Sunnie Kenowsky

Evidence and mechanisms of retrogenesis in Alzheimer's and other dementias: Management and treatment import

Retrogenesis is the process by which degenerative mechanisms reverse the order of acquisition in normal development. Alzheimers disease (AD) and related conditions in the senium have long been noted to resemble “a return to childhood.” Previously, we noted that the functional stages of AD precisely and remarkably recapitulated the acquisition of the same functional landmarks in normal human development. Subsequent work indicated that this developmental recapitulation also applied to the cognitive and related symptoms in AD. Remarkably, further investigations revealed that the same neurologic “infantile” reflexes, which mark the emergence from infancy in normal development, are equally robust indicators of corresponding stages in AD. Neuropathologic and biomolecular mechanisms for these retrogenic processes are now evident. For example, the pattern of myelin loss in AD appears to mirror the pattern of myelin acquisition in normal development. Also, recent findings indicate that mitogenic factors become reactivated in AD, and, consequently, the most actively “growing” brain regions are the most vulnerable. Because of this robust retrogenic process, the stages of AD can be translated into corresponding developmental ages (DAs). These DAs can account for the overall management and care needs of AD patients. A science of AD management can be formulated on the basis of the DA of the Alzheimers patient, taking into consideration differences of AD from normal development as well as homologies.

Retrogenesis: clinical, physiologic, and pathologic mechanisms in brain aging, Alzheimer's and other dementing processes.

Abstract Data from clinical, electrophysiologic, neurophysiologic, neuroimaging and neuropathologic sources indicates that the progression of brain aging and Alzheimer’s disease (AD) deterioration proceeds inversely to human ontogenic acquisition patterns. A word for this process of degenerative developmental recapitulation, “retrogenesis”, has been proposed. These retrogenic processes provide new insights into the pathologic mechanism of AD deterioration. An understanding of retrogenic phenonmena can also result in insights into the applicability of retrogenic pathologic mechanisms for non-AD dementing disorders. Management strategies based upon retrogenesis have recently been proposed. Retrogenic pathophysiology also points to previously unexplored pharmacologic approaches to dementia prevention and treatment.

Progression of Alzheimer’s disease: variability and consistency: ontogenic models, their applicability and relevance

Much has been learned about the clinical symptomatology of Alzheimers disease (AD) and ontogenic reciprocal relationships in the past few decades. It is now possible to describe and verify inexorable symptomatic sequences and corresponding temporal relationships. It is also possible to identify more variable symptoms in AD. Ontogenic models can be useful in providing a clearer understanding of the nature of AD symptomatology in terms of both consistency and variability. These models can also be informative in explicating the management needs of AD patients and the treatment possibilities of AD symptoms as well as the etiology of variability in AD symptoms.

The BEHAVE-AD Assessment System: A Perspective, A Commentary on New Findings, and A Historical Review

Background: Behavioral and psychological symptoms of dementia (BPSD) and associated disturbances in Alzheimers disease (AD) are a source of distress and burden for spouses, professional caregivers, and others with responsibilities for the care of individuals with AD. BPSD with behavioral disturbances are also associated with more rapid institutionalization and increased morbidity and mortality for persons with AD. Objectives: In this review and commentary, we discuss the history of the development of BPSD and behavioral disturbance assessments, which are distinct from those evaluating cognitive and functional symptoms of AD. In particular, we review the informant-based Behavioral Pathology in Alzheimers Disease Rating Scale (BEHAVE-AD), the related, potentially more sensitive, BEHAVE-AD Frequency-Weighted Severity Scale (BEHAVE-AD-FW), and the direct subject evaluation-based Empirical BEHAVE-AD Rating Scale (E-BEHAVE-AD). The kinds of medications that alleviate behavioral symptoms on these measures as well as the problems and possibilities for further advances with these medications are discussed. Finally, the importance of distinguishing BPSD and behavioral disturbance remediation in AD from the treatment of cognitive decline and other aspects of AD is emphasized in the context of appropriate assessment methodology. The objective of this paper is to provide a framework for further advances in the treatment of BPSD and associated behavioral disturbances in AD and, consequently, a framework for continuing improvements in the lives of individuals with AD and those who share the burden of the disease with the AD person.

Do many of the behavioral and psychological symptoms of dementia constitute a distinct clinical syndrome? Current evidence using the BEHAVE-AD

The Behavioral Pathology in Alzheimers Disease Rating Scale (BEHAVE-AD) was specifically designed to assess behavioral and psychological symptoms of dementia (BPSD) that would be remediable to both psychologic and pharmacologic intervention. Furthermore, the BEHAVE-AD was designed to assess categories of symptoms that would respond in a cohesive (syndrome) manner in dementia patients, independently of effects of interventions on cognition and functioning. Current data indicate that the BEHAVE-AD does indeed assess a cohesive, cognition- and function independent syndrome in AD and in related dementias that is responsive to psychologic and appropriate pharmacologic intervention. Evidence is also increasing for differential responsiveness of this BPSD syndrome to select pharmacologic agents compared with nonspecific psychologic (placebo) intervention. This article reviews the evidence for this BPSD syndrome in dementia patients, as assessed with the BEHAVE-AD.

COMPREHENSIVE, INDIVIDUALIZED, PERSON-CENTERED MANAGEMENT PROGRAM REDUCES RISK OF HOSPITALIZATION BY 67% AND EMERGENCY ROOM VISITS BY 50% IN COMMUNITY-RESIDING, ADVANCED AD PERSONS IN A 28-WEEK RANDOMIZED, CONTROLLED TRIAL

In addition, twelve speech clinicians blinded to the experimental conditions rated participants’ decisional capabilities. Results: Results showed that participants demonstrated significantly better overall decisional capacity in Understanding (p<.001), Reasoning (p<.001), and Appreciation (p<.001) when supported by visual aids. No significant differences between conditions were found for Expressing a Choice. Participants generated significantly more Rewordings and Exact Statements (p<.001), and significantly fewer Statements Not Mentioned (p<.001), in the visual condition than in the verbal condition. In addition, participants with mild dementia produced more Rewordings (p<.008), while those with moderate dementia offered more Exact Statements (p<.02). Overall, clinicians’ ratings validated participants’ decision-making performance on the experimental tasks, reflecting greater agreement in the visual condition, than in the verbal condition (p<.001 for 6 of 8 ratings). Conclusions:Visual aids were found to enable persons with mild and moderate dementia to make reliable decisions about endof-life care.

Comprehensive, Individualized, Person-Centered Management of Community-Residing Persons with Moderate-to-Severe Alzheimer Disease: A Randomized Controlled Trial.

Background/Aims: The aim was to examine added benefits of a Comprehensive, Individualized, Person-Centered Management (CI-PCM) program to memantine treatment. Methods: This was a 28-week, clinician-blinded, randomized, controlled, parallel-group study, with a similar study population, similar eligibility criteria, and a similar design to the memantine pivotal trial of Reisberg et al. [N Engl J Med 2003;348:1333-1341]. Twenty eligible community-residing Alzheimer disease (AD) subject-caregiver dyads were randomized to the CI-PCM program (n = 10) or to usual community care (n = 10). Primary outcomes were the New York University Clinicians Interview-Based Impression of Change Plus Caregiver Input (NYU-CIBIC-Plus), assessed by one clinician set, and an activities of daily living inventory, assessed by a separate clinician set at baseline and at weeks 4, 12, and 28. Results: Primary outcomes showed significant benefits of the CI-PCM program at all post-baseline evaluations. Improvement on the NYU-CIBIC-Plus in the management group at 28 weeks was 2.9 points over the comparator group. The memantine 2003 trial showed an improvement of 0.3 points on this global measure in memantine-treated versus placebo-randomized subjects at 28 weeks. Hence, globally, the management program intervention benefits were 967% greater than memantine treatment alone. Conclusion: These results are approximately 10 times those usually observed with both nonpharmacological and pharmacological treatments and indicate substantial benefits with the management program for advanced AD persons.

COMPREHENSIVE, INDIVIDUALIZED, PERSON-CENTERED MANAGEMENT PROGRAM IN SUBJECTS TREATED WITH MEMANTINE ENHANCES FUNCTIONING BY 750%, IN COMPARISON WITH MEMANTINE TREATMENT ALONE, IN PERSONS WITH MODERATE-TO-SEVERE AD IN 28-WEEK RANDOMIZED CONTROLLED TRIALS

F1-01-04 COMPREHENSIVE, INDIVIDUALIZED, PERSON-CENTERED MANAGEMENT PROGRAM IN SUBJECTS TREATEDWITH MEMANTINE ENHANCES FUNCTIONING BY 750%, IN COMPARISON WITH MEMANTINE TREATMENTALONE, IN PERSONS WITH MODERATE-TO-SEVERE AD IN 28-WEEK RANDOMIZED CONTROLLED TRIALS Sunnie Kenowsky, Isabel Monteiro, Carol Torossian, Sloane Heller, Zabeen Noorani, Yongzhao Shao, Barry Reisberg, New York University School of Medicine, New York, NY, USA; New York University Langone Medical Center, New York, NY, USA; New York University Alzheimer’s Disease Center, NYU Langone Medical Center, New York, NY, USA. Contact e-mail: sunnie.kenowsky@nyumc.org

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