Predicting memory decline in normal elderly: genetics, MRI, and cognitive reserve

Major predictors of Alzheimer's disease (AD) include apolipoprotein E (APOE)-epsilon4, hippocampal atrophy on magnetic resonance imaging (MRI), and memory dysfunction prior to diagnosis. We examined 159 normal elderly subjects with MRI and the California Verbal Learning Test (CVLT); 84 returned for longitudinal follow-up 5 years later. Analyses at baseline revealed significant variance in hippocampal volume accounted for by cerebral volume and age but not by APOE isoform. However, interactions involving APOE isoform and laterality were observed. As hypothesized, an APOE x time interaction was revealed for CVLT long-delay free recall: APOE-epsilon3/4 subjects had significantly poorer performance than APOE-epsilon3/3 subjects at follow-up. Forward stepwise multiple regression analysis predicting follow-up long-delay free recall selected baseline recall, followed by number of APOE-epsilon4 alleles, followed by left-hippocampal volume. Age and sex did not enter into the model. We conclude that APOE-epsilon4 predicts longitudinal memory decline in healthy controls and that MRI morphometry of hippocampus adds slightly to predictive value.     

Differential performances on the WRAML in children and adolescents diagnosed with epilepsy,head injury,and substance abuse

Assessment of memory in children and adolescents has been limited because of the lack of standardized instruments available. The recently released Wide Range Assessment of Memory and Learning (WRAML; Sheslow & Adams, 1990) was used in this exploratory study to examine memory skills in children and adolescents with conditions affecting neuropsychological functioning. Diagnostic categories included epilepsy, traumatic brain injury, and substance abuse, as well as a nonneurological comparison group with psychiatric disturbance. Results indicated that children with epilepsy scored significantly below those with substance abuse or psychiatric disorders on the Verbal Memory Index. Within‐group comparisons suggested that all clinical groups had more difficulty with tasks that purportedly measure auditory attentional skills. Children with epilepsy demonstrated greater variability in memory performances, suggesting possible problems with both attention and memory factors. The WRAML appears to be a potentially useful assessment tool in the measurement of memory processes in children, although further research is needed concerning subtest specificity.     

Test performance and classification statistics for the Rey Auditory Verbal Learning Test in selected clinical samples.

The Rey Auditory Verbal Learning Test [RAVLT; Rey, A. (1941). L'examen psychologique dans les cas d'encéphalopathie traumatique. Archives de Psychologie, 28, 21] is a commonly used neuropsychological measure that assesses verbal learning and memory. Normative data have been compiled [Schmidt, M. (1996). Rey Auditory and Verbal Learning Test: A handbook. Los Angeles, CA: Western Psychological Services]. When assessing an individual suspected of neurological dysfunction, useful comparisons include the extent that the patient deviates from healthy peers and also how closely the subject's performance matches those with known brain injury. This study provides the means and S.D.'s of 392 individuals with documented neurological dysfunction [closed head TBI (n=68), neoplasms (n=57), stroke (n=47), Dementia of the Alzheimer's type (n=158), and presurgical epilepsy left seizure focus (n=28), presurgical epilepsy right seizure focus (n=34)] and 122 patients with no known neurological dysfunction and psychiatric complaints. Patients were stratified into three age groups, 16-35, 36-59, and 60-88. Data were provided for trials I-V, List B, immediate recall, 30-min delayed recall, and recognition. Classification characteristics of the RAVLT using [Schmidt, M. (1996). Rey Auditory and Verbal Learning Test: A handbook. Los Angeles, CA: Western Psychological Services] meta-norms found the RAVLT to best distinguish patients suspected of Alzheimer's disease from the psychiatric comparison group.     

Latent factor structure of the Test of Memory and Learning in a pediatric traumatic brain injured sample: support for a general memory construct.

The Test of Memory and Learning (TOMAL; Reynolds, C. R., & Bigler, E. D. (1994a). Test of Memory and Learning (TOMAL). Austin, Texas: Pro-Ed; Reynolds, C. R., & Bigler, E. D. (1994b). Test of Memory and Learning (TOMAL): Examiner's manual. Austin, Texas: Pro-Ed) was published to ameliorate the paucity of developmentally appropriate instruments for the assessment of memory in children and adolescents. No studies have confirmed the latent factor structure of the TOMAL. Two structural models were subjected to confirmatory factor analysis using the TOMAL performances of 140 subjects, age 5-19, with traumatic brain injury (TBI). Model 1 was a four-factor model with a large "Complex Memory" factor and three smaller factors. Model 2 was a two-factor model with Verbal and Nonverbal Memory factors, both of which loaded on a second-order "General" memory factor. Results indicated that the model with a higher order structure demonstrated better fit than the four-factor model. Further analysis suggested that the TOMAL factor structure is characterized by a large Complex Memory and smaller, Sustained Attention factor. The study provides tentative support for a "general memory" construct.     

An exploration of the construct validity of the Heaton memory tests.

The Heaton techniques for assessing memory differ from most other memory measures by employing the combination of learning trials, repeated exposure to test stimuli, and 4-hour recall measures. The present study was designed to explore the relationship between the Heaton Story and Figure memory procedures, the California Verbal Learning Test (CVLT), and measures of attention, word fluency, and spatial perception. Data from 126 individuals were analyzed. Three separate factor analyses were performed that examined measures of attention, learning, and recall. Each revealed a three-factor solution accounting for 71, 70, and 72% of the variance, respectively. Regression analyses supported the visual components of Figure Memory and the verbal components of Story Memory obtained in the factor analyses. Overall, the findings supported the independence of the Heaton Memory procedures and the role of spatial factors in performance of Figure Memory. Additionally, both Figure and Story Memory shared variance with the CVLT, supporting the validity of both procedures as memory measures.     

MMPI-2 indices of psychological disturbance and attention and memory test performance in head injury

A number of studies have investigated the relationship between psychological disturbance and neuropsychological (NP) test performance. The current study is a replication and extension of who found that MMPI-2 indices of psychological disturbance are related to performance on NP tests of attention and memory in psychiatric and head-injured patients. In a large sample (N=381) referred for evaluation after sustaining presumed head injury, we examined the relationship between MMPI-2 indices of psychological disturbance and measures of attention and memory from the Wechsler Memory Scale-Revised (WMS-R), Wechsler Adult Intelligence Scale-Revised (WAIS-R), California Verbal Learning Test (CVLT), and the Memory Assessment Scales (MAS). Although related to other domains, MMPI-2 variables were most consistently related to measures of attention and List Learning. Even when demographic variables, injury severity, and litigation status were controlled, MMPI-2 indices significantly predicted performance on six out of eight tests. However, the correspondence between similar indices on the WMS-R and MAS were relatively low, especially for Verbal Memory and Visual Reproduction. Further, litigation was significant in predicting only 2 of 8 attention and memory indices.     

Interrelated neuropsychological and anatomical evidence of hippocampal pathology in the at-risk mental state

BACKGROUND: Verbal learning and memory deficits are frequent among patients with schizophrenia and correlate with reduced magnetic resonance imaging (MRI) volumes of the hippocampus in these patients. A crucial question is the extent to which interrelated structural-functional deficits of the hippocampus reflect a vulnerability to schizophrenia, as opposed to the disorder per se. METHOD: We combined brain structural measures and the Rey Auditory Verbal Learning Test (RAVLT) to assess hippocampal structure and function in 36 never-medicated individuals suspected to be in early (EPS) or late prodromal states (LPS) of schizophrenia relative to 30 healthy controls. RESULTS: Group comparisons revealed bilaterally reduced MRI hippocampal volumes in both EPS and LPS subjects. In LPS subjects but not in EPS subjects, these reductions were correlated with poorer performance in RAVLT delayed recall. CONCLUSIONS: Our findings suggest progressive and interrelated structural-functional pathology of the hippocampus, as prodromal symptoms and behaviours accumulate, and the level of risk for psychosis increases. Given the inverse correlation of learning and memory deficits with social and vocational functioning in established schizophrenia, our findings substantiate the rationale for developing preventive treatment strategies that maintain cognitive capacities in the at-risk mental state.     

Early patterns of verbal memory impairment in children treated for medulloblastoma

Children treated for medulloblastoma demonstrate a variety of cognitive deficits in addition to white matter and hippocampal neuropathology. This study examined 40 children treated for medulloblastoma as compared with 40 demographically matched controls on the California Verbal Learning Test-Children's Version (D. C. Delis, J. H. Kramer, E. Kaplan, & B. A. Ober, 1994). Results revealed significantly poorer performance on indices of word recall in the patient group as compared with the controls in addition to milder but still significantly poorer recognition memory. These findings suggest that children treated for medulloblastoma demonstrate a mixed profile of memory impairment consisting of both retrieval and recognition deficits. Implications of these findings for understanding neurobehavioral sequelae within pediatric medulloblastoma populations and for designing educational and remediation strategies to be used with these children are discussed.     

Differential associations between entorhinal and hippocampal volumes and memory performance in older adults

Magnetic resonance imaging-derived entorhinal and hippocampal volumes were measured in 14 nondemented, community-dwelling older adults. Participants were selected so that memory scores from 2 years prior to scanning varied widely but were not deficient relative to age-appropriate norms. A median split of these memory scores defined high-memory and low-memory groups. Verbal memory scores at the time of imaging were lower, and entorhinal and hippocampal volumes were smaller, in the low-memory group than in the high-memory group. Left entorhinal cortex volume showed the strongest correlation (r= .79) with immediate recall of word lists. Left hippocampal volume showed the strongest correlation (r= .57) with delayed paragraph recall. These results suggest that entorhinal and hippocampal volumes are related to individual differences in dissociable kinds of memory performance among healthy older adults.     

Multimodal surface-based morphometry reveals diffuse cortical atrophy in traumatic brain injury.

Background

Normal aging involves a decline in cognitive function that has been shown to correlate with volumetric change in the hippocampus, and with genetic variability in the APOE-gene. In the present study we utilize 3D MR imaging, genetic analysis and assessment of verbal memory function to investigate relationships between these factors in a sample of 170 healthy volunteers (age range 46–77 years).

Methods

Brain morphometric analysis was performed with the automated segmentation work-flow implemented in FreeSurfer. Genetic analysis of the APOE genotype was determined with polymerase chain reaction (PCR) on DNA from whole-blood. All individuals were subjected to extensive neuropsychological testing, including the California Verbal Learning Test-II (CVLT). To obtain robust and easily interpretable relationships between explanatory variables and verbal memory function we applied the recent method of conditional inference trees in addition to scatterplot matrices and simple pairwise linear least-squares regression analysis.

Results

APOE genotype had no significant impact on the CVLT results (scores on long delay free recall, CVLT-LD) or the ICV-normalized hippocampal volumes. Hippocampal volumes were found to decrease with age and a right-larger-than-left hippocampal asymmetry was also found. These findings are in accordance with previous studies. CVLT-LD score was shown to correlate with hippocampal volume. Multivariate conditional inference analysis showed that gender and left hippocampal volume largely dominated predictive values for CVLT-LD scores in our sample. Left hippocampal volume dominated predictive values for females but not for males. APOE genotype did not alter the model significantly, and age was only partly influencing the results.

Conclusion

Gender and left hippocampal volumes are main predictors for verbal memory function in normal aging. APOE genotype did not affect the results in any part of our analysis.     

人参皂苷Rg1对癫痫大鼠海马神经元损伤和小胶质细胞活化的影响

目的探讨人参皂苷Rg1对癫痫大鼠海马神经元损伤和小胶质细胞活化的影响及其作用机制。方法 SD大鼠分为对照组(control组)、癫痫模型组(model组)、人参皂苷Rg1低剂量组(Rg1-L组)和人参皂苷剂量组(Rg1-H组),采用氯化锂-匹罗卡品腹腔注射制备癫痫大鼠模型;记录各组大鼠行为学发作情况;ELISA检测各组大鼠海马组织的氧化应激水平;qRT-PCR检测各组海马组织中炎症因子的表达;HE染色观察各组大鼠海马神经元结构和病理形态变化;免疫荧光组织化学染色检测各组大鼠小胶质细胞中iNOS、Arg-1蛋白表达。结果 model组大鼠症状达到Ⅲ级及Ⅲ级以上较control组显著增加,人参皂苷Rg1使大鼠的癫痫症状得到改善;与control组相比,model组大鼠海马组织中MDA(P<0.001)、TNF-αm RNA(P<0.001)、IL-1βmRNA(P<0.001)的表达水平上调,SOD(P<0.001)、IL-10 m RNA(P<0.001)的表达水平下调,而人参皂苷Rg1使大鼠海马组织中MDA(P<0.05)、TNF-αm RNA(P<0.05)、IL-1βmRNA(P<0.05)的表达水平下调,SOD(P<0.05)、IL-10 mRNA(P<0.05)的表达水平上调;model组大鼠海马神经元形态不完整,细胞间间隙增大和排列紊乱,人参皂苷Rg1组大鼠海马神经元形态明显改变,可见细胞排列较规则,大部分细胞形态正常;model组大鼠海马神经元凋亡率显著上升(P<0.001),人参皂苷Rg1组使大鼠海马神经元凋亡率下降(P<0.05);与control组相比,model组大鼠小胶质细胞数量显著增加(P<0.001),iNOS蛋白的表达显著升高(P<0.001),Arg-1蛋白表达显著降低(P<0.001),与model组相比,人参皂苷Rg1组大鼠小胶质细胞数量减少(P<0.05),iNOS蛋白的表达降低(P<0.05),Arg-1蛋白表达升高(P<0.05)。结论人参皂苷Rg1降低癫痫大鼠海马组织中iNOS蛋白的表达,增加Arg-1蛋白的表达,抑制小胶质细胞的激活,减轻氧化应激和炎症因子的表达,降低癫痫大鼠发作的等级。     

Sex differences in the association of the apolipoprotein E epsilon 4 allele with incidence of dementia,cognitive impairment,and decline

We examined longitudinal associations between the apolipoprotein E ε4 allele (ApoE4⁺ status) and several cognitive outcomes and tested effect modification by sex. Data on 644 non-Hispanic Caucasian adults, from the Baltimore Longitudinal Study of Aging (BLSA) were used. Dementia onset, cognitive impairment and decline were assessed longitudinally. After 27.5 years median follow-up, 113 participants developed dementia. ApoE4⁺ predicted dementia significantly (hazard ratio [HR] = 2.89; 95% confidence interval [CI], 1.93–4.33), with nonsignificant sex differences. Taking all time points for predicting cognition, women had significantly stronger positive associations than men between ApoE4⁺ status and impairment or decline on the California Verbal Learning Test (CVLT; delayed recall and List A total recall) and on Verbal Fluency Test-Categories. This ApoE4 × sex interaction remained significant with Bonferroni correction only for CVLT-delayed recall. Taking time points prior to dementia for cognitive predictions, the positive association between impairment in CVLT-delayed recall and ApoE4⁺ status remained stronger among women, though only before Bonferroni correction. While ApoE4+ status appears to be a sex neutral risk factor for dementia, its association with verbal memory and learning decline and impairment was stronger among women.     

α-细辛醚对无镁细胞外液培养海马神经元构建难治性癫痫细胞模型的影响

背景：无镁细胞外液处理培养的海马神经元可诱导产生反复自发性癫痫样放电,该模型可作为临床难治性癫痫细胞模型。 目的：探讨难治性癫痫细胞模型中α-细辛醚对神经元的保护作用。 方法：分离培养新生24 h内的SD大鼠海马神经元,取经鉴定的海马神经元,加入含终浓度为7.5,15,30,60,120 mg/L α-细辛醚的维持培养液培养4 h后,换为无镁液建立难治性癫痫细胞模型,3 h后恢复含α-细辛醚的维持培养基继续培养24 h,MTT法检测海马神经元活力。 结果与结论：经无镁细胞外液培养后,海马神经元的活力显著降低(P < 0.01),α-细辛醚处理后,海马神经元的活力显著升高(P < 0.01),且随α-细辛醚浓度的增加,海马神经元的相对活力升高。说明α-细辛醚可以抑制难治性癫痫细胞模型中的神经元损伤,发挥神经元保护作用,且具有剂量依赖性。     

Strategic processing and episodic memory impairment in obsessive compulsive disorder

There is evidence that nonverbal memory problems in obsessive compulsive disorder (OCD) are mediated by impaired strategic processing. Although many studies have found verbal memory to be normal in OCD, these studies did not use tests designed to stress organizational strategies. This study examined verbal and nonverbal memory performance in 33 OCD patients and 30 normal control participants with the Rey-Osterrieth Complex Figure Test and the California Verbal Learning Test. OCD patients were impaired on verbal and nonverbal measures of organizational strategy and free recall. Multiple regression modeling indicated that free recall problems in OCD were mediated by impaired organizational strategies used during learning trials. Therefore, verbal and nonverbal episodic memory deficits in OCD are affected by impaired strategic processing. Results are consistent with neurobiological models proposing frontal-striatal system dysfunction in OCD.     

WAIS-R factor and performance on the Luria-Nebraska's Intelligence, Memory, and Motor Scales: a canonical model of relationships

The pattern and level of performance on the WAIS-R and the Luria-Nebraska's Intelligence, Memory, and Motor Scales were examined for 93 neurologically impaired adults. Maximum likelihood factor analyses of the WAIS-R indicated the presence of strongly correlated (.72) Verbal Comprehension and Perceptual Organization dimensions. Comparisons of these factors to those of the standardization group revealed an acceptable level of similarity (.94) for Verbal Comprehension, but not for Perceptual Organization (.53). Canonical correlations between WAIS-R factor scores and the three Luria-Nebraska scaled scores accounted for 82% of the total variance. Each set of procedures evidently is indexing the same theoretical constructs. Implications of these findings for our understanding of the measurement models that underlie clinical neuropsychology are discussed.     

c-JUN expression and apoptotic cell death in kainate-induced temporal lobe epilepsy

Following kainate (KA)-induced epilepsy, rat hippocampal neurons strongly express immediate early gene (IEG) products, i.e., c-FOS and c-JUN, and neural stress protein, HSP72. Prolonged expression of c-JUN and c-FOS 48 hr after cerebral ischemia has been underwent delayed neuronal death. However, it is not yet clear whether IEGs actually assume the essential roles in the cell death process or simply as a by-product due to external stimuli because of the prolonged expression of c-FOS, more than one week, on intact CA2 neurons of the hippocampus in a KA-induced epilepsy model. This study investigated the relationships between prolonged expression of c-JUN and hippocampal neuronal apoptosis in a KA-induced epilepsy model. Epileptic seizure was induced in rats by a single microinjection of KA (1 microgram/microL) into the left amygdala. Characteristic seizures and hippocampal neuronal injury were developed. The expression of c-JUN was evaluated by immunohistochemistry, and neuronal apoptosis by in situ end labeling. The seizures were associated with c-JUN expression in the hippocampal neurons, of which the level showed a positive correlation with that of apoptosis. Losses of hippocampal neurons, especially in the CA3 region, were partly caused by apoptotic cell death via a c-JUN-mediated signaling pathway. This is thought to be an important component in the pathogenesis of hippocampal neuronal injury via KA-induced epilepsy.     

Factor analysis of the Wechsler memory scale: Is the associate learning subtest an unclear measure?

A factor analysis of the Wechsler Memory Scale (WMS) with 30-minute delayed recall scores (percent retained) for the Logical Memory, Visual Reproduction, and Associate Learning subtests indicated that this variant of the WMS taps different types of learning and memory for new material. With regard to the verbal learning/recall subtests, Logical Memory appears to be related to attention/ concentration ability, while Associate Learning is relatively independent. The results also showed that both the easy and hard items from Associate Learning tap the same ability, providing evidence that this subtest is a measure of rote verbal learning. These results support the clinical utility of the WMS with delayed recalls in neuropsychiatric populations.     

Suppression of pilocarpine-induced status epilepticus and the late development of epilepsy in rats

Status epilepticus (SE) has been related to subsequent development of epilepsy. The present work was aimed at elucidating the relationship between the duration of pilocarpine- (PILO)-induced SE and the subsequent development of epilepsy in rats. The latency for the appearance of the first spontaneous seizure, the frequency of spontaneous seizures, the cell density in the hippocampal formation and the density of supragranular neo-Timmstaining were monitored. At 30 min, 1, 2 and 6 h after the beginning of SE, animals were treated with diazepam plus pentobarbital. In non-treated rats, SE remitted spontaneously. Animals exhibiting 30 min of PILO-induced SE did not develop spontaneous seizures. Hippocampal cell counts and the density of neo-Timm staining in these animals were similar to those observed in control rats. In the other groups longer SE durations were related to: shorter latency for the appearance of the first spontaneous seizure, increased number of the spontaneous recurrent seizures, severe cell loss in the hippocampal formation, or increased supragranular neo-Timm staining. These data suggest that more than 30 min of SE is required to produce hippocampal damage with subsequent synaptic reorganization of the mossy fibre pathway that could account for SRSs observed in the PILO model of epilepsy.     

Affective verbal learning in hostility: an increased primacy effect and bias for negative emotional material.

The current experiment examined the effects of hostility and a pain stressor on affective verbal learning. Participants were classified as high or low hostile and randomly assigned to a cold pressor or a non-cold pressor group. The subsequent effects on acquisition of the Auditory Affective Verbal Learning Test [AAVLT; Snyder, K. A., & Harrison, D. W. (1997). The Affective Verbal Learning Test. Archives of Clinical Neuropsychology, 12(5), 477-482] were measured. As expected, high hostiles learned negative emotional words significantly better than they learned positive words. Additionally, high hostiles were impaired in their acquisition of verbal material relative to low hostile participants. A significant primacy effect for negative emotional words and an overall better recall of negative information was also found. These results support the idea that high hostiles differ from low hostiles in a number of modalities and demonstrate the persistence of negative emotional material. Future work should address the implications these results have on high hostiles in daily interactions.     

Incidence and clinical profile of extra-medial-temporal epilepsy with hippocampal atrophy

We tried to investigate the incidence and the clinical profile of intractable epilepsy with hippocampal atrophy and ictal onset zones located in areas other than the hippocampus (extra-medial-temporal epilepsy; EMTE). We included patients who had hippocampal atrophy confirmed by MRI but with extra-medial-temporal ictal onset zones as verified by invasive intracranial electrodes or video-EEG monitoring. The case histories, interictal EEG, ictal semiology, other MRI findings in addition to hippocampal atrophy, and results of ictal SPECT and PET scans were evaluated. Results were compared with those of surgically proven medial temporal lobe epilepsy with hippocampal atrophy recruited during the same period. 8.5% of the intractable epilepsy patients with hippocampal atrophy had extra-medial temporal epileptogenic zones. A history of encephalitis and hemiconvulsion-hemiparesis were significantly common in the EMTE group. Most of the interictal EEGs of EMTE patients showed extratemporal irritative zones. MRI, ictal SPECT, and FDG-PET seemed to be helpful at localizing the true epileptogenic zones. The predominant EMTE seizure type was focal motor seizure with secondary generalization. Some portion of intractable epilepsy patients with hippocampal atrophy had extra-medial-temporal epileptogenic foci and careful analysis of semiology and neuroimagings could yield clues to correct diagnosis.