Apolipoprotein E epsilon 4 allele is associated with increased atrophy in progressive mild cognitive impairment: a voxel-based morphometric study.

BACKGROUND: The apolipoprotein E (APOE) epsilon4 allele is a risk factor for Alzheimer's disease. Earlier studies have shown differences in brain structure according to the APOE epsilon4 status. OBJECTIVE: To assess possible differences in brain structure according to the APOE epsilon4 status in mild cognitive impairment (MCI) subjects in relation to conversion to dementia. METHODS: In a follow-up study of 56 MCI subjects, 13 MCI subjects progressed to dementia (PMCI) during a mean follow-up time of 31 months. Brain structure differences in both stable MCI (SMCI) and PMCI epsilon4 carriers and noncarriers in the baseline MRI scan were assessed with voxel-based morphometry. RESULTS: The SMCI epsilon4 carriers had atrophy in the amygdala and hippocampus compared to the SMCI noncarriers. The PMCI epsilon4 carriers revealed atrophy of the left inferior frontal gyrus and parietal cortex compared to the PMCI noncarriers. CONCLUSION: The rate of brain atrophy in certain brain areas may be increased in epsilon4-positive MCI subjects progressing to dementia.

Short-term and long-term memory in elderly patients with NIDDM.

OBJECTIVE: To determine cognitive and memory dysfunction associated with non-insulin-dependent diabetes mellitus (NIDDM) and its relationship with depression, metabolic control, and serum lipids. RESEARCH DESIGN AND METHODS: We studied a well-characterized group of 20 elderly patients with NIDDM and 22 control subjects with normal glucose tolerance recruited from a larger population-based sample. In addition to clinical and laboratory examinations, self-rating questionnaires that assess minor psychiatric disorder (General Health Questionnaire) and depression (Zung scale) were completed by patients and control subjects. Memory was examined with digit and block-span tests, word-list learning, Heaton Visual Memory Test, and Moss Visual Span Test. Executive functions were examined by Trail-Making A and B test and by Verbal and Category Fluency Tests. Visuoconstructive reasoning was examined with the block design subtest of the Wechsler Adult Intelligence Scale. RESULTS: The NIDDM patients showed preserved memory span, but poor performance in learning tasks compared with control subjects. The patients recalled no fewer words than the control subjects, but the process of of learning seemed to be different in the two groups. The recognition of the learned words was not impaired. Elevated serum total and very-low-density lipoprotein triglyceride levels, measured either before examinations or 5 or 10 years earlier, were associated with effects on retrieval from semantic memory in NIDDM patients. CONCLUSIONS: The NIDDM patients had impaired control of their learning processes. Elevated serum triglyceride levels may be related to control of mental processing in diabetic patients.

Cognitive function in an elderly population with persistent impaired glucose tolerance.

OBJECTIVE: To study cognitive function in an elderly population with persistent impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Fasting and postload 2-h plasma glucose and insulin levels were determined at baseline in a population-based sample of 1,300 people and repeated an average of 3.5 years later in 980 subjects. At follow-up, cognitive function was evaluated in subjects with persistent normal glucose tolerance (NGT; n = 506) and IGT (n = 80) with a brief neuropsychological test battery. RESULTS: Subjects with persistent IGT scored lower in the Mini-Mental State Examination (MMSE) and in the Buschke Selective Reminding Test long-term memory scores. Multiple linear regression analysis revealed that age, education, and insulin levels (either fasting or 2-h value) were associated with the MMSE score in subjects with persistent IGT. Other potential risk factors for impaired cognitive function were not significantly associated with the MMSE score. CONCLUSIONS: Our study showed that persistent IGT in the elderly is associated with mildly impaired cognitive function, and hyperinsulinemia may account for this association.

Essential hypertension and cognitive function. The role of hyperinsulinemia.

The relation between hypertension and cognitive function is not well established. Therefore, we examined cognitive function in a random sample of 744 nondiabetic elderly inhabitants of Kuopio, East Finland. Five brief neuropsychological tests known to be sensitive to cognitive impairment due to dementia--the Mini-Mental State Examination (MMSE), the Trail Making Test (TMT), the Buschke Selective Reminding Test (BSR), Russell's Adaptation of the Visual Reproduction Test (HVR), and the Verbal Fluency Test (VFT)--were used to evaluate cognitive function. The performance of the hypertensive group (n = 378) was impaired in almost all test items compared with that of the normotensive group (n = 366), but the difference between these two groups was statistically significant in 5 of 19 test items only. Moreover, within the hypertensive group, hyperinsulinemic (fasting plasma insulin > 17.9 mU/L) hypertensive subjects (n = 57) scored worse than normoinsulinemic hypertensive subjects (n = 321) in 16 of 19 test items and worse than the normotensive subjects in the same 16 of 19 test items. The difference between the hyperinsulinemic hypertensive and normotensive groups was significant in 11 test items that reflected complex cognitive function such as calculation, language, semantic memory, and problem solving. This difference in neuropsychological tests among the three study groups (normotensive, normoinsulinemic hypertensive, and hyperinsulinemic hypertensive subjects) persisted after adjustment for fasting plasma glucose, age, sex, and education in 3 test items measuring calculation, copying, and semantic memory. Thus, essential hypertension in the elderly is associated with an impairment in complex cognitive function.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

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.

Prevalence of age-associated memory impairment in a randomly selected population from eastern Finland.

Aging has multiple effects on memory in normal subjects. However, information on the prevalence of age-associated memory impairment (AAMI) is scanty. We studied the prevalence of AAMI in a randomly selected population of 1,049 subjects aged 60 to 78 years from eastern Finland. Research criteria proposed by the National Institute of Mental Health (NIMH) Work Group were applied. We calculated prevalence rates for AAMI by the inclusion criteria alone (subjective and objective memory impairment and no dementia) as well as by the inclusion and exclusion criteria (evidence of any neurologic or other medical disorder that could produce cognitive deterioration) for the total study population, for both sexes, and for four age groups (60 to 64, 65 to 69, 70 to 74, and 75 to 78 years). Subjective memory impairment was present in 76.3% of the subjects. Prevalence rates for objective memory impairment ranged from 31.9 to 78.4% in individual tests. A total of 564 subjects (239 men, 325 women) were classified as having AAMI by the inclusion criteria alone, giving a prevalence rate of 53.8% (men, 57.4%; women, 51.3%). When we included the exclusion criteria, the prevalence of AAMI decreased to 38.4% (men, 42.5%; women, 35.7%). By both methods, age- and sex-specific prevalence rates were highest in the youngest group, aged 60 to 64 years, and lowest in the oldest group, aged 75 to 78 years. We conclude that the prevalence of AAMI, by the diagnostic criteria of the NIMH Work Group, is high in the elderly Finnish population.(ABSTRACT TRUNCATED AT 250 WORDS)

Hippocampal volumes in Alzheimer's disease, Parkinson's disease with and without dementia, and in vascular dementia: An MRI study.

Hippocampal atrophy detected by volumetric MRI is a sensitive feature of early Alzheimer's disease (AD), but there are no studies evaluating hippocampal atrophy by MR volumetry in other dementing diseases. We therefore compared hippocampal volumes in a total of 113 subjects: 50 patients with mild to moderate AD, 9 patients with vascular dementia (VaD), 12 patients with idiopathic Parkinson's disease (PD) without dementia, 8 patients with PD and dementia (PDD), and 34 elderly control subjects. Thin, coronal, contiguous images were obtained by a 1.5-T MR imager. All patient groups had significantly smaller volumes of the hippocampus compared with the control group. In the PDD group, the absolute volumes were even smaller than in the AD group. In the PD group, the volumes were diminished to a lesser but significant extent. The volumes in the VaD group varied: of nine patients, two had no atrophy, three had unilateral, and four had bilateral atrophy. We postulate that hippocampal atrophy does not seem to be a specific phenomenon of dementia in AD but also occurs in VaD and PDD, and even in PD when no dementia is present. However, coexistence of AD pathology in our PD and VaD patients cannot be ruled out. Further studies with access to neuropathologic data are needed.

Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study.

OBJECTIVE: To evaluate the impact of midlife elevated serum cholesterol levels and blood pressure on the subsequent development of mild cognitive impairment (MCI) and to investigate the prevalence of MCI in elderly Finnish population, applying the MCI criteria devised by the Mayo Clinic Alzheimer's Disease Research Center. BACKGROUND: MCI has been considered as a predictor of AD. Vascular risk factors may be important in the development of cognitive impairment and AD. However, the role of vascular risk factors in MCI and the prevalence of MCI still remain virtually unknown. METHODS: Subjects were derived from random, population-based samples previously studied in surveys carried out in 1972, 1977, 1982, and 1987. After an average follow-up of 21 years, 1,449 subjects aged 65 to 79 years were reexamined in 1998. RESULTS: Eighty-two subjects, 6.1% of the population (average age, 72 years) met the criteria for MCI. Midlife elevated serum cholesterol level (> or =6.5 mmol/L) was a significant risk factor for MCI (OR, 1.9; 95% CI, 1.2 to 3.0, adjusted for age and body mass index); the effect of systolic blood pressure approached significance. CONCLUSION: Data point to a role for midlife vascular risk factors in the development of MCI in late life.

Clinical and neuropsychological characteristics in familial and sporadic Alzheimer's disease: relation to apolipoprotein E polymorphism.

Alzheimer's disease (AD) is a heterogeneous entity presenting as sporadic and familial disease. In familial AD, there is evidence for genetic linkage to a yet undefined gene on chromosome 14 in early-onset pedigrees and on chromosome 19 in late-onset pedigrees. In a few early-onset kindreds, there were mutations in the amyloid precursor gene on chromosome 21. There is an increased frequency of apolipoprotein E (ApoE) epsilon4 allele in patients with late-onset AD. We studied the clinical presentation and profile of cognitive deficits in 58 AD patients at the early stage of the disease. We divided the AD patients into subgroups of sporadic late-onset (SLO) (> or = 65 years), familial late-onset (FLO) (> or = 65 years), sporadic early-onset (SEO) (<65 years), and familial early-onset (FEO) (<65 years) patients and into three subgroups according to their ApoE genotype zero epsilon4, one epsilon4, and two epsilon4 alleles. The AD subgroups did not differ in the global clinical severity of dementia or the duration of the disease. SLO, FLO, SEO, and FEO subgroups did not differ in clinical characteristics such as occurrence of rigidity, hypokinesia, tremor, myoclonus, hallucinations, delusions, or epileptic seizures nor in the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions. The epsilon4++ allele frequency was 0.43 for all AD patients and did not differ across subgroups divided according to the familial aggregation and age of onset. Patients with two epsilon4 alleles had earlier age at onset of dementia than those with no epsilon4 allele (63 +/- 9 versus 68 +/- 9 years), but otherwise the clinical symptoms and signs were not related to the ApoE genotype. However, the AD patients with two epsilon 4 alleles had lowest scores on memory tests and differed significantly from those with one or zero epsilon4 allele in the delayed list learning (p<0.05) and from those with zero epsilon4 allele in the immediate and delayed story recall. In contrast, verbal functions were better preserved in two epsilon4 patients than in those with other ApoE genotypes. This study failed to confirm the earlier reports of severe aphasia, agnosia, and apraxia in familial AD patients, but the clinical phenotype was similar irrespective to the familial aggregation. However, AD patients with two epsilon4 alleles are characterized by more severe memory loss and earlier age of onset than those without the epsilon4 allele.

Midlife income, occupation, APOE status, and dementia: a population-based study.

OBJECTIVE: To examine the relationship between socioeconomic factors and APOE carrier status on the development of dementia. METHODS: Subjects were derived from random, population-based samples previously studied in surveys carried out in 1972, 1977, 1982, and 1987. After an average follow-up of 21 years, 1449 (73%) subjects aged 65 to 79 years were re-examined in 1998. The diagnosis of dementia among the nonparticipants was derived from patient records of the local hospitals and primary health care clinics. RESULTS: Low income level at old age was related to dementia, but low income level at midlife was not a risk factor for dementia. Dementia was also associated with decreasing income level, from midlife to old age 21 years later, when dementia was diagnosed. A sedentary occupation (office, service, or intellectual work) was associated with a decreased risk for dementia among participants; however, when the nonparticipants were included in the analysis, the associations were no longer significant. Low educational level and the APOE epsilon4 allele independently increased the risk for dementia. CONCLUSIONS: Reduction in income level during follow-up and low income level at old age might be the consequence of a dementing process rather than being associated with risk evolution of dementia.

APOE-epsilon4 is associated with weight loss in women with AD: a population-based study.

OBJECTIVE: To investigate whether the APOE-epsilon4 allele is associated with weight loss in patients with AD or in nondemented elderly subjects. BACKGROUND: Weight loss has been considered a typical feature of AD. APOE-epsilon4 is a risk factor for AD and was recently proposed to be associated with weight loss in elderly women. It is not known whether APOE-epsilon4 is associated with weight loss in patients with AD or in the general population. METHODS: Weight and BMI measurements at an average interval of 3.5 years and APOE phenotype determination were performed in an elderly population (n = 980), including 46 patients with AD and 911 control subjects at the end of the follow-up. RESULTS: On average, patients with AD with the epsilon4 allele lost 1.9 +/- 4.0 kg (BMI 0.8 +/- 1.8 kg/m2) whereas epsilon4 noncarriers gained 1.2 +/- 3.8 kg (BMI 0.4 +/- 1.5 kg/m2) (both p < 0.05), after controlling for diabetes and exercise. However, when men and women were analyzed separately, weight loss was observed only in those women with AD with the epsilon4 allele. Clinically significant weight loss, defined as loss of > or = 5% of body weight, occurred more frequently in both patients with AD (30% versus 6%; p < 0.05) and control subjects (28% versus 18%; p < 0.001) carrying the epsilon4 allele. CONCLUSIONS: The APOE-epsilon4 allele may contribute to the unexplained weight loss in AD, especially in women.

Different error pattern of episodic and semantic memory in Alzheimer's disease and Parkinson's disease with dementia.

To evaluate the possible differences in memory dysfunction we analysed the episodic and semantic memory of patients with Alzheimer's disease (AD) and Parkinson's disease (PD) with dementia, and age-matched normal controls (NC). The memory was examined with story recall tests, list learning test with Buschke selective reminding method and category naming test. Both AD and PD groups committed more prior-story intrusion errors as compared with the NC subjects, but only the AD patients committed more extra-story intrusion errors. Both patient groups committed more extra-list intrusion errors than the NC group. Furthermore, the AD patients made more extra-list intrusion errors and recognized more false positive targets than the PD patients did. The results suggest that AD and PD patients have different patterns of memory dysfunction. The AD patients seem to perform poorly because of their inability to inhibit irrelevant information and because of increased sensitivity to interference, whereas the deficits of PD patients only reflect sensitivity to proactive interference.

Slowing of electroencephalogram and choline acetyltransferase activity in post mortem frontal cortex in definite Alzheimer's disease.

Twenty-five (96%) of 26 patients with histologically verified moderate to severe Alzheimer's disease had abnormal electroencephalograms. The patients with the slowest (5-6 Hz) dominant occipital rhythms had significantly lower choline acetyltransferase activity in the post mortem frontal cortex than the patients with highest rhythm (8-9 Hz) (analysis of covariance adjusted for the neuropsychological test score). Concentrations of dopamine, noradrenaline or serotonin in the frontal cortex did not differ in the patient groups with the slowest and highest rhythms. Neither did scores of senile plaques or neurofibrillary tangles differ between these groups. In Alzheimer patients, the frequency of the dominant occipital rhythm correlated with the total score of the neuropsychological test (r = 0.58, P less than 0.01) and with the subscales of praxic functions and expressive speech, memory and general reasoning. The results suggest that the cholinergic deficit may contribute to the slowing of the electroencephalogram found in patients with Alzheimer's disease.

Volumes of hippocampus, amygdala and frontal lobe in Alzheimer patients with different apolipoprotein E genotypes.

An increased frequency of apolipoprotein E E4 allele has been reported in patients with late onset Alzheimer's disease. Apolipoprotein E participates in the transport of cholesterol and other lipids and interferes with the growth and regeneration of both peripheral and central nervous system tissues during development and after injury. Apolipoprotein E is also implicated in synaptogenesis. Apolipoprotein E isoforms differ in binding to amyloid-beta-protein and tau protein in vitro. Here, we wanted to study the effect of apolipoprotein E genotype on the magnitude of damage in the hippocampus, where a marked synapse loss exists in Alzheimer's disease. We measured by magnetic resonance imaging the volumes of the hippocampus, amygdala, and frontal lobes in the three Alzheimer subgroups: patients with 2, 1 or 0 E4 alleles. We also investigated the profile of deficits on tests assessing memory, language, visuospatial, executive, and praxic functions of these Alzheimer subgroups. All Alzheimer patients were at early stage of the disease. We found that Alzheimer patients with E4/4 genotype (N = 5) had smaller volumes of the hippocampus and the amygdala than those with E3/4 (N = 9) and those with E3/3 or E2/3 (N = 12). The difference was significant for the right hippocampus (-54% of control) and the right amygdala (-37% of control). The volumes of the frontal lobes were similar across the Alzheimer subgroups. The patients with E4/4 also showed lowest scores on delayed memory tests and differed from E3/3, 3/2 patients in the list learning test (< 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related cognitive decline and electroencephalogram slowing in Down's syndrome as a model of Alzheimer's disease.

We studied quantitative electroencephalogram and neuropsychological performance in an aging series of 31 patients with Down's syndrome and compared the findings with those of 36 patients with probable Alzheimer's disease and age-matched controls. We found an age-related decline of cortical functions and slowing of the electroencephalogram in Down's syndrome patients aged from 20 to 60 years. Slowing of the electroencephalogram, i.e. the decrease of the peak frequency, was significantly related to Mini-Mental status scores, and visual, praxic and speech functions, as well as memory in the Down patients, similar to the Alzheimer patients. Similar correlations were not demonstrated for young or elderly controls. This study provides neuropsychological and electrophysiological data to suggest that studying Down's syndrome patients of different ages can serve as a model for progression of Alzheimer's disease.

Tetrahydroaminoacridine improves the recency effect in Alzheimer's disease.

We investigated the effects of a single administration of tetrahydroaminoacridine (25 and 50 mg, orally), a cholinesterase inhibitor, on memory function in Alzheimer's disease patients. The recall of memory items from the end of the word list (recency effect) was improved in a subgroup of Alzheimer's disease patients (responders 10 out of 28) by tetrahydroaminoacridine 50 mg. However, tetrahydroaminoacridine 50 mg had no effect on the recall of those words from the beginning or middle of the list. Tetrahydroaminoacridine did not markedly improve non-verbal delayed matching to sample or paired associates learning in any of the Alzheimer's disease patients. The "responders" performed better than the "non-responders" in tests measuring memory and frontal functions. The responders had less severe hippocampal atrophy and less prefrontal blood flow defect, and had a lower frequency of the apolipoprotein E4 allele than the "non-responders". These results suggest that acute tetrahydroaminoacridine treatment may stimulate the recency effect, and that a severe dysfunction of hippocampus and prefrontal regions blocks this effect of tetrahydroaminoacridine on short-term memory performance.