Long-term tetrahydroaminoacridine treatment and quantitative EEG in Alzheimer's disease.

The development of therapies for Alzheimer's disease (AD) has focused on drugs designed to correct the loss of cholinergic function within the central nervous system. Quantitative EEG (qEEG) changes associated with AD consist of background slowing. One way to study the effects of cholinergic drugs may be through assessment of their qEEG effects. The aim of the current work was to evaluate the effect of long-term treatment with tetrahydroaminoacridine (THA) on qEEG in AD patients.

Incidence of dementia in patients with subjective memory complaints.

BACKGROUND: The risk of developing dementia by elderly patients with only subjective memory complaints (SMC) is unclear. Our objective was to assess the prognosis of such patients regarding subsequent development of dementia. METHODS: From 1992 to 1996, 211 consecutive patients (age 67.4 +/- 9.4 years, mean +/- SD) were diagnosed as having SMC. These patients were followed for 3 years or to the time they were diagnosed with dementia, whichever came first. A survival analysis was performed for occurrence of dementia within 3 years. RESULTS: The duration of memory decline was shorter among patients who developed dementia than among those who did not (32.6 vs. 49.9 months, F = 3.3, p = 0.07). Patients who developed dementia tended to be older at the reported onset of memory decline (71 vs. 66.2 years, F = 3.2, p = 0.07). Lower risk of dementia was associated with higher cognitive performance at entry [odds ratio (OR) = 0.74 (0.59-0.92)] and longer time from onset of memory decline to referral [OR = 0.91 (0.85-0.98)]. CONCLUSION: Subjects with SMC have an increased risk of developing dementia, particularly those with lower cognitive status at entry and with older age at onset of memory complaints, and shorter duration of their memory complaints.

High b value q-space-analyzed diffusion MRI in vascular dementia: a preliminary study.

High b value diffusion weighted magnetic resonance imaging (high-b DWI) was used to characterize white matter changes in the brain of patients with vascular dementia (VaD). Hyperintense white matter areas detected by T2-weighted magnetic resonance imaging (MRI) represent lesions, also termed leukoaraiosis that are very common in VaD as well as in other types of dementia. Therefore, the role of white matter changes in the cognitive and memory decline that occurs in VaD patients is still under debate. High-b DWI, analyzed using the q-space approach, is a more sensitive MRI method for detection of white matter changes. High-b DWI revealed massive white matter loss in VaD patients that surpassed the boundaries of T2 hyperintensities. This technique, therefore, might serve as a better indication for the extensive nerve fiber loss in the white matter that is caused by vascular disease.

Demented patients' participation in a clinical trial: factors affecting the caregivers' decision.

Clinical trials for Alzheimer's disease take place in medical centers all over the world. Patients and caregivers have to decide whether or not to agree to participate in clinical trials. This study aimed to investigate the motivation that determines the caregivers' choice. Nineteen caregivers of demented patients who consented to participate in a clinical trial in our Memory Clinic and 10 caregivers who refused to participate were interviewed. The data were gathered by a self-report questionnaire covering various aspects of the caregivers' decision-making process. Among the reasons for agreeing to participate in the clinical trial were the respondents' belief that it would improve or help to maintain the patients' condition. Most of the respondents of both groups indicated that information regarding side effects and success probability was adequately provided in advance. The primary reason for refusal was the potential side effects of the drug. The implications of the findings are discussed.

Recruitment rate to drug trials for dementia of the Alzheimer type.

Sample size calculations are important for planning drug trials and require anticipation of the proportion of potential patients finally recruited. Because most recent drug studies for dementia have similar requirements, it could be helpful to analyze the recruitment rate of recent studies. Records of demented patients candidates for drug trials for treatment of dementia of the Alzheimer type in 1994-1995 were analyzed for recruitment rate and reasons for nonrecruitment. From 279 patients with dementia of the Alzheimer type, only 13% were finally included in drug studies. The main reasons for non-enrollment included (1) cognitive test scores out of range for study inclusion criteria (Mini-Mental State Examination [MMSE] <12 [30%], MMSE >24 [5%]), (2) behavioral disturbances (25%), and (3) concomitant diseases (12%). Consent was refused in 8% of those to whom the experimental drug was offered. This low rate of enrollment, 13% of potential candidates, does not include postrecruitment drop-out cases, nor the availability of nonexperimental therapy for DAT. Further, the high selection may limit the generalizability of the results of such studies.

Apolipoprotein E4 in Parkinson disease and dementia: new data and meta-analysis of published studies.

The authors examined whether the epsilon4 allele might be associated with dementia in Parkinson disease (PD), given that the dementia of PD shares neuroanatomic and neurochemical features with Alzheimer disease (AD) and that many recent studies have found a high prevalence of the epsilon4 allele of apolipoprotein E (ApoE) in AD. The authors examined patients with PD (n=125, 47 demented) and unrelated controls (n=93) using a short mental test. DNA was obtained from blood leukocytes. The relevant portion of the apolipoprotein E (ApoE) gene was amplified by polymerase chain reaction, and the epsilon4 allele was identified using a restriction enzyme. The frequency of the ApoE epsilon4 allele in demented patients with PD (14%) was not greater than that in nondemented patients (17%), whereas patients with PD as a whole showed a trend toward a higher epsilon4 allele frequency (16%) than age-matched controls (10%, p=0.07). The epsilon4 allele frequency in nondemented patients with PD was significantly higher than in controls (p=0.055). These results and the meta-analysis of four published reports fail to support the hypothesis that the epsilon4 allele is associated with dementia in PD.

APOE-epsilon 4 in patients with Alzheimer disease and vascular dementia.

The apolipoprotein E (APOE) epsilon 4 allele has been consistently found to be frequent in patients with progressive degenerative dementia of the Alzheimer type (DAT). Vascular dementia (VD) may occur as strokes superimposed on presymptomatic DAT, in which case APOE-epsilon 4 frequency should also be increased in VD. We have examined the distribution of APOE-epsilon 4 in patients with DAT (n = 176) or VD (n = 74) and controls (n = 133), and evaluated the risk of dementia associated with APOE-epsilon 4. APOE-epsilon 4 allele frequency was 27% in DAT patients, 21% in VD patients, and 11% in controls. The difference in the distribution of the epsilon 4 allele between DAT or VD patients and controls was statistically significant (chi(2) test, p < 0.05), with a 3.6- and 2.1-fold risk of dementia in DAT and VD patients carrying an epsilon 4 allele. The result that the APOE-epsilon 4 allele is more frequent in DAT patients than in controls, with VD patients falling in between, is consistent with the assumption that VD is a heterogeneous condition, with some patients having an underlying preclinical brain degeneration, in whom the dementia was precipitated by strokes.

M1 agonists for the treatment of Alzheimer's disease. Novel properties and clinical update.

The AF series compounds, AF102B and congeners of AF150(S), are functionally selective agonists for m1 muscarinic receptors (m1AChRs). This is shown in stable transfected CHO and PC12 cells (PC12M1) with m1m5AChRs and m1AChRs, respectively. AF102B and AF150(S) are partial agonists, but AF150, AF151, and AF151 (S) are full agonists in stimulating phosphoinositides hydrolysis or arachidonic acid release in these cells. Yet, all these compounds behave as antagonists when compared with carbachol in elevating cAMP levels. In PC12M1 cells, unlike carbachol, the AF series compounds induce only minimal to moderate neurite outgrowth. Yet, these agonists synergize strongly with NGF, which by itself mediates only a mild response. Stimulation of m1AChRs by AF102B, AF150(S) and AF151(S) in PC12M1 cells enhances secretion of beta/A4 amyloid precursor protein derivatives (APPs). The enhanced APPs secretion induced by AF102B is potentiated by NGF. AF102B also stimulates APPs secretion from rat cortical slices. Stimulation of m1AChR in PC12M1 cells with carbachol or AF102B decreases tau phosphorylation as indicated by specific tau-1 mAb and alkaline phosphatase treatment. Due to the above mentioned properties m1 agonists may be of unique value in delaying the progression of Alzheimer's disease (AD). The AF series compounds show a wide safety margin and improve memory and learning deficits in animal models for AD. There is a dearth of clinical reports on m1 agonists. These include studies on AF102B and xanomeline, another m1 selective agonist. We tested AF102B in escalating doses of 20, 40, 60 mg, tid, po, (each dose for 2 weeks) for a total of 10 weeks. This was a single-blind placebo-controlled, parallel-group study in patients with probable AD. AF102B was significantly effective at 40 and 60 mg, tid in the ADAS, ADAS-cognitive and ADAS-word recognition scales.