est encadrée par le règlement délégué (UE) 2016/128 sur les DADFMS. La HAS préconise que les CNO doivent apporter au moins 30 g de protéines et/ou 400 kcal par jour. A ce jour, de nombreux CNO sont proposés, afin de répondre aux besoins nutritionnels, aux textures adaptées et aux goûts des sujets dénutris. Selon la catégorie, les CNO contiennent des lipides, à hauteur de 26 à 42 % de l’AET et d’origines variées : colza, tournesol, lipides laitiers. Or, dans la prise en charge de la dénutrition, tous les lipides ne sont pas équivalents ; s’ils fournissent tous l’énergie indispensable, certains seraient impliqués dans la modulation de l’inflammation, d’autres dans l’équilibre de la flore intestinale ou des fonctions cognitives. Ils peuvent ainsi contribuer à l’efficacité des CNO dont le rôle majeur est l’amélioration du statut nutritionnel des patients afin qu’ils puissent être soignés plus efficacement.

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From Age-Related Cognitive Decline to Alzheimer’s Disease: A Translational Overview of the Potential Role for Phosphodiesterases

Cited by 25 publications

References 163 publications

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

Longitudinal Speech Biomarkers for Automated Alzheimer's Detection

La place des lipides dans les compléments nutritionnels oraux (CNO)

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