Emile Franssen

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.

Equilibrium and Limb Coordination in Mild Cognitive Impairment and Mild Alzheimer's Disease

OBJECTIVE: To examine changes in equilibrium and limb coordination in normal aging, mild cognitive impairment, and moderate cognitive impairment associated with early probable Alzheimers disease (AD), by means of parametric clinical measures.

Contractures and Loss of Function in Patients with Alzheimer's Disease

OBJECTIVE: To investigate the prevalence of contractures in patients with Alzheimers disease and to assess possible associations between contractures and cognitive and functional decline in Alzheimers disease.

The Behavior Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) : Reliability and analysis of symptom category scores

The interrater reliability of the Behavior Pathology in Alzheimers Disease Rating Scale (BEHAVE‐AD), a psychiatric rating scale especially designed for the evaluation of behavioral disturbances in dementia patients, was studied in both English‐speaking US patients and a French‐speaking elderly patient population from France. Additionally, the quantitative relationship between severity of Alzheimers disease (AD) and mean scores on each of the BEHAVE‐AD categories and mean total BEHAVE‐AD score was determined in a separate study of 140 patients diagnosed as having probable AD. In both reliability studies significant correlations were obtained for all BEHAVE‐AD symptom category scores and for mean total BEHAVE‐AD scores. Analysis of BEHAVE‐AD scores as a function of disease severity demonstrated a non‐linear relationship between severity of behavioral symptoms and the global and cognitive advance of AD. Moreover, score analysis of the BEHAVE‐AD indicates that these behavioral disturbances become most severe in the moderate and moderately severe stages of the illness. The results of these studies provide support for the reliability of the BEHAVE‐AD. Additionally, the BEHAVE‐AD provides basic knowledge about the nature and severity of the behavioral symptoms in AD. The latter information may be useful for the development of appropriate and effective psychopharmacologic intervention strategies for these difficult to manage behaviors. Furthermore, these results have implications for the methodology of pharmacologic trials of putative cognitive‐enhancer compounds in AD.

Mortality and Temporal Course of Probable Alzheimer's Disease: A 5-Year Prospective Study

Alzheimers disease (AD) is associated with an increased mortality in comparison with aged control populations. The relationship between the clinical and the temporal course of AD has not been well studied over significant intervals. Community-residing patients with probable AD (N = 103, 42 men, mean age = 70.2 +/- 8.0 years) were studied at baseline on demographic and clinical variables, including measures of global deterioration (Global Deterioration Scale; GDS), mental status and cognition (e.g., Mini-Mental State Examination; MMSE), and functional impairment (Functional Assessment Staging; FAST). Baseline characteristics included a GDS range of Stage 4, 5, or 6 (38.8%, 39.8%, and 21.4%, respectively) and a mean MMSE score of 15.4 +/- 5.6. The mean follow-up interval was 4.6 +/- 1.4 years. Follow-ups were done blind to baseline measures and when necessary were conducted in residential and nursing home settings. Of locatable subjects (n = 95, 92%), 30 (31.6%) were decreased. Survivors (n = 65) had a mean GDS stage of 6.2 +/- 0.9 and a mean MMSE score of 5.1 +/- 6.9; 51% had MMSE scores of 0. Increased age and male gender, but not baseline clinical dementia variables, increased the risk of death (ps < .01). Change in clinical variables correlated significantly with time elapsed (r = .32, p < .05, for MMSE change, to r = .48, p < .001, for GDS change). Significant variance in temporal change (i.e., time elapsed) was accounted for by change in two of the five clinical measures studied (i.e., GDS and FAST; multiple r = .53). The results support previous estimates of mean duration of the GDS and FAST stages. For subjects with probable AD followed over approximately 5 years, clinical variables changed significantly over time in survivors. However, the majority of temporal variance in the course of AD remains unexplained.

BEHAVE-AD: A Clinical Rating Scale for the Assessment of Pharmacologically Remediable Behavioral Symptomatology in Alzheimer’s Disease

The clinical characteristics of Alzheimer’s disease have only begun to be described in detail over the course of the past few years. In our laboratory, we initially described three broad clinical phases of the progression of the disease (Reisberg, 1981; Schneck et al., 1982). Subsequently, we published detailed descriptions of seven, clinically identifiable global stages in the progression from normal aging to most severe Alzheimer’s disease (Reisberg et al., 1982). Corresponding levels of cognitive abilities in terms of assessments of concentration, recent memory, past memory, orientation, and functioning and self-care have also been described (Reisberg et al., 1983a; Reisberg et al., 1984; Reisberg et al., 1985a) as has the stage-specific longitudinal outcome of subjects with normal aging and has progressive Alzheimer’s disease (Reisberg et al., 1986).

Age‐associated memory impairment: The clinical syndrome

Clinical concepts of age‐associated memory impairment (AAMI) have inevitably been linked to distinctions between this entity and progressive dementia, particularly Alzheimers disease (AD). Kral was perhaps the first modern clinician to attempt to delineate these distinctions. More recently, Folstein has suggested mental status boundaries between AAMI and progressive dementia, including AD. We have delineated clinically distinguishable stages of progressive cognitive impairment in AAMI and in AD. Present longitudinal investigations suggest clinical and mental status boundaries between these conditions. Cumulatively, these studies indicate that relatively precise clinical criteria for a diagnosis of AAMI and for a definition of boundaries between AAMI and AD can presently be formulated for the selection of appropriate study populations.

Symptomatic Changes in CNS Aging and Dementia of the Alzheimer Type: Cross-sectional, Temporal, and Remediable Concomitants

At the beginning of this decade, there was relatively little information available regarding the clinical symptomatology of Alzheimer’s disease (AD), the borders between “normal CNS aging” and AD, and the course of AD.

Neuromotor Changes in Alzheimer's Disease: Implications for Patient Care

As a result of the neuropathologic process of Alzheimers disease (AD), significant changes occur in neuromotor function (e.g., paratonia and compulsive grasping). These changes become manifest in the moderately severe stage of AD, when patients begin to require ongoing assistance with activities of daily life (ADL), and they are prominent in the severe stage of AD, when patients are continuously dependent on a caregiver. Patients in these stages often display behavioral disturbances during care activities. These disturbing behaviors result not only from cognitive impairment, but also from a patients physical inability to cooperate with the caregiver. When care management strategies take into account the characteristic physical restrictions resulting from the neuromotor changes that accompany advanced AD, the caregiving process may be significantly facilitated.