Alzheimer's research & therapy
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Alzheimers Res Ther · Jan 2014
Performance on a pattern separation task by Alzheimer's patients shows possible links between disrupted dentate gyrus activity and apolipoprotein E ∈4 status and cerebrospinal fluid amyloid-β42 levels.
Emerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer's disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein E (ApoE) ∈4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-β (Aβ) plaques and an increase in the number of Aβ-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown to reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer's patients to investigate relationships between task performance and both ApoE status and cerebrospinal fluid (CSF) Aβ42 levels. ⋯ These are, to our knowledge, the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD, as well as a relationship to Aβ42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in ApoE ∈4 homocygotes.
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Alzheimers Res Ther · Jan 2014
Pro: Are we ready to translate Alzheimer's disease modifying therapies to people with Down syndrome?
Down Syndrome (DS) is caused by trisomy of chromosome 21, which includes the gene for the amyloid precursor protein (APP) and leads to overproduction of beta-amyloid. Clinical-pathological studies indicate that individuals with DS begin demonstrating Alzheimer's disease (AD) pathology during adolescence and that 100% exhibit such changes by age 40. Individuals with DS therefore represent a highly enriched population for AD. Additionally, owing to their baseline intellectual disability, people with DS represent a more vulnerable group of individuals as compared with other populations. Given the recent developments in AD biomarkers, combined with the prospect of achieving greater efficacy with earlier therapeutic intervention, it is logical to include adults with DS in prevention trials for AD. ⋯ Individuals with DS comprise perhaps the largest group of people with genetically determined AD, with a worldwide population of about 6 million people. Only by inclusion can we provide access to rational therapies that offer the greatest chance of benefiting this highly at-risk population.
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Alzheimers Res Ther · Jul 2013
Role of emerging neuroimaging modalities in patients with cognitive impairment: a review from the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012.
The Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD4) was held 3 to 4 May 2012 in Montreal, Quebec, Canada. A group of neuroimaging experts were assigned the task of reviewing and summarizing the literature on clinical and research applications of different neuroimaging modalities in cognitive disorders. This paper summarizes the literature and recommendations made to the conference regarding the role of several emerging neuroimaging modalities in cognitive disorders. ⋯ However, in the research setting, each modality provides a unique contribution to the understanding of basic mechanisms and neuropathological markers of cognitive disorders, to the identification of markers for early detection and for the risk of conversion to dementia in the at-risk populations, to the differentiation between different types of cognitive disorders, and to the identification of treatment targets and indicators of treatment response. In conclusion, for all of the neuroimaging modalities discussed in this paper, further studies are needed to establish diagnostic utility such as validity, reliability, and predictive and prognostic value. More multicenter studies are therefore needed with standardized image acquisition, experimental protocols, definition of the clinical population studied, larger numbers of participants, and longer duration of follow-up to allow generalizability of the results to the individual patient.
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Alzheimers Res Ther · Jan 2013
Neuroprotective effects of D-Ala(2)GIP on Alzheimer's disease biomarkers in an APP/PS1 mouse model.
Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). An impairment of insulin signaling as well as a desensitization of its receptor has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP) normalises insulin signaling by facilitating insulin release. GIP directly modulates neurotransmitter release, LTP formation, and protects synapses from the detrimental effects of beta-amyloid fragments on LTP formation, and cell proliferation of progenitor cells in the dentate gyrus. Here we investigate the potential therapeutic property of the new long lasting incretin hormone analogue D-Ala(2)GIP on key symptoms found in a mouse model of Alzheimer' disease (APPswe/PS1detaE9). ⋯ The results demonstrate that D-Ala(2)GIP has neuroprotective properties on key hallmarks found in AD. This finding shows that novel GIP analogues have the potential as a novel therapeutic for AD.