Type 2 diabetes mellitus and cerebrospinal fluid Alzheimer's disease biomarker amyloid β1-42 in Alzheimer's Disease Neuroimaging Initiative participants

Introduction Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease. Cerebrospinal fluid (CSF) amyloid β (Aβ) 1-42 is an important Alzheimer's disease biomarker. However, it is inconclusive on how T2DM is related to CSF Aβ1-42. Methods Participants with T2DM were selected from the Alzheimer's Disease Neuroimaging Initiative by searching keywords from the medical history database. A two-way analysis of covariance model was used to analyze how T2DM associates with CSF Aβ1-42 or cerebral cortical Aβ. Results CSF Aβ1-42 was higher in the T2DM group than the nondiabetic group. The inverse relation between CSF Aβ1-42 and cerebral cortical Aβ was independent of T2DM status. Participants with T2DM had a lower cerebral cortical Aβ in anterior cingulate, precuneus, and temporal lobe than controls. Discussion T2DM is positively associated with CSF Aβ1-42 but negatively with cerebral cortical Aβ. The decreased cerebral cortical Aβ associated with T2DM is preferentially located in certain brain regions

Increased circulating insulin-like growth factor-1 in late-onset Alzheimer's disease

Background: Insulin-like growth factor (IGF)-1 has been implicated in the pathogenesis of Alzheimer's disease ( AD). Methods: We compared the level of circulating total and bioavailable IGF-1, by simultaneous measurements of IGF-1 and IGF binding protein ( IGFBP)-3, between 87 patients diagnosed with AD and 126 age and sex matched control subjects without cognitive impairment. Blood samples were collected and IGF-1 and IGFBP-3 measured by ELISA. Subjects were also genotyped for apolipoprotein E. Results: Total circulating IGF-1 levels were significantly raised in the AD group as compared to the control group (p = 0.022). There was no significant difference in the circulating level of IGFBP-3 between the two groups. When the IGF-1 levels were ratioed against IGFBP-3 levels as an indicator of unbound, bioavailable circulating IGF-1, there was a significant increase in the molar IGF-1:IGFBP-3 ratio in the AD subjects (0.181 +/- 0.006) as compared to the controls (0.156 +/- 0.004) (p < 0.001). Logistic regression analysis revealed that an increase in the IGF-1: IGFBP-3 molar ratio increased the risk of AD significantly. Conclusion: The results of increased total and free circulating IGF-1 support the hypothesis that in its early stages late-onset AD reflects a state of resistance to IGF-1

Effects of selctive lesions of the nucleus basalis magnocellularis on working memory in rats.

The nucleus basalis magnocellularis (NBM) of the rat brain is analogous to the nucleus basalis of Meynert found in humans. Alzheimer's disease patients have working memory impairments, which may be attributable to damage to the basal nucleus of Meynert. Excitotoxins such as quisqualic and ibotenic acid have been previously used to make lesions of the NBM in research animals. NBM lesions made with ibotenic or quisqualic acid are known to impair working memory. However, in addition to damaging the cholinergic neurons of the NBM, the lesions made by these excitotoxins also destroy cells of other nearby structures, and it is unclear whether the impairments found are due to damage to the NBM or to surrounding non-cholinergic structures. With the recent advent ofthe highly selective immunotoxin 192 IgG-saporin, it may be possible to determine if lesions involving only the cortically projecting NBM cholinergic neurons impair working memory. The current experiment tests the hypothesis that selective lesions of cholinergic neurons of the NBM impair working memory. To test this hypothesis, a delayed non-matching-to-position-task was used as a test for working memory. Results of this experiment provide novel evidence of the involvement of the cholinergic neurons of the NBM in working memory and will contribute to our understanding of the cognitive impairments seen in Alzheimer's disease.Michelle Marie NobleButt, Allen.EDuong,TaihungHermann,DouglasSheets, VirgilMaster of ArtsDepartment of PsychologyCunningham Memorial library, Terre Haute,Indiana State UniversityILL-ETD-039MastersTitle from document title page. Document formatted into pages: contains 46 p.: ill. Includes abstract and appendix

Smoking, dementia and cognitive decline in the elderly, a systematic review.

Background. Nicotine may aid reaction time, learning and memory, but smoking increases cardiovascular risk. Cardiovascular risk factors have been linked to increased risk of dementia. A previous meta-analysis found that current smokers were at higher risk of subsequent dementia, Alzheimers disease, vascular dementia and cognitive decline. Methods. In order to update and examine this further a systematic review and meta-analysis was carried out using different search and inclusion criteria, database selection and more recent publications. Both reviews were restricted to those aged 65 and over. Results. The review reported here found a significantly increased risk of Alzheimers disease with current smoking and a likely but not significantly increased risk of vascular dementia, dementia unspecified and cognitive decline. Neither review found clear relationships with former smoking. Conclusion. Current smoking increases risk of Alzheimers disease and may increase risk of other dementias. This reinforces need for smoking cessation, particularly aged 65 and over. Nicotine alone needs further investigation. © 2008 Peters et al; licensee BioMed Central Ltd

Plasma REST: a novel candidate biomarker of Alzheimer's disease is modified by psychological intervention in an at-risk population.

The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain's stress response. It is reduced in conditions of stress and Alzheimer's disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress-reduction intervention-mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly&gt;stable MCI&gt;converter MCI&gt;AD, F=6.35, P&lt;0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps&lt;0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps&lt;0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit

Plasma REST: A novel candidate biomarker of Alzheimer\u27s disease is modified by psychological intervention in an at-risk population

The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain’s stress response. It is reduced in conditions of stress and Alzheimer’s disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress-reduction intervention—mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly&gt;stable MCI&gt;converter MCI&gt;AD, F=6.35, P&lt;0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps&lt;0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps&lt;0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit

Semantic Memory Functional MRI and Cognitive Function After Exercise Intervention in Mild Cognitive Impairment

Mild cognitive impairment (MCI) is associated with early memory loss, Alzheimer\u27s disease (AD) neuropathology, inefficient or ineffective neural processing, and increased risk for AD. Unfortunately, treatments aimed at improving clinical symptoms or markers of brain function generally have been of limited value. Physical exercise is often recommended for people diagnosed with MCI, primarily because of its widely reported cognitive benefits in healthy older adults. However, it is unknown if exercise actually benefits brain function during memory retrieval in MCI. Here, we examined the effects of exercise training on semantic memory activation during functional magnetic resonance imaging (fMRI). Seventeen MCI participants and 18 cognitively intact controls, similar in sex, age, education, genetic risk, and medication use, volunteered for a 12-week exercise intervention consisting of supervised treadmill walking at a moderate intensity. Both MCI and control participants significantly increased their cardiorespiratory fitness by approximately 10% on a treadmill exercise test. Before and after the exercise intervention, participants completed an fMRI famous name discrimination task and a neuropsychological battery, Performance on Trial 1 of a list-learning task significantly improved in the MCI participants. Eleven brain regions activated during the semantic memory task showed a significant decrease in activation intensity following the intervention that was similar between groups (p-values ranged 0.048 to 0.0001). These findings suggest exercise may improve neural efficiency during semantic memory retrieval in MCI and cognitively intact older adults, and may lead to improvement in cognitive function. Clinical trials are needed to determine if exercise is effective to delay conversion to AD

Interactive Effects of Physical Activity and APOE-ε4 on BOLD Semantic Memory Activation in Healthy Elders

Evidence suggests that physical activity (PA) is associated with the maintenance of cognitive function across the lifespan. In contrast, the apolipoproteinE-ε4 (APOE-ε4) allele, a genetic risk factor for Alzheimer\u27s disease (AD), is associated with impaired cognitive function. The objective of this study was to examine the interactive effects of PA and APOE-ε4 on brain activation during memory processing in older (ages 65–85) cognitively intact adults. A cross-sectional design was used with four groups (n = 17 each): (1) Low Risk/Low PA; (2) Low Risk/High PA; (3) High Risk/Low PA; and (4) High Risk/High PA. PA level was based on self-reported frequency and intensity. AD risk was based on presence or absence of an APOE-ε4 allele. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) while participants performed a famous name discrimination task. Brain activation subserving semantic memory processing occurred in 15 functional regions of interest. High PA and High Risk were associated with significantly greater semantic memory activation (famous\u3eunfamiliar) in 6 and 3 of the 15 regions, respectively. Significant interactions of PA and Risk were evident in 9 of 15 brain regions, with the High PA/High Risk group demonstrating greater semantic memory activation than the remaining three groups. These findings suggest that PA selectively increases memory-related brain activation in cognitively intact but genetically at-risk elders. Longitudinal studies are required to determine whether increased semantic memory processing in physically active at-risk individuals is protective against future cognitive decline