Andreas U. Monsch

Episodic memory changes are associated with the APOE- epsilon 4 allele in nondemented older adults

Objective: To compare the memory performances of nondemented older adults with and without the epsilon 4 allele of the apolipoprotein E (APOE- epsilon 4). Background: Few studies have examined the cognitive status of subjects at high risk for the development of dementia of the Alzheimer type (DAT). A newly reported risk factor for DAT allows for an examination of the cognitive performances of nondemented subjects who are at risk by virtue of being either heterozygous or homozygous for the APOE- epsilon 4 allele. Methods: The California Verbal Learning Test (CVLT) was administered to 52 nondemented older adults. Subjects were divided into two groups on the basis of the presence (n equals 17) or absence (n equals 35) of one or two APOE- epsilon 4 alleles. Results: APOE- epsilon 4 and non- epsilon 4 groups did not significantly differ in demographic, mental status, and functional characteristics. APOE- epsilon 4 subjects demonstrated significantly poorer mean performances than non- epsilon 4 subjects on nine CVLT variables. Seven group differences remained significant, and three approached significance (0.05 less than p less than 0.10), after the effects of age and gender were taken into account. Six of the 14 APOE- epsilon 4 subjects who completed annual follow-up evaluations developed either DAT or questionable DAT, whereas none of the 26 non- epsilon 4 subjects who received follow-up demonstrated any cognitive decline. Conclusions: Results suggest that episodic memory changes in older adults are associated with APOE- epsilon 4 allele; sensitive cognitive markers such as those of the CVLT may precede the subsequent development of DAT. NEUROLOGY 1995;45: 2203-2206

Rivastigmine for the prevention of postoperative delirium in elderly patients undergoing elective cardiac surgery : A randomized controlled trial

Objective:Cardiac surgery is frequently followed by postoperative delirium, which is associated with increased 1-year mortality, late cognitive deficits, and higher costs. Currently, there are no recommendations for pharmacologic prevention of postoperative delirium. Impaired cholinergic transmission is believed to play an important role in the development of delirium. We tested the hypothesis that prophylactic short-term administration of oral rivastigmine, a cholinesterase inhibitor, reduces the incidence of delirium in elderly patients during the first 6 days after elective cardiac surgery. Design:Double-blind, randomized, placebo-controlled trial. Setting:One Swiss University Hospital. Patients:One hundred twenty patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. Intervention:Patients were randomly assigned to receive either placebo or 3 doses of 1.5 mg of oral rivastigmine per day starting the evening before surgery and continuing until the evening of the sixth postoperative day. Measurements and Main Results:The primary predefined outcome was delirium diagnosed with the Confusion Assessment Method within 6 days postoperatively. Secondary outcome measures were the results of daily Mini-Mental State Examinations and clock drawing tests, and the use of a rescue treatment consisting of haloperidol and/or lorazepam in patients with delirium. Delirium developed in 17 of 57 (30%) and 18 of 56 (32%) patients in the placebo and rivastigmine groups, respectively (p = 0.8). There was no treatment effect on the time course of Mini-Mental State Examinations and clock drawing tests (p = 0.4 and p = 0.8, respectively). There was no significant difference in the number of patients receiving haloperidol (18 of 57 and 17 of 56, p = 0.9) or lorazepam (38 of 57 and 35 of 56, p = 0.6) in the placebo and rivastigmine groups, respectively. Conclusion:This negative or, because of methodologic issues, possibly failed trial does not support short-term prophylactic administration of oral rivastigmine to prevent postoperative delirium in elderly patients undergoing elective cardiac surgery with cardiopulmonary bypass.

Increased neurofilament light chain blood levels in neurodegenerative neurological diseases

Objective Neuronal damage is the morphological substrate of persisting neurological disability. Neurofilaments (Nf) are cytoskeletal proteins of neurons and their release into cerebrospinal fluid has shown encouraging results as a biomarker for neurodegeneration. This study aimed to validate the quantification of the Nf light chain (NfL) in blood samples, as a biofluid source easily accessible for longitudinal studies. Methods We developed and applied a highly sensitive electrochemiluminescence (ECL) based immunoassay for quantification of NfL in blood and CSF. Results Patients with Alzheimer’s disease (AD) (30.8 pg/ml, n=20), Guillain-Barré-syndrome (GBS) (79.4 pg/ml, n=19) or amyotrophic lateral sclerosis (ALS) (95.4 pg/ml, n=46) had higher serum NfL values than a control group of neurological patients without evidence of structural CNS damage (control patients, CP) (4.4 pg/ml, n=68, p<0.0001 for each comparison, p=0.002 for AD patients) and healthy controls (HC) (3.3 pg/ml, n=67, p<0.0001). Similar differences were seen in corresponding CSF samples. CSF and serum levels correlated in AD (r=0.48, p=0.033), GBS (r=0.79, p<0.0001) and ALS (r=0.70, p<0.0001), but not in CP (r=0.11, p=0.3739). The sensitivity and specificity of serum NfL for separating ALS from healthy controls was 91.3% and 91.0%. Conclusions We developed and validated a novel ECL based sandwich immunoassay for the NfL protein in serum (NfLUmea47:3); levels in ALS were more than 20-fold higher than in controls. Our data supports further longitudinal studies of serum NfL in neurodegenerative diseases as a potential biomarker of on-going disease progression, and as a potential surrogate to quantify effects of neuroprotective drugs in clinical trials.

Neuropsychological studies of asymptomatic human immunodeficiency virus-type-1 infected individuals. The HNRC Group. HIV Neurobehavioral Research Center.

The current review was conducted to address the ongoing debate regarding the presence or absence of neuropsychological impairment in asymptomatic HIV-Type 1 (HIV-1) seropositive individuals. Results were summarized from 57 studies that compared the performances of seropositive asymptomatic and seronegative individuals. Overall, the differences observed between median rates of impairment for asymptomatic (35%) and seronegative (12%) groups provided the clearest indication of deficits in asymptomatics. In addition, five variables were examined as possible contributors to inconsistencies found in the literature: mode of infection, test battery type, test battery size, sample size, and method of data analysis. Of these variables, only mode of infection and test battery size appeared to substantially influence the outcome of the studies reviewed with regard to identifying neuropsychological impairment in asymptomatics.

Schooling mediates brain reserve in Alzheimer's disease: findings of fluoro-deoxy-glucose-positron emission tomography.

Background: Functional imaging studies report that higher education is associated with more severe pathology in patients with Alzheimer’s disease, controlling for disease severity. Therefore, schooling seems to provide brain reserve against neurodegeneration. Objective: To provide further evidence for brain reserve in a large sample, using a sensitive technique for the indirect assessment of brain abnormality (18F-fluoro-deoxy-glucose-positron emission tomography (FDG-PET)), a comprehensive measure of global cognitive impairment to control for disease severity (total score of the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Battery) and an approach unbiased by predefined regions of interest for the statistical analysis (statistical parametric mapping (SPM)). Methods: 93 patients with mild Alzheimer’s disease and 16 healthy controls underwent 18F-FDG-PET imaging of the brain. A linear regression analysis with education as independent and glucose utilisation as dependent variables, adjusted for global cognitive status and demographic variables, was conducted in SPM2. Results: The regression analysis showed a marked inverse association between years of schooling and glucose metabolism in the posterior temporo-occipital association cortex and the precuneus in the left hemisphere. Conclusions: In line with previous reports, the findings suggest that education is associated with brain reserve and that people with higher education can cope with brain damage for a longer time.

Brain Microstructure Reveals Early Abnormalities more than Two Years prior to Clinical Progression from Mild Cognitive Impairment to Alzheimer's Disease

Diffusion imaging is a promising marker of microstructural damage in neurodegenerative disorders, but interpretation of its relationship with underlying neuropathology can be complex. Here, we examined both volumetric and brain microstructure abnormalities in 13 amnestic patients with mild cognitive impairment (MCI), who progressed to probable Alzheimers disease (AD) no earlier than 2 years after baseline scanning, in order to focus on early, and hence more sensitive, imaging markers. We compared them to 22 stable amnestic MCI patients with similar cognitive performance and episodic memory impairment but who did not show progression of symptoms for at least 3 years. Significant group differences were mainly found in the volume and microstructure of the left hippocampus, while white matter group differences were also found in the body of the fornix, left fimbria, and superior longitudinal fasciculus (SLF). Diffusion index abnormalities in the SLF were the sign of a subtle microstructural injury not detected by standard atrophy measures in the corresponding gray matter regions. The microstructural measure obtained in the left hippocampus using diffusion imaging showed the most substantial differences between the two groups and was the best single predictor of future progression to AD. An optimal prediction model (91% accuracy, 85% sensitivity, 96% specificity) was obtained by combining MRI measures and CSF protein biomarkers. These results highlight the benefit of using the information of brain microstructural damage, in addition to traditional gray matter volume, to detect early, subtle abnormalities in MCI prior to clinical progression to probable AD and, in combination with CSF markers, to accurately predict such progression.

A common brain network links development, aging, and vulnerability to disease.

Significance Many evolutionary–developmental models have attempted to relate development and aging, with one popular hypothesis proposing that healthy age-related brain decline mirrors developmental maturation. But this elegant hypothesis has so far lacked clear and direct data to support it. Here, we describe intrinsic, entirely data-driven evidence that healthy brain degeneration and developmental process mirror one another in certain brain regions. Specifically, a data-driven decomposition of structural brain images in 484 healthy participants reveals a network of mainly higher-order regions that develop relatively late during adolescence, demonstrate accelerated degeneration in old age, and show heightened vulnerability to disorders that impact on brain structure during adolescence and aging. These results provide a fundamental link between development, aging, and disease processes in the brain. Several theories link processes of development and aging in humans. In neuroscience, one model posits for instance that healthy age-related brain degeneration mirrors development, with the areas of the brain thought to develop later also degenerating earlier. However, intrinsic evidence for such a link between healthy aging and development in brain structure remains elusive. Here, we show that a data-driven analysis of brain structural variation across 484 healthy participants (8–85 y) reveals a largely—but not only—transmodal network whose lifespan pattern of age-related change intrinsically supports this model of mirroring development and aging. We further demonstrate that this network of brain regions, which develops relatively late during adolescence and shows accelerated degeneration in old age compared with the rest of the brain, characterizes areas of heightened vulnerability to unhealthy developmental and aging processes, as exemplified by schizophrenia and Alzheimer’s disease, respectively. Specifically, this network, while derived solely from healthy subjects, spatially recapitulates the pattern of brain abnormalities observed in both schizophrenia and Alzheimer’s disease. This network is further associated in our large-scale healthy population with intellectual ability and episodic memory, whose impairment contributes to key symptoms of schizophrenia and Alzheimer’s disease. Taken together, our results suggest that the common spatial pattern of abnormalities observed in these two disorders, which emerge at opposite ends of the life spectrum, might be influenced by the timing of their separate and distinct pathological processes in disrupting healthy cerebral development and aging, respectively.

Improving the diagnostic accuracy of the Mini‐Mental State Examination

Introduction– We determined the diagnostic accuracy of the Mini‐Mental State Examination (MMSE) for dementia of the Alzheimer type (DAT) in an outpatient geriatric referral center in Switzerland. Material & methods– DAT patients and elderly controls were assigned to two groups: a validation sample (70 DAT patients; 50 controls) and a cross‐validation sample (133 DAT patients; 43 controls). A Receiver Operating Characteristic curve was generated to derive the optimal MMSE cut‐off score in the validation sample. Results ‐ The optimal MMSE cut‐off was < 26/30 (sensitivity of 74%, specificity of 100%). Adjustments for age and education were necessary. The cross‐validation confirmed these findings. Conclusion– In a clinical setting the MMSE cut‐off should be increased to < 26/30. A thorough neurobehavioral assessment is still necessary for a complete evaluation.

Modifiable and Nonmodifiable Risk Factors for Postoperative Delirium After Cardiac Surgery With Cardiopulmonary Bypass

OBJECTIVES Postoperative delirium after cardiac surgery is associated with increased morbidity and mortality as well as prolonged stay in both the intensive care unit and the hospital. The authors sought to identify modifiable risk factors associated with the development of postoperative delirium in elderly patients after elective cardiac surgery in order to be able to design follow-up studies aimed at the prevention of delirium by optimizing perioperative management. DESIGN A post hoc analysis of data from patients enrolled in a randomized controlled trial was performed. SETTING A single university hospital. PARTICIPANTS One hundred thirteen patients aged 65 or older undergoing elective cardiac surgery with cardiopulmonary bypass. INTERVENTIONS None. MEASUREMENTS AND MAINS RESULTS: Screening for delirium was performed using the Confusion Assessment Method (CAM) on the first 6 postoperative days. A multivariable logistic regression model was developed to identify significant risk factors and to control for confounders. Delirium developed in 35 of 113 patients (30%). The multivariable model showed the maximum value of C-reactive protein measured postoperatively, the dose of fentanyl per kilogram of body weight administered intraoperatively, and the duration of mechanical ventilation to be independently associated with delirium. CONCLUSIONS In this post hoc analysis, larger doses of fentanyl administered intraoperatively and longer duration of mechanical ventilation were associated with postoperative delirium in the elderly after cardiac surgery. Prospective randomized trials should be performed to test the hypotheses that a reduced dose of fentanyl administered intraoperatively, the use of a different opioid, or weaning protocols aimed at early extubation prevent delirium in these patients.

Argyrophilic grain disease : distribution of grains in patients with and without dementia

Abstract In a previous study we reported on a late onset dementia which occurred in only half of the patients with argyrophilic grain disease (AgD) investigated. To find a correlation between the distribution of argyrophilic grains (ArG) and the occurrence of a late onset dementia, we examined the limbic area in 35 subjects who had ArG as the main neuropathological finding. A retrospective clinical analysis was performed by collecting information from hospital charts supplemented by standardized interviews based on DSM IV criteria for dementia. Sections from the rostral and caudal hippocampal regions, including the entorhinal/transentorhinal and parahippocampal cortex on both sides, were strained by the Gallays method. Nineteen subjects were diagnosed as demented according to these criteria; 16 were considered to have been cognitively normal. High numbers of ArG were observed in the anterior part of the CA1 subfield in all cases. However, the posterior half of CA1 was involved significantly more often and more severely in demented than in non-demented individuals (P < 0.01). Moreover, the distribution of ArG in the entorhinal/transentorhinal and parahippocampal cortex was more widespread in the group of demented patients (P < 0.05). These results show that the intellectual status of patients with AgD was related to the extension of ArG in the limbic area. We suggest that AgD is a progressive neurodegenerative disorder with early subclincial lesions in the anterior part of the hippocampal formation. To provide a more accurate clinicopathological correlation, the rostrocaudal extension of ArG in the limbic area should be evaluated in AgD cases.