Aug 2026
E. Bredesen DaleCorresponding author
Background/Objectives The etiology and pathophysiology of neurodegenerative diseases are incompletely understood, and the treatments largely ineffective. A unifying theory that explains otherwise poorly understood observations may help to enhance therapeutic outcomes. Methods Here is proposed a unifying theory of neurodegenerative disease, the Pr2 theory, describing the origin, pathophysiology, optimal evaluation and treatment of patients, explanation of observations not explained by previous theories, and implications for further research and translation. The theory proposes that neurodegenerative diseases represent network insufficiencies, networks jeopardized by antagonistic pleiotropy. Through repeated evolutionary selection for performance over durability, highly functional and finely tuned neural subnetworks subserving key survival features such as lethal force and behavioral modification have evolved at the expense of durability and reserve. The Pr2 theory focuses on the physiology associated with the causes of neurodegeneration rather than the pathology that is largely reactive but has been the focus of the lion’s share of the research and attempted treatment of neurodegenerative diseases. Results Initial translation of the Pr2 theory to a precision medicine approach to cognitive decline has led to superior outcomes compared to other therapeutic approaches, and at least in some cases, sustained improvement for over a decade has been achieved. Conclusions The proposed theory explains key features of neurodegenerative disease pathophysiology and suggests novel therapeutic targets. Initial predictions have been validated in two proof-of-concept trials and one randomized controlled trial for patients with mild cognitive impairment or early-stage dementia.
Nov 2021 DOI 10.14302/issn.2641-4538.jphi-21-3993
Adenike Adeyemo-Salami OluwatoyinCorresponding author
Nutritional and Industrial Biochemistry Unit, Department of Biochemistry, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria.
Chlorogenic acid (CA), abundantly found in green coffee beans, is a phenolic compound with antioxidant and anti-inflammatory properties amongst others. Exposure to rotenone, a natural pesticide, induces Parkinsonism (a type of neurodegeneration) through the induction of mitochondria dysfunction and oxidative stress. Phytochemicals with antioxidant properties may be promising in attenuating this condition. In this research, the ameliorative role of CA on rotenone-induced toxicity in Drosophila melanogaster was evaluated. Drosophila melanogaster (Harwich strain, 1- 3 days old) was used. 6 groups of five vials each with 50 flies/vial were exposed to CA (0; control (2% ethanol), 7.5, 15, 30, 45 and 60 mg/kg diet) for 28 days in the longevity analysis. A 28-day survival assay was carried out with rotenone (0, 250 and 500 μM). CA (30 mg/kg diet) was selected to evaluate its ameliorative potential on rotenone. For the study, the flies were divided into four groups of five vials each and exposed to CA and rotenone; Group A- control (2% ethanol), Group B- CA only, Group C- rotenone only and Group D- CA (30 mg/kg diet)+ rotenone (500 μM)for 7 days. Thereafter, the homogenate was evaluated for oxidative stress status, rate of emergence, negative geotaxis and acetyl cholinesterase activity. CA (30 mg/kg diet) extended the lifespan of flies by 21.4%. Also, CA ameliorated rotenone-induced perturbation in catalase, glutathione-S-transferase and acetyl cholinesterase activities, total thiol and glutathione levels, and behavioral deficit (p < 0.05). CA may have ameliorative effect against rotenone-induced toxicity and Parkinsonism.
Mar 2016 DOI 10.14302/issn.2476-1710.jdt-15-719
Dhikav VikasCorresponding author
Postgraduate Institute of Medical Education & Research & Dr. Ram Manohar Lohia Hospital, New Delhi, INDIA
This clinical study explores associations among basal serum cortisol, depressive symptoms, and medial temporal lobe atrophy in patients with MCI and Alzheimer's disease. It discusses stress‑axis dysregulation as a potential contributor to neurodegeneration and outlines implications for assessment and intervention.