Current Alzheimer Research - Volume 2, Issue 5, 2005

During normal development of the nervous system, a major reduction occurs in the initially excessive number of neurons and synapses. This "pruning" process is heavily influenced by patterns of electrical activity in the synaptic circuits being pruned. Many of the cell biological and molecular mechanisms involved in this activity-dependent modification of nervous system structure and function have been explicated, and the area is one of intense study. Similarly, an explosive increase has occurred in knowledge about the molecular pathogenesis of Alzheimer disease (AD). There are significant mechanistic commonalities between the normal neurodevelopmental process and development of AD. We hypothesize that abnormalities in neural activity patterns, or in the coupling between neural activity and maintenance of neurons and synaptic circuits, may be a key determinant in the pathogenesis of AD that is late in onset, sporadic in nature, and in which the genes for the presenilins and the beta amyloid precursor protein are normal. Behavioral data suggests that an active, socially engaged life-style may be associated with a reduced risk for AD. If so, mechanisms linking neural activity with synaptic circuit integrity are probably involved and provide a target for ameliorative pharmacological intervention.

Programmed cell death (PCD) also called apoptosis, is a normal and genetically controlled event that could play, when mis-regulated, a pivotal role in the development of several neurodegenerative disorders such as Parkinson's disease. Sporadic Alzheimer's disease is one of the most prominent age-related syndromes whose etiology, although still unknown, could be related to biochemical or environmental causes. A few cases of Alzheimer's disease are likely of genetic origin and linked to mutations on the genes coding for the amyloid precursor protein (bAPP) and presenilins 1 and 2. Although still discussed, the hypothesis of an implication of apoptotic cell death in Alzheimer's disease neuropathology has been recently supported by a growing body of biochemical evidences. Thus, the implication of presenilins in apoptotic processes in vitro has been well documented but the mechanisms underlying this function are still a matter of intense research. The aim of this review is to focus on the mechanisms by which presenilin 2 affects the programmed cell death with special emphasis on the role of the proteolytically derived presenilin fragments generated by both presenilinase- and caspases. The distinct apoptotic phenotypes elicited by the two parent proteins presenilins 1 and 2 and their functional cross talk will be briefly discussed.

Early stage Alzheimer disease patients and matched elderly unaffected controls (n=16/group) were evaluated with the P300 event-related brain potential (ERP). All subjects performed four oddball tasks that varied systematically in task difficulty and were each presented in the auditory and visual modalities. P300 amplitude was smaller and peak latency longer for the Alzheimer patients compared to elderly control subjects across tasks and modalities. P300 differences between Alzheimer patients and controls were largest for the relatively easy tasks, with little influence of stimulus modality observed. The results suggest that the P300 brain potential is sensitive to Alzheimer's disease processes during its early stages, and that easily performed stimulus discrimination tasks are the clinically most useful. Theoretical and practical implications are reviewed.

Cholesterol clearly plays an influential role in promoting the production of amyloid β (Aβ) and possibly the progression of Alzheimer's Disease (AD). The AD Cholesterol-Lowering Treatment trial (ADCLT; 1 year duration) tested atorvastatin and found significant benefit on measures of cognition and depressive symptoms in treated patients (N=32) compared to placebo (N=31). We assessed the circulating levels of Aβ1-40, Aβ1-42, ceruloplasmin (copper chaperone), apolipoprotein E and HDL-cholesterol in blood collected at each clinical visit during the ADCLT. We also determined the circulating cholesterol, ceruloplasmin, and Aβ levels in AD and MCI (mild cognitive impairment) patients, and controls (two groups stratified by function; high and low) participating in our Brain Bank Program. Each Brain Bank individual was clinically assessed for performance on the Mini-Mental Status Exam (MMSE), Rey auditory verbal learning test (AVLT), Clock draw, and UPSIT (smell identification test). Among individuals of equal age and education, scores on the MMSE were significantly reduced in AD compared to both MCI and controls, as were scores on the UPSIT. Ability on delayed verbal recall was significantly reduced in AD compared to MCI, and in MCI compared to both control groups. Performance on the Clock draw was similar for AD and MCI patients, but was significantly reduced when comparing MCI to control. Both cholesterol and ceruloplasmin levels were significantly increased in low-function controls compared to the high-function control group, but were not different from levels identified in the MCI and AD patients. Significantly increased levels of Aβ1-40 occurred in low- compared to highfunction controls, with a further significant increase in MCI compared to low-function controls. Circulating Aβ1-40 levels were decreased in AD compared to MCI. Levels of Aβ1-42 were not significantly different between the groups. The slight gradual increase in circulating Ab1-40 and Ab1-42 levels produced by atorvastatin treatment in the ADCLT were not significant compared placebo. There was a trend for significant reduction in circulating ceruloplasmin levels after a year of atorvastatin therapy compared to levels observed at screen. The levels of HDL-cholesterol remained stable in the atorvastatin treated AD patients for 9 months and then decreased significantly compared to the placebo group at the 1-year time-point. The combined data support a role for cholesterol in AD and a possible influence of increasing circulating copper levels. The deterioration of function in controls and transition to MCI may be associated with concomitant incremental increases in circulating Aβ1-40 levels. Increased cholesterol and ceruloplasmin levels may be associated with slight deterioration in function among controls as a precursor to impairment considered MCI. The clinical benefit of atorvastatin therapy is clearly not associated with decreased circulating Aβ or increased HDL-cholesterol, but a positive influence of reduced copper (ceruloplasmin) levels may be a consideration.

Context: Previous studies of Ginkgo biloba extract (GbE) in patients with various forms of cognitive impairment or dementia have shown promising results. Objective: To determine the clinical efficacy of GbE in mild to moderate dementia of the Alzheimer type. Design: Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial. Setting: Outpatient clinics of universities and private research centers specialized in dementia. Patients: 513 outpatients with uncomplicated dementia of the Alzheimer's type scoring 10 to 24 on the Mini-Mental State Examination and less than 4 on the modified Hachinski Ischemic Score, free of other serious illnesses and not requiring continuous treatment with any psychoactive drug. Intervention: 26-week treatment with GbE at daily doses of 120 mg or 240 mg or placebo. Main Outcomes: Cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC). Results: There were no significant between-group differences for the whole sample. There was little cognitive and functional decline of the placebo-treated patients, however. For a subgroup of patients with neuropsychiatric symptoms there was a greater decline of placebo-treated patients and significantly better cognitive performance and global assessment scores for the patients on GbE. Conclusion: The trial did not show efficacy of GbE, however, the lack of decline of the placebo patients may have compromised the sensitivity of the trial to detect a treatment effect. Thus, the study remains inconclusive with respect to the efficacy of GbE.

OBJECTIVE: The Alzheimer's Disease Cooperative Study (ADCS) is conducting a clinical trial to address whether chronic valproate treatment can delay emergence of behavioral symptoms in outpatients with AD. Since there were no data on the safety and tolerability of divalproex sodium in outpatients with dementia, we undertook a pilot study to inform the design of the ADCS study. METHODS: We recruited 20 outpatients with probable AD, MMSE 10-20, without history of agitation or psychosis. This was a 10-week randomized, double-blind, placebo-controlled study assessing the safety and tolerability of 1,000 mg/day and 1,500 mg/day of divalproex sodium delayed-release for 8 weeks followed by extended-release for 2 weeks. Other outcome measures addressed cognition, function, global status, side effects, and laboratory data. RESULTS: Participants assigned to active treatment ingested approximately 30% less of their prescribed study medication compared to those receiving placebo (p < .05 Wilcoxon Rank Sum test). The average tolerated dose for all participants at week 8 was 810 mg/day or 11.5 mg/kg/day, similar to the dose tolerated by nursing home patients. The most common side effects were sleepiness and tiredness, with worse cognitive performance in those assigned to 1500 mg/day. CONCLUSIONS: These results were used to design the multi-center ADCS trial. Doses of less than 1000 mg/day of divalproex sodium were the maximum tolerated by these outpatients with AD. A larger study of divalproex sodium dose tolerability is needed to define treatment in outpatients with Alzheimer's disease.

Novel experiments with Ultrasound Associated with High Frequency Electromagnetic Field (UAHFEMF) irradiation on rats and mice found evidences of characteristic Alzheimer's disease (AD) degenerations including neurite plaques, beta-amyloid, TAU plaque and deposition in cells, Neuro-Fibrillary Tangle and Paired Helical Filament (PHF) with rats and mice irradiated up to 2454 hours. Concomitant passive avoidance test was performed on six mice, and all showed signs of visual and auditory agnosia and lost cognition of threatening condition. The post section Thioflavin-S fluorescent microscopy found dilated ventricles and dense amyloid-deposition in Ca3 and dentate gyrus. In addition, PHF was identified in the 2454 hours-irradiated rat brain by electron microscope. A human T-cell activation RhoGTPaseactivating protein (TAGAP) isoform b homolog (GenBank accession # P84107) induced in the UAHFEMF-treated rat brain was identified using electron spray ionization (ESI) liquid chromatography tandem mass spectrometry (LC/MS/MS). We hypothesized that one of the causes of AD can be the UAHFEMF discharges in human brain.

To compare differences in evolutionary progressions from Mild Cognitive Impairment (MCI) to dementia of Alzheimer's type (DAT) or to vascular dementia (VaD) versus normal aging, subjects identified as MCI or as cognitively normal (CN) during standard cognitive evaluations among a large epidemiological study designed to determine prevalence and incidence of dementia and its major subtypes in Beijing, China were re-examined after an interval of approximately 3 years, repeating the same investigation protocol as at baseline. MCI subjects meeting criteria for dementia and the two major subtypes, DAT and VaD were identified at follow-up evaluation. Annual conversion rates for combined dementias and for major subtypes of DAT and VaD, from MCI, were compared with conversion rates among CN subjects. Relative risks for conversion from MCI to major subtypes of dementia were also compared with CN subjects by Cox regression models. 175 MCI and 400 CN subjects were identified at baseline. Among 121 MCI subjects available at followup, 51 were diagnosed with dementia (29 with DAT, 18 with VaD and 4 with other dementias), compared with 14(10 DAT, 3 VaD and 1 other type dementia) diagnosed as dementia among 281 CN subjects available at follow-up. Annual conversion rates calculated from MCI to all dementias, compared with conversion rates from CNs, were 14.1% versus 1.6%. Specifically for DAT, annual conversion rates were 8.0% versus 1.1% and for VaD were 5.0% versus 0.3%. Relative risks for developing all dementias, DAT and VaD among MCI subjects were 9, 6 and 5 times greater than among CN subjects. Conversion rates among MCI subjects to dementia, and major subtypes, for elderly Chinese residents of Beijing were comparable with results reported among similar studies worldwide. Risks of developing dementia, and major subtypes, among MCI subjects in Beijing were significantly higher than among normal subjects. Identification of MCI among elderly populations provides the possibilities for dementia prevention and treatment within prodromal stages.

Background and Objectives: Mild Cognitive Impairments (MCIs) are identifiable clinical entities, in neurodegenerative forms, as prodromal for Alzheimer's type (DAT) or in vascular forms, as prodromal for vascular dementia (VaD). The present longitudinal study compares and contrasts MRI abnormalities among MCI subjects as they progress to DAT versus VaD. Subjects converting to DAT and VaD confirmed ultimate diagnosis during MCI staging. In "mixed cases" the predominant MRI pathology was judged the primary cause. Subjects and Methods: Subjects (n=153) were selected from elderly outpatient volunteers who have been enrolled for 25 years in planned longitudinal studies of aging, stroke and dementia. Cognitively normal (CN, n=52), MCI of neurodegenerative (N-MCI, n=30) and vascular (V-MCI),n=35) subtypes, plus converted DAT (n=19) and VaD (n=17) were diagnosed according to established protocols. Combined Mini-Mental-Cognitive Capacity Screening Examinations (CMC) screened, identified and confirmed MCIs or dementias. Cerebral MRI abnormalities were analyzed utilizing volumetric measurements and visual rating scales. Results: Compared with persistently cognitively normal subjects, MCI subjects and converted dementias were significantly older without significant gender differences, but cognitively impaired subjects were older than the CN group since age is a risk factor for cognitive decline. Histories of hypertension, heart disease, diabetes mellitus, TIAs and strokes were more frequent among subjects with VMCI and VaD, confirming that all vascular risk factors contribute to vascular cognitive decline, but since vascular risk factors were treated, not all progressed to VAD. Family history of neurodegenerative disease, particularly DAT, were more prevalent among NMCI and converted DAT subjects. VMCI showed more extensive leucoaraiosis and lacunar infarcts than subjects with NMCI. NMCI, prodromal for dementia of Alzheimer's type (DAT), showed more medial temporal lobe atrophy with enlarged temporal horns, and fewer vascular lesions.