Studies of therapeutic agents in SCI treatment and resultant Alzheimer's disease prevention appear to be feasible. These trials are also necessary from a public health perspective.

Before the development of the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) rating scale in 1987 by Reisberg and colleagues and its predecessor scale, the Symptoms of Psychosis in Alzheimer's Disease (SPAD) rating scale, in 1985 by Reisberg and Ferris, other scales were available for measuring behavioral disturbances and psychiatric disorders in patients with Alzheimer's disease. However, these scales generally mixed together cognitive disturbances with behavioral symptoms and sometimes included functional impairments as well. These predecessor scales also were not specifically designed to assess the types of behavioral problems seen in Alzheimer's disease. If a scale did address behavioral disturbances of dementia, it tended to be seriously underspecified in terms of the nature of behavioral disturbances.

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.

Several investigators have suggested that the pathological progression of Alzheimer's disease appears to recapitulate the developmental maturation pattern, a process termed retrogenesis. Diffusion tensor imaging was used to test the hypothesis that the microstructural integrity of superior frontal and temporal white matter, one of the last regions to mature, would be reduced in vivo in early Alzheimer's disease. Five consecutive slices, from the orbitofrontal to periventricular frontal regions, as well as temporal and corpus callosal white matter regions, were sampled. Fractional anisotropy, mean diffusivity, axial diffusion, and radial diffusion of 10 patients with early Alzheimer's disease and 10 age-similar healthy control subjects were compared. Patients with Alzheimer's disease were found to have significantly reduced fractional anisotropy, increased mean diffusivity, and increased radial diffusion in superior frontal white matter. These data suggest that the integrity of periventricular frontal white matter rather than orbitofrontal white matter appears to be altered in early Alzheimer's disease and that the white matter abnormalities involve compromised myelin, consistent with the retrogenesis theory.

Alzheimer's disease (AD) is asociated 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 year. 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 deceased. 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.

Triplication of chromosome 21 in Down syndrome (DS) results in overexpression of the minibrain kinase/dual-specificity tyrosine phosphorylated and regulated kinase 1A gene (DYRK1A). DYRK1A phosphorylates cytoplasmic tau protein and appears in intraneuronal neurofibrillary tangles (NFTs). We have previously shown significantly more DYRK1A-positive NFTs in DS brains than in sporadic Alzheimer disease (AD) brains. This study demonstrates a gene dosage–proportional increase in the level of DYRK1A in DS in the cytoplasm and the cell nucleus and enhanced cytoplasmic and nuclear immunoreactivity of DYRK1A in DS. The results suggest that overexpressed DYRK1A may alter both phosphorylation of tau and alternative splicing factor (ASF). Two-dimensional electrophoresis revealed modification of ASF phosphorylation in DS/AD and AD in comparison to controls. Altered phosphorylation of ASF by overexpressed nuclear DYRK1A may contribute to the alternative splicing of the tau gene and an increase by 2.68× of the 3R/4R ratio in DS/AD, and a several-fold increase in the number of 3R-tau–positive NFTs in DS/AD subjects compared to in sporadic AD subjects. These data support the hypothesis that phosphorylation of ASF by overexpressed DYRK1A may contribute to alternative splicing of exon 10, increased expression of 3R tau, and early onset of neurofibrillary degeneration in DS.

The Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) is a well-established instrument, designed to assess potentially remediable behavioral symptoms in Alzheimer's disease (AD) patients as well as to evaluate treatment outcome. It consists of 25 symptoms grouped into seven categories. Each symptom is scored on the basis of severity on a four-point scale. A knowledgeable caregiver is queried and items are scored on the basis of symptoms noted in the preceding two weeks. Reliability, construct validity and criterion validity data for the BEHAVE-AD have previously been published. Because of the significance of psychopathology in dementia, it is necessary to optimally describe and define the nature, magnitude and prevalence of behavioral symptomatology. Accordingly, a frequency component was added to each of the 25 items of the BEHAVE-AD scale. The objective of the present report is to describe this new Behavioral Pathology in Alzheimer's Disease Frequency-Weighted Severity Scale (BEHAVE-AD-FW) and to establish its inter-rater reliability. In this investigation the BEHAVE-AD-FW scale was administered to caregivers of 28 patients with either mildly impaired cognitive function or a dementia diagnosis. Two clinicians separately and independently rated the responses. Analyses determined that the intraclass correlation coefficients (ICCs) for the frequency component varied between 0.86 and 0.97 for each of the seven BEHAVE-AD categories (p(s) < 0.001). ICCs for the frequency-weighted scores (item severity score x item frequency score) ranged from 0.69 to 0.98 for the seven symptom categories (p(s) < 0.001). For the BEHAVE-AD-FW total scores, the ICC was 0.91 (P < 0.001). These results indicate that the frequency-weighted component is a reliable addition to the BEHAVE-AD scale.

A clinician should not rely entirely upon a caregiver's report regarding behavioral pathology when planning a treatment strategy. Direct observational evaluation instruments as well as caregiver-based assessments are necessary. A new scale for the empirical (observational) evaluation of behavioral symptoms in Alzheimer's disease (AD) and related dementias, the Empirical Behavioral Pathology in Alzheimer's Disease Rating Scale (E-BEHAVEAD) was developed. Interrater reliability of this new assessment instrument was examined. Additionally, the relationship between the observed occurrence of behavioral symptomatology on this new rating instrument was compared with the occurrence using a similarly designed, caregiver-based instrument. The interrater reliability study consisted of two raters who simultaneously evaluated 20 dementia patients. The comparative study employed a cross-sectional design (N = 49). Individuals were evaluated in an outpatient clinic setting. The study population consisted of cognitively normal individuals and dementia patients. Evaluations included the new, observationally based behavioral assessment (the E-BEHAVE-AD), a caregiver-based behavioral assessment (the Behavioral Pathology in Alzheimer's Disease Rating Scale; BEHAVE-AD), a clinical global measure (the Global Deterioration Scale), and a mental status assessment (the Mini-Mental State Examination). The interrater reliability study revealed an intraclass correlation coefficient of .97 (p < .01) for total scores on the new E-BEHAVE-AD rating scale. The correlation coefficient for the amount of agreement on the presence of symptoms in six symptomatic categories between caregiver-based information about the patient's behavioral pathology assessed on the BEHAVE-AD and the clinician's observations assessed with the new E-BEHAVE-AD rating instrument was .51 (p < .01). The New E-BEHAVE-AD rating instrument showed excellent interrater reliability. Furthermore, there was a statistically significant relationship between clinician observation of the occurrence of behavioral pathology assessed using the E-BEHAVE-AD and caregive-reported pathology assessed with the BEHAVE-AD. However the magnitude of the correlation between these measures indicated that the majority of variance was independent and nonoverlapping. Consequently, these data support theoretical models suggesting that the assessment of behavioral pathology in dementia might ideally encompass both direct observational and caregiver-report approaches, using measures such as the E-BEHAVE-AD as well as measures such as the BEHAVE-AD.