Memory Deficits In Alzheimer's Disease Research Articles

A novel effect of rivastigmine on pre‐synaptic proteins and neuronal viability in a neurodegeneration model of fetal rat primary cortical cultures and its implication in Alzheimer’s disease

Alzheimer's disease (AD) is characterized by deposition of amyloid-beta peptide plaque, disrupted amyloid-beta-precursor protein (APP) metabolism, hyperphosphorylation of Tau leading to neurofibrillary tangles and associated neurotoxicity. Moreover, there is synaptic loss in AD, which occurs early and may precede frank amyloidosis. The central cholinergic system is especially vulnerable to the toxic events associated with AD, and reduced acetylcholine levels in specific brain regions is thought to be central to memory deficits in AD. First-generation cholinesterase inhibitors have provided only symptomatic relief to patients with AD by prolonging the action of remaining acetylcholine with little or no change in the course of the disease. Some second-generation cholinesterase inhibitors are multifunctional drugs that may provide more than purely palliative results. To evaluate the effects of the dual acetylcholinesterase and butyrylcholinesterase inhibitor rivastigmine on key aspects of AD, embryonic day 16 rat primary cortical cultures were treated with rivastigmine under media conditions observed to induce time-dependent neurodegeneration. Samples were subjected to western blotting and immunocytochemistry techniques to determine what influence this drug may have on synaptic proteins and neuronal morphology. There was a strong increase in relative cell viability associated with rivastigmine treatment. Significant dose-dependent increases were observed in the levels of synaptic markers synaptosomal-associated protein of 25 kDa (SNAP-25) and synaptophysin, as well as the neuron-specific form of enolase. Together with an observed enhancement of neuronal morphology, our results suggest a rivastigmine-mediated novel neuroprotective and/or neurorestorative effects involving the synapse. Our observations may explain the potential for rivastigmine to alter the course of AD, and warrant further investigations into using butyrylcholinesterase inhibition as a therapeutic strategy for AD, especially with regard to restoration of synaptic function.

Les troubles précoces de la mémoire épisodique dans la maladie d’Alzheimer

Patients with Alzheimer's disease (AD) show early episodic memory impairments. Such deficits reflect specific impairments affecting one or several stages of encoding, storage and retrieval processes. However, AD patients not only have great difficulty retrieving memories and information but also suffer from distortions of memory, as intrusions and false recognitions. Intrusions can be defined as the unintentional recall of inappropriate information in a laboratory-learning tasks such as word-list recall and story recall. False recognition refers to the erroneous recognition of information that was not previously presented. The first objective of this review is to present studies from the litterature that allowed a better understanding of the nature of episodic memory deficits in AD, and to examine recent research on false memories. The second part of this review is aimed at presenting recent research conducted on prospective memory (PM) in Alzheimer's disease. Prospective memory situations involve forming intentions and then realizing those intentions at some appropriate time in the future. Everyday examples of prospective memory include remembering to buy bread on the way home from work, remembering to give friends a message upon next encountering them, and remembering to take medication. Patients suffering from AD show difficulties in performing prospective tasks in daily life, according to the complaints of their care givers, and these difficulties are massively present at the first stages of the disease. Nevertheless, very few studies have been dedicated to this subject, although the evaluation of PM could be helpful for the early diagnosis of AD.

Inhibitors of Cathepsin B Improve Memory and Reduce β-Amyloid in Transgenic Alzheimer Disease Mice Expressing the Wild-type, but Not the Swedish Mutant, β-Secretase Site of the Amyloid Precursor Protein

Elucidation of Abeta-lowering agents that inhibit processing of the wild-type (WT) beta-secretase amyloid precursor protein (APP) site, present in most Alzheimer disease (AD) patients, is a logical approach for improving memory deficit in AD. The cysteine protease inhibitors CA074Me and E64d were selected by inhibition of beta-secretase activity in regulated secretory vesicles that produce beta-amyloid (Abeta). The regulated secretory vesicle activity, represented by cathepsin B, selectively cleaves the WT beta-secretase site but not the rare Swedish mutant beta-secretase site. In vivo treatment of London APP mice, expressing the WT beta-secretase site, with these inhibitors resulted in substantial improvement in memory deficit assessed by the Morris water maze test. After inhibitor treatment, the improved memory function was accompanied by reduced amyloid plaque load, decreased Abeta40 and Abeta42, and reduced C-terminal beta-secretase fragment derived from APP by beta-secretase. However, the inhibitors had no effects on any of these parameters in mice expressing the Swedish mutant beta-secretase site of APP. The notable efficacy of these inhibitors to improve memory and reduce Abeta in an AD animal model expressing the WT beta-secretase APP site present in the majority of AD patients provides support for CA074Me and E64d inhibitors as potential AD therapeutic agents.

Cyclic AMP Enhancers and Aβ Oligomerization Blockers as Potential Therapeutic Agents in Alzheimers Disease

One of the earliest manifestations of Alzheimer's disease (AD) is the characteristic inability of affected individuals to form new memories. Memory impairment appears to significantly predate the death of nerve cells, implying that neuronal dysfunction is responsible for the pathophysiology of early stage AD. Mounting evidence now indicates that soluble oligomers of the amyloid-beta peptide (Abeta) are the main neurotoxins that lead to early neuronal dysfunction and memory deficits in AD. Cyclic AMP (cAMP) is a central component of intracellular signaling pathways that regulate a wide range of biological functions, including memory. Among other actions, cAMP triggers the phosphorylation and activation of the cAMP responsive element binding protein (CREB), a transcription factor that regulates the expression of genes that are important for long-term memory. Here, we discuss recent evidence suggesting that cAMP enhancing compounds may find applications as neurocognitive enhancers in AD and in other neurological disorders, as well as possible roles of cAMP in the regulation of neuronal regeneration. In particular, we review recent results showing that low concentrations of 2,4-dinitrophenol (DNP) upregulate neuronal cAMP and tau levels, promote neurite outgrowth and neuronal differentiation and block the oligomerization and neurotoxicity of Abeta. Possible implications of these findings in the development of novel therapeutic approaches in AD are discussed.

Le déficit neuropsychologique dans la maladie d’Alzheimer débutante

This analysis is centered on the study of cognitive disorders in Alzheimer's disease (AD), mainly for major neuro-psychological functions. We insist on the heterogeneity of the clinical picture peculiarly in the early stages of the illness, even if the deficits of episodic memory and of attentional/executive capacities are the first to deteriorate, preceding impairment in perceptual and language function and potentially having a substantial impact on the patient's capacity to cope independently. An episodic memory deficit is the hallmark of AD, but it must be stressed that this deficit may take different forms and its origin may be traced back to different cognitive mechanisms. One of the most striking aspects of episodic memory impairment in AD is the rapidity of forgetfulness on which screening and diagnostic tests of AD are based. There is some evidence that the episodic memory deficit in AD is one of learning (encoding and storage) of information rather than to a deficit of retrieval. Furthermore, episodic memory performance in AD depends on the integrity of semantic memory abilities, so giving support to a hierarchical model of organization of human memory. Finally, recent results show that an impairment of conscious recollection is responsible for the poor performance of AD patients in recognition memory. Executive deficits appear predominantly in tasks requiring cognitive flexibility and self-monitoring. With the progression of the disease, additional deficits are observed in the verbal concept formation abilities. These findings might be also very useful in the differential diagnosis between AD and the other cortical and subcortical dementias, as well as in the differentiation between AD and fronto-temporal dementia. We consider that studying early stages of the illness is necessary to delineate the diagnostic signs, to validate the new therapeutic experiments, to predict stages of decline. Recent research suggested that onset of AD is commonly preceded by an interim phase known as mild cognitive impairment (MCI). MCI refers to the clinical condition in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. Persons who experience this condition are at increased risk for the development of AD. In MCI, despite the comparable global cognitive functioning, the findings show more impaired retrieval from long-term storage than in NC. The cued recall improves slightly the total recall but the recognition is significantly impaired. Moreover, the data indicate that MCI patients had additional problems with response inhibition, switching and cognitive flexibility. This suggests, that MCI may be identified by using a more detailed procedure for the assessment of cognitive decline than the evaluation of memory alone. As preventive strategies are developed and new cognitive enhancing therapies emerge, these results may also help us to define which domains are expected to improve in MCI populations.

Distinct Memory Profiles in Alzheimer's Disease

Memory impairment is a prominent defining feature of Alzheimer's disease (AD), yet the degree to which the profile of memory impairment is uniform across patients is not fully resolved. The study examined patterns of memory impairment in a large cohort of AD patients, with particular attention to the relationship between working and long-term declarative memory. Tests of working memory, visual and verbal recall and recognition, and recent personal memory were administered to 67 AD patients in the early to moderate stages of disease and to 30 age-matched controls. Performance on all measures was significantly poorer in patients than in controls. Factor analysis of test scores delineated five factors representing the domains of working memory, visual recall, verbal recall, recognition, and personal memory, indicating that these aspects of memory can break down separately. Cluster analysis revealed distinct memory profiles. Some patients showed predominant problems in working memory, with relatively superior long term retention, whereas other patients showed the reverse pattern. Qualitatively distinct profiles arose at comparable levels of severity. Problems in working memory, but not long term memory were associated with the presence of language and perceptuospatial deficits. The results reinforce previous findings that both working and long term memory failure contribute to the memory symptoms of AD patients, and demonstrate dissociations in memory breakdown across the cohort. The link between working memory and language performance, together with findings of posterior hemisphere abnormalities on neuroimaging, lead us to reassess the nature of working memory deficits in AD.

Sentence Comprehension Deficits in Alzheimer's Disease: A Comparison of Off-Line vs. On-Line Sentence Processing

Two studies explored whether sentence comprehension impairments in Alzheimer's disease (AD) are due to deficits in syntactic processing or memory. Study 1 used a picture-pointing sentence comprehension task to measure the final outcome of comprehension in an off-line fashion. It showed the comprehension of 30 patients with AD to be impaired, but suggested that the deficits could not be attributed solely to syntactic impairments. Study 2 investigated the effects of memory on sentence comprehension by comparing off-line (grammaticality judgment) with on-line (cross-modal naming) language processing in 11 AD and 9 control subjects. The results revealed impaired performance in the off-line task but normal performance in the on-line task using the same sentences. Performance on the off-line task correlated with independent measures of verbal working memory. These data are used to argue that sentence comprehension impairments are related to verbal working memory deficits in AD.

123Iodo-MK-801: A spect agent for imaging the pattern and extent of glutamate (NMDA) receptor activation in Alzheimer's disease

Glutamate, and the NMDA glutamate receptor, may be involved in Alzheimer's Disease (AD). Reductions in NMDA receptors are found in AD, possibly contributing to memory deficits. However the NMDA receptor is involved in excitotoxicity, which may play a role in cell death and the production of neurofibrillary tangles in AD; although with lower levels of glutamate than occur in cerebral ischaemia. Therefore reductions in the NMDA receptor may worsen memory deficit in AD, but increased stimulation of the receptor may contribute to the progress of the disease. MK-801 has been used to image excessive glutamate activation following ischaemia in rats. However, it is unclear how effective MK-801 is in conditions with lower levels of glutamate release. This study attempts to gain insight into the utility of the tracer in these conditions, exploring glutamatergic mechanisms in AD. It describes the retention and elimination of 123iodo-MK-801 in five AD and five control subjects, comparing this to regional cerebral blood flow (rCBF). The initial uptake of 123I-MK-801 is dominated by delivery of the ligand. However, despite significant reductions in rCBF in the AD patients, there is no significant difference in the uptake of 123I-MK-801. This suggests increased retention of 123I-MK-801 in the AD patients. In addition the washout of 123I-MK-801 was less in the AD patients, again suggesting increased retention, although this only reached significance in one region. Theses data hint at possible increases in NMDA activation in AD but ultimately 123I-MK-801 does not provide a sufficiently accurate measurement to demonstrate this conclusively. Further NMDA ligands are now at a late stage of development and may provide more conclusive answers to the role of glutamate in AD.

Alterations in hippocampal mossy fiber pathway in Schizophrenia and Alzheimer' s disease

Schizophrenia and Alzheimer's disease (AD) both involve pathology of the medial temporal lobe. Structural abnormalities of the entorhinal cortex (Arnold et al 1991a; Arnold et al 1991b) and behavioral deficits implicating medial temporal circuits (Saykin et al 1991) have been reported in schizophrenia. The entorhinal cortex is the first and among the most severely effected regions in AD (Braak and Braak 1992). The entorhinal cortex receives input from higher-order multimodal and sensory-specific association cortices and transmits that information to the hippocampus via its connections with the dentate gyrus (Rosene an Van Hoesen 1987). The memory deficit in AD has been related to the disruption of this connection to the hippocampus, the perforant pathway (Hyman et al 1984). Despite the strong evidence of neuropathological changes in the entorhinal cortex in AD and schizophrenia, it is not known if they result in transneuronal changes of intrahippocampal connections. One method for testing this is to examine whether the density of mossy fibers, arising from the granule cells of the dentate gyrus and innervating the hilus, CA4 and CA3 subfields of the hippocampus (Rosene and Van Hoesen 1987), is altered. Experimentally induced unilateral entorhinal lesions lead to sprouting of the hippocampal mossy fibers (Steward 1992). Examination of the density of mossy fibers arising from the dentate granule cells has not been previously report4ed for these two diseases. We examined the staining intensity of the mossy fibers, following