Executive function deficits in early Alzheimer's disease and their relations with episodic memory.

Previous research suggests that patients with Alzheimer's disease (AD) are impaired on executive function early in the course of disease, but negative findings were reported. To evaluate the performance on executive tasks in early AD and to determine the involvement of memory on the outcome of executive tasks. Thirty-six AD patients were divided into two subgroups on the basis of the MMSE: very mild and mild. The comparison with 17 normal controls shows that very mild AD patients had deficits on visuospatial short-term memory, episodic memory, flexibility and self-monitoring abilities, concept formation and reasoning. The mild AD patients showed additional deficits on the Similarities test. Episodic memory and executive deficits occur in the very early stage of AD and precede impairment in constructional praxis, language and sustained attention. With the progression of the disease, additional deficit is observed in abstract thinking. In mild AD, memory failure is also related to executive impairment.     

Everyday memory deficits in very mild Alzheimer's disease

Memory complaints of patients sometimes are not verified via standard cognitive testing. Acquisition of information in everyday life requires memorization in complex three-dimensional environments. The authors mimicked this with a photorealistic virtual environment (VE). Memory for verbal material and spatial scenery was tested in healthy controls (HC) and patients with mild Alzheimer's disease (AD); mini-mental state evaluation (MMSE) 25.7 ± 1.8 (mean ± standard deviation). The number of memorized items increased to 90% in both classical list learning and for items memorized in VE in HC. In contrast, only 40% of items were recalled in list learning and 20% in VE in AD patients. Unlike the gender difference favoring female HC on list learning, performance was alike for both genders in VE. We conclude that verbal learning abilities in healthy elderly subjects are alike in standard settings and under virtual reality conditions. In AD patients memory deficits that are relevant to everyday life yet not detectable with list learning are unmasked in virtual reality. In future, this may aid objective appraisal of interventions with regard to their everyday relevance.     

Episodic memory deficits in Alzheimer's disease: a behaviorally anchored scale.

This research represents an investigation into a behaviorally anchored scale for assessment of episodic memory. The Episodic Memory Scale (EMS) was theoretically derived and developed for use in a professional office environment. Performances of patients diagnosed with dementia of the Alzheimer's Type (N = 17) were significantly worse (p <.002) on the EMS than a comparison group (N = 17) of patients with cognitive dysfunction not associated with Alzheimer's disease. The EMS was positively and significantly correlated with other measures of episodic memory and less so with a measure of semantic memory. The extent to which episodic and semantic memory deficits relate to caregiver functional assessment ratings was explored. Findings are discussed with respect to ecological validity of the EMS and implications for reality monitoring ability. Utility of measuring episodic memory processes for purposes of neuropsychological assessment and caregiver decision-making are also discussed.     

Superior episodic memory is associated with interhemispheric processing.

The dependence of episodic memories on interhemispheric processing was tested. In Experiment 1, positive familial sinistrality (FS+; e.g., presence of left-handed relatives) was associated with superior episodic memory and inferior implicit memory in comparison with negative familial sinistrality (i.e., FS-). This reflected a greater degree of interhemispheric interaction in FS+ participants, which was hypothesized as facilitating episodic memory. In Experiment 2, the authors directly manipulated inter- versus intrahemispheric processing using tests of episodic (recognition) and semantic (lexical decision) memory in which letter strings were presented twice within trial blocks. Semantic memory was superior when the 2nd presentation went to the same hemisphere as the 1st. Episodic memory, however, was superior when the 2nd presentation of a stimulus went to the opposite hemisphere. Results support an interhemispheric processing basis for episodic memories.     

When memory does not fail: familiarity-based recognition in mild cognitive impairment and Alzheimer's disease

Recognition can be guided by familiarity, a restricted form of retrieval devoid of contextual recall, or by recollection, which occurs when retrieval is sufficient to support the full experience of remembering an episode. Recollection and familiarity were disentangled by testing recognition memory using silhouette object drawings, high target-foil resemblance, and both yes-no and forced-choice procedures. Theoretically, forced-choice recognition could be mediated by familiarity alone. Alzheimer's disease and its preclinical stage, mild cognitive impairment (MCI), were associated with memory impairments that were greater on the yes-no test. Remarkably, forced-choice recognition was unequivocally normal in patients with MCI compared with age-matched controls. Neuropathology in hippocampus and entorhinal cortex, known to be present in MCI, presumably disrupted recollection while leaving familiarity-based recognition intact.     

Apocynin administration does not improve behavioral and neuropathological deficits in a transgenic mouse model of Alzheimer's disease

In addition to mitochondria, NADPH oxidase (NOX) is a source of oxidative stress, which can induce oxidative damage in Alzheimer's disease (AD). For this reason, several groups have investigated the effect of its inhibition. In AD mice, NADPH oxidase 2 (NOX2) deficiency improved behavior and cerebrovascular function, and reduced oxidative stress. In our study, we administered the NOX inhibitor apocynin to Tg19959 mice, and found that it did not improve cognitive and synaptic deficits, and did not decrease amyloid deposition, microgliosis and hyperphosphorylated tau. However, apocynin reduced carbonyl levels in the cerebral cortex but not the hippocampus, which may have not been sufficient to ameliorate symptoms. Also, the reduction of NOX-mediated oxidative stress may not be sufficient to prevent AD, since other sources of reactive oxygen species such as mitochondria may be more important.     

Experimental silicosis does not aggravate collagen-induced arthritis in mice

Objectives

To investigate the effect of chronic lung inflammation on the incidence and severity of collagen-induced arthritis in mice.

Methods

Chronic lung inflammation in the form of silicosis was induced via intranasal application of silica particles. Immunization with collagen Type II commenced one week later and mice were sacrificed six weeks after booster immunization. Thereafter, silicosis was confirmed via flow cytometry and arthritis was evaluated performing knee and paw histology.

Results

Pronounced lung inflammation in the silica-treated compared to PBS-treated control mice was demonstrated by significantly elevated broncho-alveolar lavage (BAL) cell count, attributable to increased numbers of macrophages and granulocytes. Inflammation in the lungs was not associated with elevated PAD2 and PAD4 expression, yet silica treated animals had significantly higher aCCP serum titers. However, lung inflammation did not lead to an increase in the incidence of arthritis, nor did it exacerbate the macroscopic or histologic joint scores.

Conclusions

Chronic lung inflammation resulting from silicosis does not aggravate collagen-induced arthritis in mice.

     

The pontomesencephalotegmental cholinergic system does not degenerate in Alzheimer's disease

The pedunculopontine and laterodorsal tegmental nuclei comprising the pontomesencephalotegmental (PMT) cholinergic system were examined for the presence of neuropathology and loss of presumed cholinergic cells in patients diagnosed with Alzheimer's disease-senile dementia of the Alzheimer type (AD-SDAT), Parkinsonian dementia, and multi-infarct dementia. Although neurofibrillary changes and plaque-like entities were observed in both nuclei in AD-SDAT and Parkinson's disease dementia, these pathologic indices were not seen consistently in control individuals or in those with multi-infarct dementia, and in none of the diagnostic categories was loss of neuronal somata found in the PMT cholinergic complex. Because appreciable degeneration of cholinergic neurons does occur in the basal forebrain in AD-SDAT, it is concluded that cholinergic phenotype alone is not a sufficient condition indicating predilection for neuronal loss in that dementing illness.     

CALHM1 variant is not associated with Alzheimer's disease among Asians

In a case control study involving 484 study subjects, we showed that the CALHM1 allele (13.5% vs 16.7%) and genotype frequency was not significantly different between Alzheimer's disease (AD) and controls. Logistic regression analysis did not reveal any interaction between ApoE4 allele and CALHM1 allele.     

Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model

We have previously shown that chronic treatment with the monoclonal antibody m266, which is specific for amyloid beta-peptide (Abeta), increases plasma concentrations of Abeta and reduces Abeta burden in the PDAPP transgenic mouse model of Alzheimer's disease (AD). We now report that administration of m266 to PDAPP mice can rapidly reverse memory deficits in both an object recognition task and a holeboard learning and memory task, but without altering brain Abeta burden. We also found that an Abeta/antibody complex was present in both the plasma and the cerebrospinal fluid of m266-treated mice. Our data indicate that passive immunization with this anti-Abeta monoclonal antibody can very rapidly reverse memory impairment in certain learning and memory tasks in the PDAPP mouse model of AD, owing perhaps to enhanced peripheral clearance and (or) sequestration of a soluble brain Abeta species.     

The C677T methylenetetrahydrofolate reductase mutation is not associated with Alzheimer's disease.

The methylenetetrahydrofolate reductase (MTHFR) gene has been recently considered as a candidate gene for Alzheimer's disease (AD). MTHFR is a key enzyme in the metabolism of homocysteine and elevated levels of that amino acid have been associated to Vascular Dementia and AD. A T-->C transition at codon 677 produces a thermolabile type of the enzyme. However, contrasting results on the distribution of the MTHFR C677T common polymorphism in AD have been published. We analyzed the distribution of the MTHFR and apolipoprotein E (APOE) polymorphisms in Italian patients with sporadic AD. The distribution of the C677T polymorphism did not differ in AD and controls. Our data suggest that the MTHFR polymorphism does not contribute to genetic susceptibility in Italian sporadic AD and does not mitigate the effect of ApoE epsilon4 allele on AD risk.     

Alpha-2-macroglobulin intronic polymorphism is not associated with autopsy-confirmed late-onset Alzheimer's disease.

Alpha-2-macroglobulin (A2M) intronic polymorphism has recently been reported to be associated with late-onset Alzheimer's disease (LOAD). To corroborate this association, we analysed the A2M and apolipoprotein E (APOE) polymorphisms in autopsy cases of the MRC Alzheimer's Disease Brain Bank, Institute of Psychiatry, London. The frequencies of the insertion and deletion alleles in AD were 0.81 and 0.19, respectively, and these were not significantly different from control frequencies. After pooling the AD cases in epsilon4 positive and negative subgroups, there was again no significant difference between the A2M allele frequency in the two subgroups. In our present study, we were unable to corroborate the association between A2M intronic polymorphism and LOAD in autopsy cases.     

Clusterin variants are not associated with southern Chinese patients with Alzheimer's disease

Recent genome-wide association studies identified clusterin (CLU) to be associated with sporadic Alzheimer's disease. To help clarify the relevance of CLU as genetic determinant of AD, we analyzed its association in southern Chinese Han population. This study comprised 499 sporadic Alzheimer's disease patients and 592 unrelated age- and sex-matched healthy controls. Four single-nucleotide polymorphisms (rs2279590, rs9331888, rs11136000, and rs1532278) within CLU were selected for genotyping. No positive association was found between the CLU variants and AD. Our study suggests that CLU variants may not be an AD susceptibility factor in southern Chinese Han population.     

Levodopa ameliorates learning and memory deficits in a murine model of Alzheimer's disease

Dopamine plays an important role in learning and memory processes. A deficit of this neurotransmitter as it is apparent in Alzheimer's disease (AD) may contribute to cognitive decline, a major symptom of AD patients. The aim of this study was to elucidate whether or not stimulation of the dopaminergic system leads to an improvement of cognitive function and reduction of non-cognitive behavioral alterations in a murine model of AD. Transgenic and wild type male mice of the TgCRND8 line were treated either with the dopamine precursor levodopa or vehicle and tested in two learning tasks, the object-recognition task and the Barnes maze test. Additionally 24 h spontaneous behavior in the home cage was analyzed. In both memory tasks wild type mice performed significantly better than transgenics. However, transgenics treated with levodopa showed a significant object recognition memory and improved acquisition of spatial memory in the Barnes maze compared to vehicle treated transgenics. Concerning spontaneous behavior transgenic mice performed much more stereotypies than wild types. However, there was a trend for reduced stereotypies in the levodopa group in the time the drug was active. Neurochemical analysis revealed elevated levels of dopamine in the neostriata and frontal cortices and reduced levels in the hippocampi of transgenic mice compared to wild types. Thus cognitive deficits and stereotypies may be due to changes in the dopaminergic system as they could be ameliorated by levodopa treatment, that might also have a therapeutic significance for AD.     

GAB2 is not associated with late-onset Alzheimer's disease in Japanese

The varepsilon4 allele of the apolipoprotein E gene (APOE) is unequivocally recognized as a genetic risk factor for late-onset Alzheimer's disease (LOAD). Recently, single-nucleotide polymorphisms (SNPs) of the GRB2-associated binding protein 2 gene (GAB2) were shown to be associated with LOAD in Caucasians carrying the APOE-varepsilon4 allele through a genome-wide association study. Here, we attempted to replicate the finding by genotyping these SNPs in a large clinical cohort of Japanese. We observed no association of any of the SNPs with LOAD. GAB2 may not be a disease susceptibility gene for LOAD in Japanese.     

Changes in sleep theta rhythm are related to episodic memory impairment in early Alzheimer's disease

Impairments have been reported both in sleep structure and episodic memory in Alzheimer's disease [AD]. Our objective was to investigate the relationships between episodic memory deficits and electro-encephalography [EEG] abnormalities occurring during sleep in patients with early AD. Postlearning sleep was recorded in 14 patients with mild to moderate AD, and 14 healthy elderly controls after they performed an episodic memory task derived from the Grober and Buschke's procedure. For each sleep stage, the relative power and mean frequency in each band were analyzed. Relative to agematched controls, AD patients presented faster mean theta frequency in both REM sleep and slow wave sleep [SWS]. In AD patients, a correlative analysis revealed that faster theta frequency during SWS was associated with better delayed episodic recall. We assume that increased theta activity reflects changes in neuronal activity to maintain memory performance, indicating that compensatory mechanisms already described at the waking state could also be engaged during SWS.     

KIBRA gene variants are associated with episodic memory performance in subjective memory complaints

The KIBRA gene encodes a cytoplasmatic protein, a member of the signal transduction protein family, expressed mainly in the brain. Recent studies have implicated the involvement of a genetic variation in the KIBRA gene (T allele) in human memory in normal subjects and in the risk of developing Alzheimer's disease (AD). We report here the distribution of the KIBRA genetic variant and the Apolipoprotein E (ApoE) epsilon4 allele and their association with neuropsychological measures in older adults reporting problems with everyday memory (subjective memory complaints, SMC). We found that SMC subjects with the CT/TT genotype performed more poorly than those with the CC genotype on long-term memory tests. Thus, in our opinion, these data suggest that the KIBRA genotype could affect memory performance in a different way in those that complain of memory deficits compared to those that do not.     

Remote memory in advanced Alzheimer's disease.

The present study investigated remote memory functioning in advanced dementia of Alzheimer type (DAT). Remote memory measures included the Autobiographical Memory Enquiry (AME) and autobiographical fluency (AF), as well as recognition of remote public events and famous faces. Ten DAT patients were selected with Mini-Mental State Exam (MMSE) scores less than 15. Compared to healthy controls, DAT patients were impaired on all measures of remote memory, although autobiographical fluency for names was only borderline impaired. There was no clear evidence of a monotonic temporal gradient with the AME; however, both subjects groups showed better preserved early compared to more recent public-event memory. A measure of semantic fluency was correlated with autobiographical and remote public-event memory among the patients only. Overall, results indicate a minimal outline of preserved remote memory in advanced DAT, with evidence of an association between remote memory performance and executive functioning.