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  1. Article ; Online: Rationale for a Multi-Factorial Approach for the Reversal of Cognitive Decline in Alzheimer's Disease and MCI: A Review.

    Rao, Rammohan V / Subramaniam, Kaavya G / Gregory, Julie / Bredesen, Aida L / Coward, Christine / Okada, Sho / Kelly, Lance / Bredesen, Dale E

    International journal of molecular sciences

    2023  Volume 24, Issue 2

    Abstract: ... of abnormalities, such as insulin resistance, chronic inflammation, hypovitaminosis D, hormonal deficiencies, and ...

    Abstract Alzheimer's disease (AD) is a multifactorial, progressive, neurodegenerative disease typically characterized by memory loss, personality changes, and a decline in overall cognitive function. Usually manifesting in individuals over the age of 60, this is the most prevalent type of dementia and remains the fifth leading cause of death among Americans aged 65 and older. While the development of effective treatment and prevention for AD is a major healthcare goal, unfortunately, therapeutic approaches to date have yet to find a treatment plan that produces long-term cognitive improvement. Drugs that may be able to slow down the progression rate of AD are being introduced to the market; however, there has been no previous solution for preventing or reversing the disease-associated cognitive decline. Recent studies have identified several factors that contribute to the progression and severity of the disease: diet, lifestyle, stress, sleep, nutrient deficiencies, mental health, socialization, and toxins. Thus, increasing evidence supports dietary and other lifestyle changes as potentially effective ways to prevent, slow, or reverse AD progression. Studies also have demonstrated that a personalized, multi-therapeutic approach is needed to improve metabolic abnormalities and AD-associated cognitive decline. These studies suggest the effects of abnormalities, such as insulin resistance, chronic inflammation, hypovitaminosis D, hormonal deficiencies, and hyperhomocysteinemia, in the AD process. Therefore a personalized, multi-therapeutic program based on an individual's genetics and biochemistry may be preferable over a single-drug/mono-therapeutic approach. This article reviews these multi-therapeutic strategies that identify and attenuate all the risk factors specific to each affected individual. This article systematically reviews studies that have incorporated multiple strategies that target numerous factors simultaneously to reverse or treat cognitive decline. We included high-quality clinical trials and observational studies that focused on the cognitive effects of programs comprising lifestyle, physical, and mental activity, as well as nutritional aspects. Articles from PubMed Central, Scopus, and Google Scholar databases were collected, and abstracts were reviewed for relevance to the subject matter. Epidemiological, pathological, toxicological, genetic, and biochemical studies have all concluded that AD represents a complex network insufficiency. The research studies explored in this manuscript confirm the need for a multifactorial approach to target the various risk factors of AD. A single-drug approach may delay the progression of memory loss but, to date, has not prevented or reversed it. Diet, physical activity, sleep, stress, and environment all contribute to the progression of the disease, and, therefore, a multi-factorial optimization of network support and function offers a rational therapeutic strategy. Thus, a multi-therapeutic program that simultaneously targets multiple factors underlying the AD network may be more effective than a mono-therapeutic approach.
    MeSH term(s) Humans ; Alzheimer Disease/pathology ; Neurodegenerative Diseases/complications ; Cognitive Dysfunction/drug therapy ; Cognition ; Memory Disorders/complications
    Language English
    Publishing date 2023-01-14
    Publishing country Switzerland
    Document type Systematic Review ; Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms24021659
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease.

    Chwa, Won Jong / Raji, Cyrus A / Toups, Kat / Hathaway, Ann / Gordon, Deborah / Chung, Henrianna / Boyd, Alan / Hill, Benjamin D / Hausman-Cohen, Sharon / Attarha, Mouna / Jarrett, Michael / Bredesen, Dale E

    Journal of Alzheimer's disease : JAD

    2023  Volume 96, Issue 3, Page(s) 1051–1058

    Abstract: Background: Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and ... ...

    Abstract Background: Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized.
    Objective: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI).
    Methods: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios.
    Results: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.
    MeSH term(s) Humans ; Gray Matter/diagnostic imaging ; Gray Matter/pathology ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/therapy ; Precision Medicine ; Magnetic Resonance Imaging/methods ; Brain/diagnostic imaging ; Brain/pathology ; White Matter/diagnostic imaging ; White Matter/pathology ; Cognitive Dysfunction/diagnostic imaging ; Cognitive Dysfunction/pathology ; Atrophy/pathology
    Language English
    Publishing date 2023-11-27
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-230481
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Precision Medicine Approach to Alzheimer's Disease: Rationale and Implications.

    Bredesen, Dale E / Toups, Kat / Hathaway, Ann / Gordon, Deborah / Chung, Henrianna / Raji, Cyrus / Boyd, Alan / Hill, Benjamin D / Hausman-Cohen, Sharon / Attarha, Mouna / Chwa, Won Jong / Kurakin, Alexei / Jarrett, Michael

    Journal of Alzheimer's disease : JAD

    2023  Volume 96, Issue 2, Page(s) 429–437

    Abstract: The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical ... ...

    Abstract The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer's disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.
    MeSH term(s) Humans ; Alzheimer Disease/drug therapy ; Precision Medicine/methods ; Neurodegenerative Diseases ; Cognitive Dysfunction
    Language English
    Publishing date 2023-10-05
    Publishing country Netherlands
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-230467
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Neurology: neurologic manifestations of AIDS.

    Bredesen, D E

    The Western journal of medicine

    2008  Volume 142, Issue 1, Page(s) 84

    Language English
    Publishing date 2008-08-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 189235-6
    ISSN 1476-2978 ; 0093-0415 ; 0008-1264
    ISSN (online) 1476-2978
    ISSN 0093-0415 ; 0008-1264
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Precision Medicine Approach to Alzheimer's Disease: Successful Pilot Project.

    Toups, Kat / Hathaway, Ann / Gordon, Deborah / Chung, Henrianna / Raji, Cyrus / Boyd, Alan / Hill, Benjamin D / Hausman-Cohen, Sharon / Attarha, Mouna / Chwa, Won Jong / Jarrett, Michael / Bredesen, Dale E

    Journal of Alzheimer's disease : JAD

    2022  Volume 88, Issue 4, Page(s) 1411–1421

    Abstract: Background: Effective therapeutics for Alzheimer's disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of ...

    Abstract Background: Effective therapeutics for Alzheimer's disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy.
    Objective: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial.
    Methods: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months.
    Results: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved.
    Conclusion: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.
    MeSH term(s) Alzheimer Disease/complications ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/therapy ; Cognition ; Cognitive Dysfunction/diagnosis ; Humans ; Pilot Projects ; Precision Medicine
    Language English
    Publishing date 2022-07-27
    Publishing country Netherlands
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-215707
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Next generation therapeutics for Alzheimer's disease.

    Bredesen, Dale E / John, Varghese

    EMBO molecular medicine

    2013  Volume 5, Issue 6, Page(s) 795–798

    Abstract: To date, no truly effective therapy has been developed for Alzheimer's disease or mild cognitive impairment. In searching for new approaches that may succeed where previous ones have failed, it may be instructive to consider the successful therapeutic ... ...

    Abstract To date, no truly effective therapy has been developed for Alzheimer's disease or mild cognitive impairment. In searching for new approaches that may succeed where previous ones have failed, it may be instructive to consider the successful therapeutic developments for other chronic illnesses such as cancer and human immunodeficiency virus.
    MeSH term(s) Aging ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Alzheimer Disease/therapy ; Amyloid beta-Peptides/antagonists & inhibitors ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Apolipoprotein E4/genetics ; Apolipoprotein E4/metabolism ; Humans ; Mice ; Vitamin D/metabolism
    Chemical Substances Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Apolipoprotein E4 ; Vitamin D (1406-16-2)
    Language English
    Publishing date 2013-05-23
    Publishing country England
    Document type Journal Article
    ZDB-ID 2467145-9
    ISSN 1757-4684 ; 1757-4676
    ISSN (online) 1757-4684
    ISSN 1757-4676
    DOI 10.1002/emmm.201202307
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: ReCODE: A Personalized, Targeted, Multi-Factorial Therapeutic Program for Reversal of Cognitive Decline.

    Rao, Rammohan V / Kumar, Sharanya / Gregory, Julie / Coward, Christine / Okada, Sho / Lipa, William / Kelly, Lance / Bredesen, Dale E

    Biomedicines

    2021  Volume 9, Issue 10

    Abstract: ... HOMA-IR, and vitamin D significantly improved in the participant pool. Our findings provide evidence ...

    Abstract Background: Alzheimer's disease (AD) is the major cause of age-associated cognitive decline, and in the absence of effective therapeutics is progressive and ultimately fatal, creating a dire need for successful prevention and treatment strategies. We recently reported results of a successful proof-of-concept trial, using a personalized, precision medicine protocol, but whether such an approach is readily scalable is unknown.
    Objective: In the case of AD, there is not a single therapeutic that exerts anything beyond a marginal, unsustained, symptomatic effect. This suggests that the monotherapeutic approach of drug development for AD may not be an optimal one, at least when used alone. Using a novel, comprehensive, and personalized therapeutic system called ReCODE (reversal of cognitive decline), which proved successful in a small, proof-of-concept trial, we sought to determine whether the program could be scaled to improve cognitive and metabolic function in individuals diagnosed with subjective cognitive impairment, mild cognitive impairment, and early-stage AD.
    Methods: 255 individuals submitted blood samples, took the Montreal Cognitive Assessment (MoCA) test, and answered intake questions. Individuals who enrolled in the ReCODE program had consultations with clinical practitioners, and explanations of the program were provided. Participants had follow-up visits that included education regarding diet, lifestyle choices, medications, supplements, repeat blood sample analysis, and MoCA testing between 2 and 12 months after participating in the ReCODE program. Pre- and post-treatment measures were compared using the non-parametric Wilcoxon signed rank test.
    Results and conclusions: By comparing baseline to follow-up testing, we observed that MoCA scores either significantly improved or stabilized in the entire participant pool-results that were not as successful as those in the proof-of-concept trial, but more successful than anti-amyloid therapies-and other risk factors including blood glucose, high-sensitivity C-reactive protein, HOMA-IR, and vitamin D significantly improved in the participant pool. Our findings provide evidence that a multi-factorial, comprehensive, and personalized therapeutic program designed to mitigate AD risk factors can improve risk factor scores and stabilize or reverse the decline in cognitive function. Since superior results were obtained in the proof-of-concept trial, which was conducted by a small group of highly trained and experienced physicians, it is possible that results from the use of this personalized approach would be enhanced by further training and experience of the practicing physicians. Nonetheless, the current results provide further support indicating the potential of such an approach for the prevention and reversal of cognitive decline.
    Language English
    Publishing date 2021-09-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2720867-9
    ISSN 2227-9059
    ISSN 2227-9059
    DOI 10.3390/biomedicines9101348
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Neurodegenerative disease and cancer: two sides of a coin?

    Bredesen, D E

    Hospital practice (1995)

    2001  Volume 36, Issue 9, Page(s) 39–42, 45

    Abstract: The mechanisms underlying disruption of physiologic cell-death programs are slowly being revealed. Information gleaned from genetic profiles soon may allow physicians to delay onset of many silent, age-related diseases. While development of actual cures ... ...

    Abstract The mechanisms underlying disruption of physiologic cell-death programs are slowly being revealed. Information gleaned from genetic profiles soon may allow physicians to delay onset of many silent, age-related diseases. While development of actual cures could prove elusive, simply postponing clinical onset would have an impressive effect on the goal of healthy aging.
    MeSH term(s) Aging/physiology ; Apoptosis/genetics ; Humans ; Neoplasms/etiology ; Neoplasms/genetics ; Neurodegenerative Diseases/etiology ; Receptors, Androgen/metabolism ; Signal Transduction
    Chemical Substances Receptors, Androgen
    Language English
    Publishing date 2001-08-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 2570453-9
    ISSN 2377-1003 ; 2154-8331 ; 8750-2836
    ISSN (online) 2377-1003
    ISSN 2154-8331 ; 8750-2836
    DOI 10.1080/21548331.2001.11444144
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Apoptosis: overview and signal transduction pathways.

    Bredesen, D E

    Journal of neurotrauma

    2000  Volume 17, Issue 10, Page(s) 801–810

    Abstract: Apoptosis is a form of cell death that is driven by an intrinsic cellular suicide program. The roles of apoptosis and other forms of programmed cell death in neural development, maintenance, and disease states are increasingly being recognized and ... ...

    Abstract Apoptosis is a form of cell death that is driven by an intrinsic cellular suicide program. The roles of apoptosis and other forms of programmed cell death in neural development, maintenance, and disease states are increasingly being recognized and defined. Therapies directed at the apoptotic program have seen at least some degree of success in animal models of neurodegenerative disease, vascular disease, and traumatic CNS injury. This article describes the signal transduction pathways that mediate apoptosis. Broadly speaking, intrinsic and extrinsic pathways for apoptosis activation may be distinguished, as can be cross-talk between these two. These pathways converge on a system of proteases referred to as "capases" (cysteinyl aspartic proteinases), and modulators exist that multimerize, activate, amplify, or inhibit caspases. Activated caspases are the executioners of the apoptotic program, and carry out this function by cleaving specific cellular substrates. Modulation of this process holds promise as a therapeutic approach in neurotrauma.
    MeSH term(s) Animals ; Apoptosis/genetics ; Caspases/metabolism ; Humans ; Nerve Degeneration/pathology ; Nerve Degeneration/physiopathology ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Receptors, Cell Surface/metabolism ; Signal Transduction/physiology
    Chemical Substances Proto-Oncogene Proteins c-bcl-2 ; Receptors, Cell Surface ; Caspases (EC 3.4.22.-)
    Language English
    Publishing date 2000-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S. ; Review
    ZDB-ID 645092-1
    ISSN 1557-9042 ; 0897-7151
    ISSN (online) 1557-9042
    ISSN 0897-7151
    DOI 10.1089/neu.2000.17.801
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Genetic control of neural cell apoptosis.

    Bredesen, D E

    Perspectives on developmental neurobiology

    1996  Volume 3, Issue 2, Page(s) 101–109

    Abstract: Apoptosis is a mode of cell death in which the cell plays an active role in its own death. Apoptosis occurs both within and outside the nervous system. Neural apoptosis occurs not only in neural development, but also in pathophysiological states such as ... ...

    Abstract Apoptosis is a mode of cell death in which the cell plays an active role in its own death. Apoptosis occurs both within and outside the nervous system. Neural apoptosis occurs not only in neural development, but also in pathophysiological states such as stroke and beta-amyloid peptide toxicity. The mechanism by which apoptosis occurs is unknown, but several genes controlling the process have been identified. In some cases, these genes also have an effect on necrotic neural cell death. The finding that the cell plays an active role in its own death, and that specific gene products are involved, suggests that therapeutic intervention may be feasible.
    MeSH term(s) Animals ; Apoptosis/physiology ; Caenorhabditis elegans/physiology ; Cell Death/physiology ; Genes ; Humans ; Nervous System/growth & development ; Neurons/physiology ; Terminology as Topic
    Language English
    Publishing date 1996
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 914744-5
    ISSN 1064-0517
    ISSN 1064-0517
    Database MEDical Literature Analysis and Retrieval System OnLINE

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