Neuropsychological Differences between Male Familial and Nonfamilial Alcoholics and Nonalcoholics

The hypothesis was tested that neuropsychological differences exist between males who have an alcoholic parent, sister, or brother (FH+) versus those who do not (FH-). Neuropsychological tests measuring verbal, learning/memory, abstracting/problem solving, and perceptual-motor performance were given to four groups of middle-aged subjects: alcoholic FH+ (n = 41); alcoholic FH- (n = 27); nonalcoholic FH+ (n = 19); and nonalcoholic FH- (n = 43). FH+ subjects performed significantly poorer than FH- subjects on the abstracting/problem solving and perceptual-motor tasks, and approached significance on the verbal and learning/memory measures. Alcoholics performed more poorly than nonalcoholics on abstracting/problem solving and learning/memory tasks. There were no groups by family history significant interactions. From these results we suggest: a performance deficit in abstracting/problem solving and possibly learning/memory may antedate the alcoholic stage in FH+ individuals; alcoholism and positive family history of alcoholism have independent, additive deleterious effects on cognitive-perceptual functioning; and future neuropsychological studies of alcoholism should consider the frequency of FH+ and FH- individuals in both alcoholic and control groups.     

Cognitive Functioning, ASP, and Family History of Alcoholism in Young Men at Risk for Alcoholism

Previous research has suggested that individuals with a family history of alcoholism may have cognitive deficits that predate, and possibly predispose, to the onset of alcoholism. However, these deficiencies may result from other factors, e.g., comorbid psychopathology. The current study investigated the neuropsychological functioning of young adult males at high risk for alcohol abuse due to a family history of alcoholism (FH) and/or a personal history of antisocial personality disorder (ASP). A family history of alcoholism (FH+) alone was not associated with neuropsychological impairment. Subjects with ASP, however, exhibited some difficulty with higher level motor control and with verbal concept formation compared with nonASP subjects. No clear pattern of FH x ASP interaction was evident in the measures examined. These findings suggest that previous findings suggesting cognitive deficiencies in FH+ individuals may have been related to a failure to consider co-morbid ASP. The deficits exhibited by the ASP subjects may reflect both reduced inhibitory control and a deficiency in higher level verbal skills. These deficiencies may leave ASP individuals less capable of utilizing higher level language skills to regulate behavior.     

Effect of simvastatin in familial hypercholesterolemia on the affinity of electronegative low-density lipoprotein subfractions to the low-density lipoprotein receptor

The effect of simvastatin therapy on the biologic characteristics of the electronegative low-density lipoprotein (LDL) subfraction of patients with familial hypercholesterolemia (FH) was studied. Total LDL, isolated from FH plasma at 0, 3 and 6 months of simvastatin treatment, was subfractionated into electropositive LDL (LDL[+]) and electronegative LDL (LDL[-]) by anion exchange chromatography. LDL isolated from healthy normolipemic (NL) subjects was used as a control. The LDL(-) proportion was twofold higher in patients with FH than in NL subjects (17.6 +/- 1.6% vs 7.8 +/- 1.5%, respectively; p <0.05) and was progressively reduced by simvastatin therapy (15.7 +/- 1.6% at 3 months; 13.8 +/- 2.5% at 6 months; p <0.05). Both LDL subfractions from patients with FH had a higher relative cholesterol content and decreased apolipoprotein B and triglycerides than NL subfractions. Simvastatin progressively induced changes in lipid content of both LDL subfractions in patients with FH, and lipid composition was closer to these subfractions in NL subjects after 6 months of therapy. Binding displacement experiments in human fibroblasts demonstrated that LDL(-) from both groups of subjects had a lower affinity of binding to the LDL receptor that LDL(+). In addition, LDL(+) in patients with FH presented an intermediate binding affinity between LDL(-) and LDL(+) in NL subjects. Simvastatin-induced changes in LDL composition were accompanied by a progressive increase in affinity of LDL(+) and LDL(-) in patients with FH. After 6 months of therapy, LDL(+) in FH had an affinity similar to that of LDL(+) in NL subjects. The LDL(-)-induced release of chemokines interleukin-8 and monocyte chemotactic protein-1 from cultured endothelial cells was twofold higher compared with that of LDL(+). No difference in chemokine release between patients with FH and NL subjects or the effect of simvastatin were observed. We conclude that simvastatin therapy was able to modify LDL subfraction composition in subjects with FH and increase their affinity to the LDL receptor. This improvement could contribute to the observed reduction in LDL(-) proportion induced by simvastatin.     

Executive dysfunction and clinical outcome in chronic alcoholics

BACKGROUND: The purpose of this study was to investigate which of 12 neuropsychological tests predict alcoholic patients' alcohol-specific and/or alcoholic-nonspecific outcome. Our hypothesis was that the ecologically valid neuropsychological tests that measure executive function are better predictors of alcoholics' functional outcome. METHODS: We administered 12 neuropsychological tests to chronic alcoholics. Included in the tests were tasks of Reaction Time, Symbol Digit Modalities, Figure Position, Digit Span, Block Design, Trail Making, and six subtests of a battery called the Behavioral Assessment of the Dysexecutive Syndrome (BADS). Previous investigators have suggested that the BADS has ecological validity. Twenty-two male alcoholics were compared with 15 nonalcoholic control subjects on these neuropsychological measures 7 weeks after detoxification. Two functional outcome indices, i.e., resumption of drinking and occupation, were evaluated 18 months after discharge. RESULTS: The total profile score and the score on three of the six subtests of the BADS were lower in alcoholics than in nonalcoholic controls. Alcoholics' performance on the BADS predicted alcohol-nonspecific outcome (occupation) but not alcohol-specific (drinking) outcome. In contrast, other neuropsychological tests did not predict either of the two outcome indices. CONCLUSIONS: The BADS total profile score is related to alcohol-nonspecific outcome but not to alcohol-specific outcome.     

Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism

Having a parent affected with late-onset Alzheimer's disease (AD) is a risk factor for developing AD among cognitively normal subjects. We examined whether cognitively normal subjects with a parental family history of AD show cerebral metabolic rate of glucose (CMRglc) reductions consistent with AD as compared with those without a family history and whether there are parent gender effects. Forty-nine 50- to 80-year-old normal subjects were examined who received clinical, neuropsychological, and 2-[(18)F]fluoro-2-deoxy-d-glucose-positron emission tomography examinations, including 16 subjects with a maternal (FHm) and eight with a paternal (FHp) family history of AD and 25 with no family history (FH(-)). FH groups were comparable for demographic and neuropsychological measures. As compared with both FH(-) and FHp groups, FHm subjects showed CMRglc reductions in the same regions as clinically affected AD patients, involving the posterior cingulate cortex/precuneus, parietotemporal and frontal cortices, and medial temporal lobes (P < 0.05, corrected for multiple comparisons). These effects remained significant after accounting for possible risk factors for AD, including age, gender, education, apolipoprotein E genotype, and subjective memory complaints. No CMRglc differences were found between FHp and FH(-) subjects. This study shows a relationship between reduced CMRglc in AD-vulnerable brain regions and a maternal family history of AD in cognitively normal individuals.     

The effects of a three-month exercise programme on neuropsychological function in elderly institutionalized women: a randomized controlled trial

This randomized controlled trial examined the effect of a 3-month exercise programme on neuropsychological function in a population of very elderly institutionalized women. Baseline neuropsychological testing was performed, and following 3 months of exercise or control intervention, subjects were retested 3-7 days after the completion of the study period. Apart from the Word Fluency Test, there was no significant improvement in any of the neuropsychological test scores. This study may not have shown any significant improvement in neuropsychological function because our exercise programme was too light to improve aerobic fitness, or because neuropsychological tests were repeated 3-7 days after exercise was completed and any acute effects of exercise may have disappeared by that time.     

Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults

PURPOSE: In our initial study of the potential effects of cholesterol-lowering interventions on cognitive functioning, treatment with lovastatin as compared with placebo caused performance decrements on several neuropsychological tests, whereas scores on other tests were unaffected. The current study was designed to confirm and extend those findings. METHODS: The study comprised 308 hypercholesterolemic adults between 35 and 70 years of age. Employing a randomized double-blind design, we assigned participants to daily treatment with placebo, 10 mg of simvastatin, or 40 mg of simvastatin for 6 months. A neuropsychological test battery was administered to assess cognitive functioning at baseline and at the end of the treatment period. RESULTS: A total of 283 subjects completed the study: 94 subjects on placebo, 96 taking 10 mg of simvastatin, and 93 taking 40 mg of simvastatin. Compared with placebo, decremental effects of simvastatin treatment were found on tests previously observed to be sensitive to statins (P = 0.008; difference in summary z scores = 0.18; 95% confidence interval [CI]: 0.07 to 0.29) and on tests not previously administered (P = 0.04; difference in summary z scores = 0.17; 95% CI: 0.05 to 0.29), but not on tests previously observed to be insensitive to statins (P = 0.84; difference in summary z scores = 0.02; 95% CI: -0.07 to 0.10). For the three tests specifically affected by simvastatin, effects on cognitive performance were small, manifest only as failure to improve during the 6 months of treatment (compared with placebo), and were confounded by baseline differences on one test. CONCLUSION: This study provides partial support for minor decrements in cognitive functioning with statins. Whether such effects have any long-term sequelae or occur with other cholesterol-lowering interventions is not known.     

A rehabilitation program for mild memory impairments

Eight subjects, 60-75 years of age, with at least 5 years of education and mild memory impairments were recruited for a rehabilitation program. Other 8 subjects, not exposed to the rehabilitative training and with the same neuropsychological profile, represented a control group. In the first day of this program an evaluation of cognitive/behavioral functions was performed. Our program consisted of a neuropsychological rehabilitative intervention along 12 weeks, with a 5-day-period of domiciliary training with a set of home exercises and a 1-day training in our Center with rehabilitative exercises administered with the aid of a personal computer, each week. Rehabilitative training administered in our Center was aimed at stimulating visuo-verbal, verbal and spatial memory and the utilization of "memory strategies". After 4, 8 and 12 weeks of therapeutic program, other evaluations of the cognitive functions with the same battery tests were performed to evaluate possible improvements: the results indicated an improvement of memory test scores that demonstrated the positive effect of neuropsychological training on memory performances. There was no improvement in the control group.     

The neuropsychological consequences of abstinence among older alcoholics: a cross-sectional study

BACKGROUND: The older alcoholic has been distinguished from the younger alcoholic with regard to both the acute effects of alcohol and also the recovery of functioning with abstinence. Few studies, however, have included samples of exclusively older subjects. In this investigation we examined the recovery of functioning in an older cohort of recovering alcoholics (age range 55-83) to determine which neuropsychological functions improve and which remain impaired with abstinence. METHODS: We used a cross-sectional design, comparing three demographically matched groups on a battery of neuropsychological tests: (a) older alcoholics who had been abstinent for greater than 6 months, (b) older alcoholics who had been abstinent for less than 6 months, and (c) a control group of older subjects without alcohol abuse histories. RESULTS: In almost all tasks, the alcoholics who were abstinent for less than 6 months performed worse than the control group. In contrast, the alcoholics who had been abstinent for more than 6 months differed from the control group on learning and recall of a word list, immediate and delayed recall of a complex figure, initial letter fluency, and clock drawing. CONCLUSIONS: Memory and executive skills appear to be resistant to recovery or at least slower to recover with abstinence in the older alcoholic. The impairment with visuospatial skills reported in prior investigations of alcoholics may be related to compromised executive functions, which interfere with the encoding of more complex visuospatial information and thus affect recall of such information. Studies that involve larger samples of older alcoholics are needed to understand their ability to recover cognitive functioning with abstinence.     

Neurocognitive abnormalities in offspring of mothers with systemic lupus erythematosus

Offspring of systemic lupus erythematosus (SLE) patients delivered during follow-up in the lupus clinic from 1973 to 1998 were assessed for SLE and by age-appropriate neurocognitive tests. Nine domains were evaluated. Controls, matched for age, sex, race and socio-economic status, underwent the same neurodevelopmental/neuropsychological evaluation. A domain was considered 'abnormal' if at least one of the tests in the domain yielded abnormal results. The number of offspring with normal/abnormal results was compared in each of the nine domains using McNemar test for matched analysis. In addition, an unmatched analysis using chi-square tests was performed. Logistic regression was run on both the matched pairs and unmatched groups to adjust for possible gender differences. A total of 106 children, 49 pairs of SLE offspring and matched controls (20 male and 29 female) and an extra eight offspring (three male and five female) of SLE patients without a control match were included. Of the 57 SLE offspring, none were diagnosed with SLE. The matched analyses of the neuropsychological domains revealed impairment in SLE children compared with matched controls in two of the nine domains: learning and memory and behaviour.     

Normalization of LDL receptor function by lymphocytes of patients with heterozygous familial hypercholesterolemia after treatment with plasma cholesterol lowering agents

Low density lipoprotein (LDL)-dependent growth of mitogen-activated lymphocytes, inhibited in their capacity to synthesize cholesterol endogenously, can be used as an assay of functional receptors for LDL. Using this technique, abnormalities can be detected in circulating lymphocytes obtained from patients with familial hypercholesterolemia (FH). Functional lymphocyte LDL receptor activity was decreased in patients with heterozygous FH. Following treatment with the specific inhibitor of cholesterol synthesis, lovastatin, alone or in combination with a bile acid-binding resin, there was increased expression of functional lymphocyte LDL receptors in five of nine patients. Plasma LDL cholesterol levels decreased in all nine patients. Three other patients who were only studied while receiving therapy also manifested increased expression of functional lymphocyte LDL receptors. The degree of improvement in plasma LDL cholesterol did not predict the effect on lymphocyte LDL receptor function. Longitudinal studies indicated that an increase in functional LDL receptor activity could be observed with 4 weeks of therapy and persisted for at least 18 months on continuous treatment. These results provide direct evidence that therapy with lovastatin and a bile acid-binding resin can lead to increased expression of functional LDL receptors by lymphocytes in the majority (eight of 12) of patients with heterozygous FH.     

A Prospective Study of Young Men at High Risk for Alcoholism: Neuropsychological Assessment

As part of the first phase of a prospective longitudinal study on alcoholism, a battery of neuropsychological tests covering general intelligence, memory, attention, field-dependence, categorizing ability, and organizing and planning, was administered to 204 18-19-year-old males. Of these, 134 subjects are the sons of alcoholic fathers and are thereby themselves at high risk for becoming alcoholic. The remaining 70 subjects comprise a control group matched for several social and familial variables. The high risk group was found to have a relatively poorer vocabulary and to perform worse on tests of categorizing ability and organization and planning. All of these findings concur with other results from this study. The anticipated future alcoholics from among the high risk subjects may prove to be those who differed most on these tests.     

Genotype of the mutant LDL receptor allele is associated with LDL particle size heterogeneity in familial hypercholesterolemia

Small, dense LDL particles have been associated with an increased risk of coronary artery disease. In order to assess the potential contribution of the genotype of the LDL receptor to LDL particle size heterogeneity in familial hypercholesterolemia (FH), we examined the electrophoretic characteristics of LDL particles in a large cohort of FH heterozygotes and controls. A total of 259 FH heterozygotes and 208 controls participated in the study. FH subjects were carriers of one of the nine French Canadian mutations in the LDL receptor gene. LDL particles were characterized by polyacrylamide gradient gel electrophoresis following a 6-week lipid-lowering drug-free baseline period. LDL-peak particle diameter (LDL-PPD), representing the most abundant LDL particle subpopulation, was significantly smaller in FH heterozygotes carrying a negative-receptor mutation than in subjects carrying a defective-receptor mutation (negative-receptor = 257.3 +/- 4.1 A versus defective-receptor = 259.0 +/- 4.3 A, p = 0.0006). No significant difference in plasma CETP concentrations was found between these two genotypic groups. Moreover, compared with controls having low triglyceride levels, negative-receptor subjects with high triglyceride levels had a relative risk of 19.6 (p < 0.0001) of having small, dense LDL particles while this risk was not significantly increased among defective-receptor subjects. Multivariate analysis showed that the LDL receptor status accounted for 5.7% of the variance in the LDL-PPD after adjustment for covariates. These results suggest that the genotype of the mutant LDL receptor allele was independently associated with variations in LDL-PPD and could partly explain why negative-receptor FH heterozygotes may be at greater risk of cardiovascular disease than defective-receptor FH subjects.     

Electronegative LDL of FH subjects: chemical characterization and induction of chemokine release from human endothelial cells

Electronegative LDL (LDL(-)) constitutes a plasma subfraction of LDL with proinflammatory properties. Its proportion is increased in familial hypercholesterolemia (FH); however, the characteristics of LDL(-) isolated from FH subjects have not been previously studied. In this work, the composition, oxidative status, and inflammatory capacity on endothelial cells of LDL(-) from FH and normolipemic (NL) subjects were evaluated. LDL(-) from FH was relatively enriched in esterified and free cholesterol and triglyceride, and had lower apoB and phospholipid content compared with the non-electronegative fraction (LDL(+)). LDL(-) also contained increased amounts of apoE, apoC-III, sialic acid, and non-esterified fatty acids (NEFAs). The same was observed in NL subjects, except that esterified cholesterol and phospholipid were similar in LDL(-) and LDL(+). No difference was observed between the two fractions concerning malondialdehyde, fatty acid hydroxides, and antioxidants, thereby indicating the absence of increased oxidation of LDL(-) compared with LDL(+). When LDL(-) (100 mg/l) from NL and FH subjects was incubated for 24 h with human umbilical vein endothelial cells (HUVECs), interleukin 8 (IL-8) and monocyte chemotactic protein 1 (MCP-1) increased twofold in the culture medium compared with LDL(+). Vascular cell adhesion molecule 1 (VCAM-1) expression was not increased by LDL(-). Our data indicate that LDL(-) from FH or NL subjects shows no evidence of increased oxidative modification compared to LDL(+); however, LDL(-) induces twofold the release of chemokines by endothelial cells. This effect, which may contribute to leukocyte recruitment and promote atherogenesis, may be greater in FH subjects in which LDL(-) can be up to eightfold higher than in NL subjects.     

Encephalopathy and neuropathy in end-stage liver disease before and after liver transplantation.

The nervous system involvement of 8 patients with end-stage liver disease was evaluated by means of clinical neurological, neuropsychological, neurophysiological and neuroradiological investigation before and 6-12 months after a successful liver transplantation. Preoperatively, all subjects (7 women, 1 man; mean age 40 years, range 30-54 years) exhibited decreased muscle strength and 2 patients manifested clinical signs of polyneuropathy. In neuropsychological tests, slight visuoconstructive apraxia, and disturbances of verbal memory and cognitive function were observed. Magnetic resonance imaging (MRI) revealed cerebral lesions in two patients. After transplantation, muscle strength reverted to normal in all patients, polyneuropathy improved and in all but 2 patients recovery of neuropsychological functioning was observed. Clinical signs of encephalopathy had disappeared. All patients were emotionally better adjusted after transplantation. Four subjects showed new, albeit mild changes in neurophysiological and neuropsychological tests postoperatively. We conclude that the majority of neurological impairment disappeared after liver transplantation. We want to stress that evaluation of neurological sequelae of liver transplantation needs to be based on assessments both before and after liver transplantation.     

Novel spacer device does not improve adherence in childhood asthma

The Funhaler (FH) is a novel spacer device (holding chamber) that has been designed to improve adherence and aerosol delivery in young asthmatic children using a metered dose inhaler. A pilot study reported a 38% increase in parent-reported adherence over 2 weeks compared with the child's normal spacer. The aim of this study was to investigate whether the FH would be associated with superior adherence in the medium term (3 months) using an objective assessment. Forty-seven children aged 18 months to 7 years were randomised to a FH or control small volume spacer. Participants were reviewed monthly for 3 months. Adherence was measured using an electronic monitoring device (Smartinhaler). Disease control was based on symptom scores and exacerbation rates. Twenty-six children were randomised to the FH and 21 to the control spacer. Three children withdrew (FH = 2). Median adherence each month for the 3 months was 74%, 54%, and 46% for the FH and 70%, 73%, and 54% for the control spacer. The difference in adherence was not statistically significant (P = 0.47, 0.37, and 0.23, respectively). There was also no significant difference in exacerbation rates or symptom scores. Seven of the FHs broke during the study. The FH was preferred by 21/24 parents randomised to the FH compared with their child's normal spacer. Despite the FH being popular with children and parents its use was not associated with improved adherence or disease control.     

Sleep disordered breathing and cognitive function in a retirement village population.

Sleep disordered breathing (SDB) may be associated with cognitive dysfunction in non-demented elderly people. A random sample of 96 retirement village residents were given both neuropsychological assessment and overnight sleep monitoring with a portable microprocessor based system (Vitalog PMS-8). Respiratory disturbance index (RDI) was calculated as the number of apnoeas and hypopnoeas per hour of sleep. RDI was not associated with 'memory', 'verbal', and 'motor' factors identified from the analysis of cognitive tests, but was associated with the 'cerebral efficiency' factor (R2 = 0.21, p less than 0.0001). Seventy-three subjects had repeat neuropsychological tests, median time to follow-up being 17 months. Baseline RDI did not predict changes in scores on the two factors identified from the second analysis. We conclude that mild to moderate disturbance of breathing during sleep is not associated with cognitive dysfunction in non-demented subjects.     

Association of heterozygous familial hypercholesterolemia with smaller HDL particle size

Small, dense HDL particles have been associated with factors known to increase the risk of cardiovascular disease, such as obesity, hypertriglyceridemia, small dense LDL particles, decreased HDL-cholesterol levels and increased apoA-I fractional catabolic rate from plasma. In order to assess the potential contribution of HDL particle size to atherosclerosis in heterozygous familial hypercholesterolemia (FH), we examined the electrophoretic characteristics of HDL particles in a large cohort of well defined FH heterozygotes and controls. A total of 259 FH heterozygotes and 208 controls participated in the study. FH subjects were carriers of one of the nine French Canadian mutations in the LDL receptor gene. All subjects were apoE3 homozygotes. HDL particles were characterized by non-denaturing polyacrylamide gradient gel electrophoresis following a 6-week lipid-lowering drug-free baseline period. The integrated HDL size was significantly smaller in the FH group compared to controls (FH = 87.3 ± 5.2 Å versus controls = 91.6 ± 4.9 Å, P < 0.0001). In each groups, men had smaller HDL particles than women. Multiple regression linear analyses showed that the FH/Control status accounted for 20.3% of the variance in the integrated HDL size. These results suggest that the FH/control status was independently associated with variations in HDL particle size and that these variations could contribute to the development of premature atherosclerosis in these patients.     

剑桥认知检查(CAMCOG)对血管性痴呆与阿尔茨海默病的神经心理学鉴别

目的 验证剑桥认知检查(CAMCOG)对血管性痴呆(VaD)与阿尔茨海默病(AD)是否具有神经心理学鉴别功能。方法 所有入选病例皆符合很可能／可能AD或VaD的诊断标准。325例中，246例AD患 者和79例VaD患者接受了CAMCOG检查。性别和其他因素比率分析用卡方检验，所有其他参数的比较分析用t检验，组间分类用逐步辨别分析方法。结果 AD组CAMCOG平均总积分低于VaD组7分以上，其中定向力、语言、记忆和视觉积分与VaD组相比具有显著性差异。这些分项积分和CAMCOG总积分对组间辨别功能具有显著贡献，对AD或VaD诊断预测的总成功率达到70％．结论 在CAMCOG区城内，AD患者和VaD患者的神经心理学表现具有显著性差异，但这种鉴别方法目前还不适宜于临床使用。     

Environmental modulation of atherosclerosis end points in familial hypercholesterolemia

In familial hypercholesterolemia (FH), early coronary heart disease (CHD) is a complex trait that results from a large monogenic component of susceptibility due to elevated LDL cholesterol. This was demonstrated by observation of the high risk of early CHD in FH subjects compared with the general population. However, not all subjects with a LDLR gene mutation suffer with early CHD. Furthermore, studies in extended multigenerational families showed that even for this strong monogenic effect the environment could substantially modulate the age at death from CHD. Anecdotal examples of apparent modulation of atherosclerosis severity by lifestyle changes were also seen in other monogenic metabolic problems, such as hepatic lipase deficiency and Dunnigan-type familial partial lipodystrophy. Thus, even within apparently clear-cut rare monogenic metabolic diseases, such as FH, among carriers there can be a variability in the expression of important quantitative end points, such as early CHD. In some cases, the environment, including lifestyle factors, appears to play a key role in modulating the disease severity. This complexity could have implications for diagnosis and treatment.