Challenges and Opportunities in Alzheimer's Disease
Ivan V. Maksimovich
Abstract
Background: Alzheimer’s disease (AD) and Binswanger’s disease (BD) are among the most common neurodegenerative disorders associated with cognitive impairment and dementia. Using energy of lasers with low output power of the red or near-infrared spectrum region called Photobiomodulation Therapy (PBMT), is an achievement in the development of methods for the treatment of these diseases.
Aims: The present study investigates the impact of Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT) on the reduction of cognitive, mental impairment and dementia in patients with various Alzheimer’s Disease and Binswanger’s Disease stages.
Methods: For the research, we selected 62 patients suffering from dementia, aged 34-81 (mean age 72.75), 25 men (40.32%), 37 women (59.68%).
Test Group 1 – 48 patients previously diagnosed with Alzheimer’s Disease. According to dementia severity, patients were subdivided: preclinical stage (dementia level TDR-0) – 4, mild stage (dementia level TDR-1) – 16, moderately severe stage (dementia level TDR-2) – 21, severe stage (dementia level TDR-3) – 7.
Test Group 2 – 14 patients with previously diagnosed Binswanger’s Disease. According to dementia severity, the patients were subdivided: mild stage (dementia level CDR-1) – 9, moderately severe stage (dementia level CDR-2) – 5.
All patients underwent Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT).
Results:
Test Group 1. Thanks to angiogenesis and neurogenesis stimulation using Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT), in all 48 (100%) cases, cerebral blood supply and microcirculation improved, cerebral involutive and atrophic changes decreased. Patients showed persistently decreasing dementia, cognitive and mental abilities improvement. The vast majority began to correspond to the group with a milder disease stage.
Test Group 2. Due to angiogenesis and neurogenesis stimulation, all 14 (100%) cases demonstrated stable dementia reduction, restoration of cognitive, mental functions and daily life activities.
Conclusion: Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT) is an effective, physiologically based method of stimulating cerebral angiogenesis and neurogenesis for Alzheimer’s Disease and Binswanger’s Disease patients. Due to complex laser exposure, patients show cerebral collateral and capillary revascularization, tissue metabolism improvement and cerebral regenerative processes development. Clinically, this leads to stable dementia level decrease, cognitive functions restoration and improvement in patients’ quality of life. The resulting clinical effect lasts for many years.
Charles S. Wilcox, Ph.D., M.P.A., M.B.A.
Abstract
The 2021 approval of aducanumab in the United States, was not followed by approvals in Europe, Canada, Australia or elsewhere; nonetheless, the initial pricing of $56,00.00/year created a firestorm of controversy. The 2023 Food and Drug Administration approval of lecanemab has been followed by approvals in Japan and China. The current (2024) costs are $26,500 in USA, $20,438 (National Health Insurance) in Japan and $28,180 (private market) in China. In Europe, a health technology assessment will drive coverage decisions and set single-payer prices for each health system for lecanemab and subsequently approved new treatments. For comparison, 2024 average pricing for the top five selling drugs for cancer [$198,273], arthritis [$83,666], hepatitis C [$75,118] and multiple sclerosis [$86,765] far exceed lecanemab’s annual cost. Could there be an anti-brain-health bias?
The International Consortium for Health Outcomes Measurement notes that patient-centered outcome measures represent the ultimate measure of quality and they are always multi-dimensional. Quality-adjusted life-years (QALY) seem to be absent from the computation of pricing for anti-dementia treatments. Although global consensus on QALY calculations remains elusive, currently extant data are compelling. The QALY calculation is the change in utility value induced by the treatment, which is then multiplied by the duration of treatment effect to provide the number of QALYs gained. QALY ranges differ quite significantly, even amongst the most industrialized nations. Value-based pricing from double-blind, placebo-controlled trial results, demonstrating statistically significant beneficial effects on cognition and/or global function, would reward manufacturers for innovation whilst also enabling payer systems to remain solvent.
Now that the first truly disease-modifying treatment for Alzheimer’s (lecanemab) has been approved, a second disease-modifying treatment (donanemab) appears to be heading for regulatory approval as well. The full value of these newest anti-dementia treatments may be understated when quantified under older pricing models and, hence, could unwittingly be a disincentive to further innovation. We now have disease-modifying and symptomatic relief treatments for Alzheimer’s disease to be included within the treating clinicians’ armamentarium and, when priced appropriately, access should be widely available whilst also encouraging further innovative anti-Alzheimer’s clinical research.
Abstract
Alzheimer’s disease (AD) is an age-related progressive neurodegenerative brain disorder with cognitive symptoms as a hallmark phenotype of the disease. Masupirdine, a pure serotonin 6 (5-HT6) receptor antagonist is being developed for the treatment of cognitive deficits in AD. The objective of the current study is the post hoc analysis of a multicenter, randomized, double-blind, parallel group, 26-week, placebo-controlled phase-2 study (NCT02580305) that evaluated the effects of masupirdine on cognition in patients with moderate AD.
Methods: Masupirdine phase 2 study included AD patients of 50 to 85 years age, mini-mental state examination (MMSE) score of 12 to 20 and diagnosis of probable AD at least 1 year prior to the screening visit. The impact of age, cognitive impairment severity, and duration of disease since diagnosis on efficacy of masupirdine as assessed by 11-item version of the Alzheimer’s Disease Assessment Scale–Cognitive subscale (ADAS-Cog 11) was evaluated. Treatment effects were assessed by Cohen’s d effect size.
Results: Cohen’s d effect size for change in ADAS-Cog 11 scores from baseline to week 26 ranged between ~0.2 and 0.4 for the subgroup of population with age ≤ 70 years, MMSE range of 18 to 20, and duration of disease over 4 years (since diagnosis).
Conclusions: Considering the linear relationship between age and cognitive decline, masupirdine effects across the subgroups could be attributed to “slowing of cognitive decline”. The study provides important findings for design of future clinical trials. Further research is warranted to confirm the potential beneficial effects of masupirdine on cognition in AD patients.
Michael S. Wolfe
Abstract
For over 30 years, the amyloid hypothesis of Alzheimer’s disease has dominated this field of biomedical investigation. The hypothesis posits that aggregation of the amyloid β-peptide (Aβ) in the brain triggers a cascade of events that ultimately lead to neurodegeneration and cognitive decline. Early genetic and biochemical evidence supported a critical role of Aβ, particularly the 42-residue form Aβ42: Dominant missense mutations in the substrate (amyloid precursor protein, APP) and enzyme (γ-secretase) that produce Aβ cause early-onset familial Alzheimer’s disease (FAD). Nevertheless, serious gaps remain in understanding pathogenic pathways, and despite intense efforts over many years, effective agents for Alzheimer’s disease have been elusive. Here I discuss recent efforts to elucidate precisely how FAD mutations alter the complex proteolytic processing of APP substrate by γ-secretase, with results suggesting pathogenic triggers other than Aβ42.
Hirohisa Ono, Yoji Nishijima, Masaki Sakamoto, Soitirou Kitamura, Yuitiou Naitoh, Keiko Suzuki, Norio Fujii, Ryouta Kikura, and Shigeo Ohta
Abstract
Introduction: Molecular hydrogen (H2) has emerged as a therapeutic medical gas that exerts multiple functions. H2 inhalation has been approved as safe, and some clinical studies showed that it effectively improved conditions of patients with a variety of disorders such as stroke, heart infarction, chronic obstructive pulmonary disease, cancer, and COVID-19. Urinary and fecal incontinences are unavoidable symptoms of advanced Alzheimer’s disease (AD) dementia. In particular, fecal incontinence increases the level of confusion for patients and caretakers suffer from increased workloads.
Materials and Methods: To assess the integrity of the neurons related to AD, the bundles of neurons passing through the hippocampus were visualized by modified diffusion tensor imaging (DTI) technology using advanced magnetic resonance imaging (MRI)
Results: A 79-year-old woman with advanced AD continued to inhale 3% H2 gas containing 21% oxygen twice daily for 1 hour and maintained clinical observations for 2 years. After the long period of inhalation of H2 gas, the patient went to the bathroom by herself for adequate excretion. She remained to be able to go to the bathroom for her bowel movements in time, afterwards. After the long-term inhalation of H2 gas, her MRI of the brain to generate DTI images with an anisotropic (FA) value of 0.2 (FA = 0.2) showed improved integrity of the hippocampal neurons along with these clinical improvements.
Conclusion: This case report casts the question on the current understanding that the advanced and severe AD patients will never improve.
Ivan V. Maksimovich
Abstract
Background: Alzheimer’s disease (AD) is the leading neurodegenerative disease associated with dementia and cognitive impairment. A major achievement in AD treatment was the use of lasers with low output power of the red or near-infrared spectral region, which was named Photobiomodulation Therapy (PBMT).
Aims: This study investigates the effect of PBMT on regression of dementia and cognitive impairment among patients with various AD stages.
Methods: For the study, 97 patients with previously diagnosed AD, aged 34-80 (mean age 67.5), 34 (35.05%) men, 63 (64.95%) women, were selected. According to AD severity, the patients were subdivided: preclinical stage TDR-0 – 10 (10.31%), mild stage TDR-1 – 28 (28.87%), moderately severe stage TDR-2 – 42 (43.30%), severe stage TDR-3 – 17 (17.52%).
Test Group – 48 (49.48%) patients, 17 (35.42%) men, 31 (54.58%) women, underwent Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT).
Control Group – 49 (50.32%) patients, 16 (32.65%) men, 33 (67.35%) women, underwent conservative treatment with Memantine and Rivastigmine.
Results:
Test Group. Due to angiogenesis and neurogenesis stimulation with Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT), all the patients had an improvement in cerebral blood supply and microcirculation and a decrease in cerebral involutive changes. Consequently, all the patients showed reduced dementia and improved cognitive abilities. The vast majority of the patients began to correspond to the group of a milder AD stage.
Control Group. No persistent expressed positive dynamics. Partial improvement was obtained only among patients with early AD stages.
Conclusion: Transcatheter Intracerebral Laser Photobiomodulation Therapy (PBMT) is an effective, physiologically based method of stimulating cerebral angiogenesis and neurogenesis. As a result of such a complex impact, patients with various AD stages have cerebral capillary collateral revascularization, their tissue metabolism improves, and regenerative processes develop in the cerebral tissue. Tissue regeneration leads to an increase in the volume of the temporal and frontoparietal sections. Clinically, this leads to a stable decrease in dementia level, cognitive functions restoration, and improved quality of patients’ life. The resulting clinical effect lasts for many years.
Conservative treatment with Memantine and Rivastigmine is not effective enough.
Md Gulzar Hussain and Ye Shiren
Abstract
Dementia, a prevalent neurodegenerative condition, is a significant aspect of Alzheimer’s disease (AD), causing progressive impairment in daily functioning. Accurate and timely classification of AD stages is crucial for effective management. Machine learning and deep learning models have shown promise in this domain. In this study, we proposed an approach that utilizes support vector machine (SVM), random forest (RF), and convolutional neural network (CNN) algorithms to classify the four stages of dementia. We augmented these algorithms with watershed segmentation to extract meaningful features from MRI images. Notably, our findings demonstrate that SVM with watershed features achieves an impressive accuracy of 96.25%, outperforming other classification methods. The evaluation of our method was performed using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, and the inclusion of watershed segmentation was found to significantly enhance the performance of the models. This study highlights the potential of incorporating watershed segmentation into machine learning-based AD classification systems, offering a promising avenue for accurate diagnosis and treatment planning.
