Apolipoprotein E, memory and Alzheimer's disease.

Apolipoprotein E (ApoE) epsilon 4 is a well-documented risk factor for Alzheimer's disease (AD). Patients with AD show neuronal damage, particularly in the medial temporal lobe structures involved in memory processing. ApoE has been implicated in nerve regeneration following injury, and synaptogenesis in the hippocampus of experimental animals. Recent studies have shown an increased accumulation of beta A4 amyloid and an increased deficit in ACh-containing neurons in the brains of AD patients that are homozygous for ApoE epsilon 4 compared with those lacking epsilon 4. Furthermore, AD patients with two ApoE epsilon 4 alleles have more-severe loss in hippocampal volume in magnetic resonance imaging (MRI) scans, and more impairment in tests assessing delayed memory, than AD patients without the epsilon 4 allele, in spite of similar global severity of dementia. Minor changes in hippocampal MRI volumetry can also be detected in nondemented elderly, particularly in those with an epsilon 4/4 genotype. Data from a population-based study revealed that elderly subjects carrying the epsilon 4 allele had worse learning ability than those with the epsilon 2/2 or epsilon 2/3 phenotypes, whereas these groups did not differ in other cognitive domains. These data suggest that ApoE epsilon 4 might influence the magnitude of medial temporal lobe atrophy and memory impairment in AD and also in nondemented elderly.

Discrimination of Alzheimer patients responding to cholinesterase inhibitor therapy.

We have studied whether it is possible to discriminate responders to tacrine treatment from patients nonresponsive to tacrine in Alzheimer's disease. The results indicate that mildly demented patients will most likely gain a benefit of tacrine treatment. Neuropsychological tests on attention and working memory after a single dose of tacrine might be useful as well as a single dose pharmaco-EEG in discriminating responders to treatment.

Long-term efficacy and cognitive effects of vigabatrin.

Vigabatrin is effective as add-on therapy in about 50% of patients with partial epilepsy refractory to drugs. Furthermore, at least half of the original responders maintain the response over several years. As monotherapy, both vigabatrin and carbamazepine seem to be successful in a similar proportion of newly diagnosed patients with epilepsy, but carbamazepine monotherapy fails more often due to side-effects and vigabatrin more often due to lack of efficacy. However, vigabatrin monotherapy seems to be extremely well tolerated, particularly in relation to cognitive function.

Hippocampus in Alzheimer's disease: a 3-year follow-up MRI study.

BACKGROUND: Due to the progressive nature of Alzheimer's disease (AD), it has been proposed that serial imaging studies tracking the course of progression might improve the diagnostic accuracy of AD. METHODS: Longitudinal changes in hippocampal volumes were evaluated using magnetic resonance imaging (MRI) over a period of 3 years in 27 AD patients and 8 control subjects. RESULTS: A statistically nonsignificant trend towards accelerated volume loss in the AD group compared to control subjects was observed. During the study period, the average shrinkage of the hippocampal volume ranged from -2.2% to -5.8% in control subjects, and from -2.3% to -15.6% in AD patients. CONCLUSIONS: The observed changes at an individual level were small, and within the accuracy range of the measurements. Therefore, serial MRI of the hippocampus did not offer any advantage over a single MRI to support the diagnosis of AD in this study sample.

CSF beta-endorphin-like immunoreactivity in delirium.

Cerebrospinal fluid beta-endorphin-like immunoreactivity (CSF BLI) was determined for 69 patients who met DSM-III criteria for delirium and for 8 controls. The CSF BLI was significantly lower in the delirious patient group than in the controls (12.5 +/- 3.0 pg/ml versus 15.0 +/- 3.4 pg/ml, p less than 0.05). CSF BLI had no correlation with age or neuroleptic drug dosage, but did have a significant positive correlation with cognitive functioning as evaluated by the Mini-Mental State. Our findings suggest a role for beta-endorphinergic dysfunction in the development of delirium.

Diabetes mellitus and brain atrophy: a computed tomography study in an elderly population.

Previous studies have suggested that noninsulin dependent diabetes mellitus (NIDDM) could lead to learning and memory deficits. We studied cognitive performance and computed tomography (CT) findings of the brain in elderly subjects with drug treated NIDDM (n = 12), with diet treated NIDDM (n = 13), and in nondiabetic individuals (ND, n = 59). The cognitive performance (orientation and up-to-date knowledge, praxic functions, understanding of speech, expressive speech, memory, general reasoning) did not differ between the groups. The drug treated diabetics had more pronounced central temporal atrophy compared to that in the ND subjects as evidenced by wider right temporal horn (ANCOVA adjusted for age, p = 0.011). The drug treated diabetics (all women) also had wider frontal horns than did the ND women. The CT measures of diet treated diabetics were comparable with those of the ND group. The fasting glucose level was positively correlated with the width of the right temporal horn but not with other CT measures in diabetic subjects. The results suggest that NIDDM and poor glucose control may carry a risk for accelerated brain atrophy in the elderly.

Dopaminergic system and monoamine oxidase-B activity in Alzheimer's disease.

The possible involvement of dopaminergic neurons in dementia of Alzheimer type (AD/SDAT) was studied in autopsied brains from 20 patients with AD/SDAT. Dopamine (DA) concentrations were decreased significantly in the temporal cortex, hippocampal cortex and hippocampus in AD/SDAT patients. Levels of homovanillic acid (HVA) were not altered compared to controls. The HVA/DA ratio was significantly higher in the hippocampus of AD/SDAT patients, suggesting overactivity of the remaining DA neurons. Histological findings of substantia nigra suggesting coexistent pathology of Parkinson's disease (PD) found in 25% of cases were associated with lowered levels of DA in striatum and with reduced HVA in CSF. The activity of monoamine oxidase-B was significantly increased in the cortical areas and in the hippocampus, obviously reflecting the underlying cell loss and substantial gliosis in these areas of the brain. In general, DA neurons seemed to be only mildly involved in AD/SDAT. Coexistent PD pathology can explain the loss of DA in the striatum and the presence of clinical PD symptoms in some patients with AD/SDAT. Otherwise the clinical relevance of these dopaminergic alterations is unclear.

MR T2 relaxometry in Alzheimer's disease and age-associated memory impairment.

A prolonged MR T2 relaxation time was proposed to mark the presence and severity of Alzheimer's disease (AD). We studied the value of T2 relaxometry in diagnosing early AD. T2 was measured from 54 patients with AD, 25 subjects with age-associated memory impairment (AAMI), 18 elderly and 16 young controls. The AD patients had longer T2 in the right hippocampal head (104 +/- 11 ms) and tail (98 +/- 10 ms) than age-matched controls (95 +/- 5 and 92 +/- 9 ms, respectively). This prolongation was not related to age. In the AD group, the T2 of the left hippocampal head also correlated with the clinical severity. The T2 of the amygdala did not differ across the groups. Increased T2 in the temporal and parietal white matter and the thalamus related to increasing age rather than to the diagnostic category. The AAMI subjects had T2 comparable with those of age-matched controls. Despite the prolongation of T2 in the AD group the possible diagnostic value was compromized by a substantial overlap between the study groups. We, thus, conclude that the T2 relaxometry is not a reliable method for diagnosing early AD.

MRI of the hippocampus in Alzheimer's disease: sensitivity, specificity, and analysis of the incorrectly classified subjects.

In this study, magnetic resonance imaging (MRI) of the hippocampus for the diagnosis of early Alzheimer's disease (AD) is evaluated. We measured hippocampal volumes and the area of the medial hippocampus with a 1.5 T MR imager in 160 subjects: 55 patients with probable AD according to the NINCDS-ADRDA criteria, 43 subjects fulfilling the NIMH criteria of age-associated memory impairment (AAMI), 42 cognitively normal elderly controls, and 20 controls younger than 50 years. Three methods for normalization were compared. The hippocampi were atrophied in the AD patients, but not in the AAMI subjects or the elderly controls. There was no significant correlation between hippocampal volumes and age in the nondemented subjects. The discrimination based on volumetry resulted in an overall correct classification of 92% of AD patients vs. nondemented elderly subjects, whereas discrimination based on hippocampal area was less accurate, producing a correct classification in 80% of the subjects. We conclude that the hippocampus as assessed by MRI volumetry is atrophied early in AD, and spared by aging or AAMI. A brief critical review of previous studies is in concordance with the presented data: all the previous studies that have used volumetry, have similarly ended up with a good classification, whereas simpler or subjective measurements, subject to various sources of bias, have produced most variable results.

Alzheimer pathology of patients carrying apolipoprotein E epsilon 4 allele.

A recent report suggested that brains of Alzheimer patients homozygous for APOE epsilon 4 show increased amyloid pathology compared to APOE epsilon 3 homozygotes. We studied APOE allele frequencies in 73 AD patients and 38 controls. We also investigated relation of APOE genotypes to beta/A4 immunopositive plaques, cerebrovascular beta/A4 deposition, neurons expressing paired helical filaments (PHFs), and synaptophysin-like immunopositivity in 22 neuropathologically verified AD patients. We also correlated APOE genotypes of definite AD patients to beta/A4 immunoreactivity in dermal vessel walls detected in lifetime skin biopsy samples. APOE allele epsilon 4 frequency was increased in AD compared to nondemented controls (0.37 vs. 0.11; p = 0.006). The number of beta/A4 immunoreactive plaques, PHFs-containing neurons, the degree of cerebrovascular beta/A4 deposition or synaptophysin-like immunoreactivity did not differ significantly in AD patients with or without epsilon 4. beta/A4 deposition in dermal vessel walls was more frequent in definite AD patients with epsilon 4 (43%) than in patients without epsilon 4 (22%). However, the difference did not reach the statistical significance.

Antiplatelet therapy is effective in primary prevention of myocardial infarction in patients with a previous cerebrovascular ischemic event.

OBJECTIVE: A secondary subgroup analysis of the European Stroke Prevention Study of the effect of antiplatelet medication on the risk of myocardial infarction. DESIGN AND SETTING: A randomized, double-blind placebo-controlled study with two parallel treatment groups (dipyridamole plus aspirin and placebo). Sixteen centers from six countries participated in the study. PATIENTS: A total of 2500 patients who had had one or more transient ischemic attacks or cerebral infarctions participated. INTERVENTION: Combination therapy with dipyridamole (75 mg three times a day) and aspirin (330 mg three times a day) was compared with placebo during 24 months' follow-up. OUTCOME MEASURES: Prevention of fatal and nonfatal myocardial infarction. RESULTS: A total of 105 myocardial infarctions occurred in the intention-to-treat analysis and 76 occurred in the explanatory analysis. The overall risk reduction of myocardial infarction with the study drugs was approximately 40% in both statistical analyses, but the result was statistically significant only in the intention-to-treat analysis. Therapeutic efficacy was better among male patients, patients younger than 65 years, and patients with hypertension. CONCLUSION: Combination therapy with dipyridamole and aspirin reduces not only the risk of cerebrovascular ischemic events but also the risk of myocardial infarction.

Long-term study with gabapentin in patients with drug-resistant epileptic seizures.

OBJECTIVE: To study the efficacy and safety of gabapentin in long-term treatment. DESIGN: A 4-year follow-up study of 25 patients with visits at 3-month intervals. SETTING: The patients were followed up in the outpatient unit of the University Hospital of Kuopio (Finland). PATIENTS: We treated 25 patients with drug-resistant complex partial seizures and secondarily generalized seizures in an open-label long-term study, using gabapentin as an additional means of therapy after a 3-month double-blind, placebo-controlled phase. Thirteen patients showed no benefit from gabapentin; the study medication was discontinued after 4 to 6 months of treatment. Of the 12 patients who responded enough to continue treatment, five were withdrawn due to different reasons, one because of loss of response. MAIN OUTCOME MEASURES: The number of patients receiving the study drug in the follow-up and reduction of seizure frequency from baseline level as analyzed by the Wilcoxon test. RESULTS: Seven patients received gabapentin therapy for more than 4 years. The median follow-up time was 54 months. There was a significant reduction in seizure frequency throughout the follow-up period. Five of seven patients had a greater than 50% seizure frequency reduction at 4 years, representing 20% of the 25 patients who entered the study. CONCLUSIONS: Gabapentin possesses good efficacy in long-term treatment of patients with partial and secondarily generalized epileptic seizures. It is safe to use, and it is fairly well tolerated even in long-term treatment.

Cross-cultural studies of dementia. A comparison of mini-mental state examination performance in Finland and China.

The Mini-Mental State Examination of Folstein et al was translated into and culturally adapted to Chinese and Finnish and used in dementia surveys involving probability samples of 2187 Shanghai elderly, aged 65 to 74 years, and 525 Finns of the same age group. The mean scores of these two groups were statistically different owing to the lower scores of Shanghai subjects who had no formal education. When this subset of 579 subjects was eliminated from the analysis, the distribution of total scores was almost identical in the two populations, suggesting that the Mini-Mental State Examination can be used in disease populations, provided education is taken into account. However, there remained cultural differences in regard to individual test items; the Chinese had better recall but did not do as well as Finnish or US subjects when asked to copy a figure.

Vigabatrin vs carbamazepine monotherapy in patients with newly diagnosed epilepsy. A randomized, controlled study.

OBJECTIVE: To evaluate the efficacy, safety, and cognitive effects of initial vigabatrin monotherapy compared with initial carbamazepine monotherapy in patients with newly diagnosed epilepsy. DESIGN: Open, randomized, controlled design. Follow-up period of 12 months. SETTING: University hospital with an epilepsy center. PATIENTS: A total of 100 patients, aged 15 to 64 years, classified as suffering from partial seizures and/or generalized tonic-clonic seizures were randomized to either vigabatrin or carbamazepine monotherapy. Fifty-nine patients with a single epileptic seizure and no antiepileptic drug treatment served as a control population for objective safety measures. OUTCOME MEASURES: To evaluate the comparative efficacy and toxicity of vigabatrin and carbamazepine, the drug success rate (ie, the proportion of patients continuing successful treatment with the randomly assigned drug) after 12 months of steady-state treatment was used. To evaluate the safety of the drugs in addition to reported side effects, visual evoked potential recordings and neuropsychological evaluation were performed during follow-up. RESULTS: During the 12-month follow-up period, 60% of patients receiving vigabatrin and carbamazepine were treated successfully. Vigabatrin caused fewer side effects that required discontinuation of therapy. However, vigabatrin had to be discontinuated more often owing to lack of efficacy, and fewer of the successfully treated patients receiving vigabatrin achieved total freedom from seizures. Vigabatrin had no detrimental effects on cognitive functions. Retrieval from both episodic and semantic memory and flexibility of mental processing improved significantly in patients successfully treated with vigabatrin. CONCLUSION: Vigabatrin seems to be an effective and safe antiepileptic drug as primary monotherapy for epilepsy with fewer cognitive side effects than carbamazepine.

Long-term antiepileptic efficacy of vigabatrin in drug-refractory epilepsy in mentally retarded patients. A 5-year follow-up study.

The long-term clinical, neurophysiologic, and psychological effects of add-on vigabatrin treatment were evaluated in a group of 36 mentally handicapped patients with drug-refractory epilepsy. After an initial 3-month follow-up period, 15 (42%) of 36 patients had at least a 50% decrease in seizure frequency compared with baseline. After a 2-year follow-up period, nine (25%) of 36 patients retained the initially observed antiepileptic effects of vigabatrin, and after 5 years, eight (22%) of 36 patients did so. Five (33%) of the 15 patients who initially exhibited a favorable antiepileptic response to vigabatrin lost that response during a 5-year follow-up. Partial-onset seizures represented the seizure type best controlled by vigabatrin. Side effects were mostly mild, and plasma levels of other antiepileptic medication remained unchanged. No impairment of psychological performance was observed during vigabatrin treatment compared with baseline. Also, no clear change was observed in the background or epileptiform activity in the electroencephalogram during the study. Our findings suggest that vigabatrin as an add-on therapeutic effectively controls seizures in a subpopulation of patients with severe epilepsy. In addition, the antiepileptic response, if achieved, is long lasting in about half of the patients.

Different patterns of cognitive decline related to normal or deteriorating EEG in a 3-year follow-up study of patients with Alzheimer's disease.

To determine if the pattern of cognitive decline in Alzheimer's disease (AD) patients with normal EEG differs from that in patients with abnormal EEG at the early stage of the disease, we have followed 12 AD patients with normal EEG (NEEG) and 12 patients with deteriorating EEG (DEEG). The AD patients with DEEG showed a decline of praxic functions, confrontation naming, and automatic speech functions. In contrast, the AD patients with NEEG did not show a deterioration of these functions during the 3-year follow-up period. Visual functions, understanding of speech, and memory functions deteriorated similarly in both groups. The clinical severity of dementia increased in both groups. Patients with DEEG showed a tendency toward a higher frequency of extrapyramidal symptoms and a higher risk of institutionalization than the patients with NEEG. Thus, an abnormal EEG at the early stage of AD may predict a more severe decline in cognitive functions.

Vigabatrin in drug-resistant partial epilepsy: a 5-year follow-up study.

We treated 75 patients with drug-resistant complex partial seizures and secondarily generalized seizures with vigabatrin as additional therapy for 6 months. Twenty-one patients either showed no benefit from vigabatrin treatment or had side effects. The remaining 54 patients entered into the long-term study. The median monthly seizure frequency decreased from 12.5 at baseline to 3.3 at the 3-month visit, and was 3.9 after 5 years of therapy in 28 patients who continued using the drug after the 5-year period. During 5 years of therapy with vigabatrin, 26 patients have withdrawn from the study because of various reasons: loss of efficacy (14), suspected side effects (5), noncompliance (3), administrative reasons (2), pregnancy (1), and epilepsy surgery (1). In all, 19 patients had a greater than 50% seizure frequency reduction at 5 years, representing 35% of the 54 patients who entered the long-term study, or 25% of the 75 patients who were initially recruited into the efficacy study.

Treatment of Alzheimer's disease with a synthetic ACTH 4-9 analog.

The synthetic ACTH 4-9 analog, Org 2766, was administered to 77 Alzheimer's patients for 6 months in a double-blind, placebo-controlled study. Although Org 2766 was tolerated well, no significant effect of Org 2766 could be demonstrated in terms of rating scales or cognitive functions.

Decline of frontal lobe functions in subjects with age-associated memory impairment.

OBJECTIVE: To assess frontal lobe functions of subjects with age-associated memory impairment (AAMI) and to examine whether performance on neuropsychological tests is correlated with the volume of the frontal lobes in magnetic resonance imaging. DESIGN: Cross-sectional two-group comparison. SETTING: The Memory Research Clinic of Kuopio University and the Magnetic Resonance Imaging Center of Kuopio University Hospital. PARTICIPANTS: Ninety subjects (mean age, 70.5 years), 43 with AAMI diagnosed according to National Institute of Mental Health criteria and 47 age-matched healthy controls. MEASUREMENTS: Four neuropsychological tests were used to assess frontal lobe function: Verbal Fluency Test (VFT), Modified Wisconsin Card Sorting Test (WCST), Trail Making Test (TMT), and Stroop Test (ST). A 1.5-T magnetic resonance imager was used for volume measurements. RESULTS: The AAMI subjects scored significantly worse on the WCST, ST, and TMT compared with controls (ANCOVA, adjusted for age and education, p < 0.05). The frontal lobe volumes did not differ between AAMI subjects and controls. CONCLUSIONS: AAMI subjects appear to be impaired not only in tests assessing memory but also in tests of executive functions. This finding agrees with previous reports suggesting a central role for frontal dysfunction in memory loss of elderly people.

The European Stroke Prevention Study: results according to sex.

The European Stroke Prevention Study was a multicenter trial comparing the effect of a combination of 75 mg dipyridamole and 330 mg acetylsalicylic acid tid with placebo in the prevention of stroke or death after one or more attacks of recent transient ischemic attacks or stroke of atherothrombotic origin. From the 2,500 patients in the intention-to-treat analysis, the proportion of women was 42%, and from the 1,861 patients in the explanatory analysis it was 44%. The endpoint incidence was significantly higher in men than in women. The endpoint reduction was statistically significant only in the intention-to-treat analysis with total endpoints. However, there was a marked percentage reduction of endpoints in both men and women in explanatory analysis. The risk reduction of strokes was 49% for men and 41% for women, and the reduction of total endpoints was 39% in men and 30% in women. Thus, antiplatelet therapy is effective in the prevention of stroke or death in both sexes.