Wei Qiao Qiu

Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer's disease: review and hypothesis

Clinical and epidemiological studies have found that type 2 diabetes, and hyperinsulinaemia, increased the risk of developing Alzheimers disease (AD) in the elderly. The link between hyperinsulinaemia and AD may be insulin-degrading enzyme (IDE). This enzyme degrades both insulin and amylin, peptides related to the pathology of type 2 diabetes, along with amyloid-beta peptide (Abeta), a short peptide found in excess in the AD brain. We review the current evidence, which suggests that hyperinsulinaemia may elevate Abeta through insulins competition with Abeta for IDE. Genetic studies have also shown that IDE gene variations are associated with the clinical symptoms of AD as well as the risk of type 2 diabetes. The deficiency of IDE can be caused by genetic variation or by the diversion of IDE from the metabolism of Abeta to the metabolism of insulin. It is intriguing to notice that both hyperinsulinaemia and IDE gene variations are related to the risk of AD when the Apolipoprotein E4 (ApoE4) allele, the major risk factor of late-onset AD, is not present. Further studies of the role of IDE in the pathogenesis of AD, which may uncover potential treatment target, are much needed.

Physical and Mental Health of Homebound Older Adults: An Overlooked Population

There are currently more than 38.9 million people aged 65 an older in the United States. Up to 3.6 million of these people are considered housebound and in need of home‐based care. Although homebound status is not defined specifically, with a broad range of disability levels, it is evident that people who are homebound suffer from a multitude of medical and psychiatric illnesses. This review examines the current literature to identify the specific physical and psychiatric factors most responsible for older adults becoming and remaining housebound. Homebound older adults suffer from metabolic, cardiovascular, cerebrovascular, and musculoskeletal diseases, as well as from cognitive impairment, dementia, and depression, at higher rates than the general elderly population. The information in this review will explain the specific types of care the homebound population needs and discuss the care that could help ease their suffering and delay their entry into a nursing home or hospital.

Diffusion Tensor Imaging, White Matter Lesions, the Corpus Callosum, and Gait in the Elderly

Background and Purpose— Gait impairment is common in the elderly, especially those with stroke and white matter hyperintensities on conventional brain MRI. Diffusion tensor imaging (DTI) is more sensitive to white matter damage than conventional MRI. The relationship between DTI measures and gait has not been previously evaluated. Our purpose was to investigate the relationship between the integrity of white matter in the corpus callosum as determined by DTI and quantitative measures of gait in the elderly. Methods— One hundred seventy-three participants of a community-dwelling elderly cohort had neurological and neuropsychological examinations and brain MRI. Gait function was measured by Tinetti gait (0 to 12), balance (0 to 16) and total (0 to 28) scores. DTI assessed fractional anisotropy in the genu and splenium of the corpus callosum. Conventional MRI was used to evaluate for brain infarcts and white matter hyperintensity volume. Results— Participants with abnormal gait had low fractional anisotropy in the genu of the corpus callosum but not the splenium. Multiple regressions analyses showed an independent association between these genu abnormalities and all 3 Tinetti scores (P<0.001). This association remained significant after adding MRI infarcts and white matter hyperintensity volume to the analysis. Conclusions— The independent association between quantitative measures of gait function and DTI findings shows that white matter integrity in the genu of corpus callosum is an important marker of gait in the elderly. DTI analyses of white matter tracts in the brain and spinal cord may improve knowledge about the pathophysiology of gait impairment and help target clinical interventions.

Executive dysfunction in homebound older people with diabetes mellitus

OBJECTIVES: To describe patterns of cognitive deficits and activities of daily living (ADLs) in older people with diabetes mellitus.

Intraperitoneal injection of the pancreatic peptide amylin potently reduces behavioral impairment and brain amyloid pathology in murine models of Alzheimer's disease.

Amylin, a pancreatic peptide, and amyloid-beta peptides (Aβ), a major component of Alzheimer’s disease (AD) brain, share similar β-sheet secondary structures, but it is not known whether pancreatic amylin affects amyloid pathogenesis in the AD brain. Using AD mouse models, we investigated the effects of amylin and its clinical analog, pramlintide, on AD pathogenesis. Surprisingly, chronic intraperitoneal (i.p.) injection of AD animals with either amylin or pramlintide reduces the amyloid burden as well as lowers the concentrations of Aβ in the brain. These treatments significantly improve their learning and memory assessed by two behavioral tests, Y maze and Morris water maze. Both amylin and pramlintide treatments increase the concentrations of Aβ1-42 in cerebral spinal fluid (CSF). A single i.p. injection of either peptide also induces a surge of Aβ in the serum, the magnitude of which is proportionate to the amount of Aβ in brain tissue. One intracerebroventricular injection of amylin induces a more significant surge in serum Aβ than one i.p. injection of the peptide. In 330 human plasma samples, a positive association between amylin and Aβ1-42 as well as Aβ1-40 is found only in patients with AD or amnestic mild cognitive impairment. As amylin readily crosses the blood–brain barrier, our study demonstrates that peripheral amylin’s action on the central nervous system results in translocation of Aβ from the brain into the CSF and blood that could be an explanation for a positive relationship between amylin and Aβ in blood. As naturally occurring amylin may play a role in regulating Aβ in brain, amylin class peptides may provide a new avenue for both treatment and diagnosis of AD.

Depression and Plasma Amyloid β Peptides in the Elderly With and Without the Apolipoprotein E4 Allele

Depression associated with low plasma amyloid-β peptide 42 (Aβ42) leading to a high ratio of Aβ40/Aβ42, a biomarker of Alzheimer disease (AD), may represent a unique depression subtype. The relationship between low plasma Aβ42 in depression and the major risk factor of AD, apolipoprotein E4 (ApoE4), is unknown. With the goal of clarifying this relationship, we analyzed 1060 homebound elders with ApoE characterization and depression status in a cross-sectional study. Plasma Aβ40 and Aβ42 were measured, and cognition were evaluated. In the absence of the ApoE4 allele, depressed subjects had lower plasma Aβ42 [median (Q1, Q3): 17.1 (11.6, 27.8) vs. 20.2 (12.9, 32.9) pg/mL, P=0.006], a higher Aβ40/Aβ42 ratio [median (Q1, Q3): 7.1 (4.6, 11.3) vs. 6.9 (3.4, 9.7), P=0.03], and lower cognitive function (mean±SD of Mini-Mental State Examination: 24.5±3.1 vs. 25.5±3.3, P<0.0001) than those without depression. In contrast, these relationships were not observed in the presence of ApoE4. Instead, regardless the depression status ApoE4 carriers had lower plasma Aβ42 and a higher Aβ40/Aβ42 ratio than non-ApoE4 carriers. Using multivariate logistic regression, it was found that depression was not associated with ApoE4 allele, but with the interaction between plasma Aβ42 and ApoE4 (odds ratio=3.94, 95% confidence interval=1.50, 10.33, P=0.005), denoting low plasma Aβ42 in the absence of ApoE4. Both ApoE4 carriers and non-ApoE4 carriers with depression had lower Aβ42 and a higher Aβ40/Aβ42 ratio in plasma compared with non-ApoE4 carriers without depression in the homebound elderly. As a combination of low plasma Aβ42 and high plasma Aβ40 has been shown to increase the risk of AD in 2 large cohort studies, amyloid-associated depression shown in this study may suggest a risk factor of AD in the absence of ApoE4.

Depression, Antidepressants, and Plasma Amyloid β (Beta) Peptides in Those Elderly Who Do Not Have Cardiovascular Disease

BACKGROUND Low plasma amyloid-beta peptide 42 (Abeta42) is associated with depressive symptoms independently of cardiovascular disease (CVD) in the elderly. It is critical to investigate whether antidepressants modify this relationship. METHODS We evaluated 324 elders without CVD in a cross-sectional study. Depression was evaluated with the Center for Epidemiological Studies Depression (CES-D) scale. Antidepressants were documented. Plasma Abeta40 and Abeta42 were measured. RESULTS In the absence of CVD, those with depression had lower plasma Abeta42 (median: 13.7 vs. 18.8 pg/mL, p = .003) than those without. Depressed subjects on antidepressant treatment had a lower concentration of plasma Abeta40 (median: 97.8 vs. 133.5 pg/mL, p = .008), but not Abeta42, than those without the treatment. Multivariate logistic regression showed that antidepressant use did not influence the relationship between depression and low plasma Abeta42 (odds ratio = .55; 95% CI = .33, .90; p = .02) after adjusting for confounders, but its use interacted with plasma Abeta40 in the model. CONCLUSIONS Lower concentration of plasma Abeta42 is associated with depression in the absence of CVD that is not related to the antidepressant use by those subjects. Prospective studies are needed to determine whether depression associated with low plasma Abeta42 predicts the onset of Alzheimers disease.

The effects of acupuncture on the brain networks for emotion and cognition: an observation of gender differences.

Acupuncture modulates brain activity at the limbic-paralimbic-neocortical network (LPNN) and the default mode network (DMN). Since these brain networks show gender differences when mediating emotional and cognitive tasks, we thus hypothesize that women and men may also respond differently to acupuncture procedure at these brain regions. In order to test this hypothesis, we retrieved the data of 38 subjects, 19 females and 19 males, who had brain fMRI during acupuncture from previous studies and reanalyzed them based on sex status. Deactivation at the LPNN/DMN during needle manipulation of acupuncture was more extensive in females than in males, particularly in the posterior cingulate (BA31), precuneus (BA7m) and angular gyrus (BA39). The functional correlations between the right BA31 and pregenual cingulate (BA32), hippocampus or contralateral BA31 were significantly stronger in females than in males. The angular gyrus (BA39) was functionally correlated with BA31 in females; in contrast, it was anticorrelated with BA31 in males. Soreness, a major component of the psychophysical responses to needle manipulation, deqi, was correlated in intensity with deactivation of the angular gyrus in females; no such relationships were observed in males. In contrast to lesser deactivation at the LPNN/DMN networks, needle manipulation during acupuncture induced greater activation at the secondary somatosensory cortex and stronger functional connectivity with the anterior-middle cingulate (BA32/24) in males than in females. Our study suggests that brains with sex dimorphism may process the acupuncture stimulation differently between women and men.

Commonality and specificity of acupuncture action at three acupoints as evidenced by fMRI

Previous work from our team and others has shown that manual acupuncture at LI4 (hegu), ST36 (zusanli), and LV3 (taichong) deactivates a limbic-paralimbic-neocortical brain network, and at the same time activates somatosensory regions of the brain. The objective of the present study was to explore the specificity and commonality of the brain response to manual acupuncture at LI4, ST36, and LV3, acupoints that are located on different meridians and are used to treat pain disorders. We used functional magnetic resonance imaging (fMRI) to monitor the brain responses to acupuncture at three different acupoints; we examined 46 healthy subjects who, according to their psychophysical responses, experienced deqi sensation during acupuncture. Brain responses to stimulation at each of the acupoints were displayed in conjunction with one another to show the spatial distribution. We found clusters of deactivation in the medial prefrontal, medial parietal and medial temporal lobes showing significant convergence of two or all three of the acupoints. The largest regions showing common responses to all three acupoints were the right subgenual BA25, right subgenual cingulate, right isthmus of the cingulum bundle, and right BA31. We also noted differences in major sections of the medial prefrontal and medial temporal lobes, with LI4 predominating in the pregenual cingulate and hippocampal formation, ST36 predominating in the subgenual cingulate, and LV3 predominating in the posterior hippocampus and posterior cingulate. The results suggest that although these acupoints are commonly used for anti-pain and modulatory effects, they may mobilize the same intrinsic global networks, with substantial overlap of common brain regions to mediate their actions. Our findings showing preferential response of certain limbic-paralimbic structures suggests acupoints may also exhibit relative specificity.

MAT1A variants are associated with hypertension, stroke, and markers of DNA damage and are modulated by plasma vitamin B-6 and folate

BACKGROUND The S-adenosylmethionine synthetase type 1 (MAT1A) gene encodes a key enzyme in one-carbon nutrient metabolism. OBJECTIVE This study aimed to determine the association of MAT1A variants with homocysteine, DNA damage, and cardiovascular disease (CVD). DESIGN Eight variants of MAT1A were examined for associations with hypertension, stroke, CVD, homocysteine, and DNA damage in 1006 participants of the Boston Puerto Rican Health Study. Two variants were replicated in 1147 participants of the Nutrition, Aging, and Memory in Elders Study. RESULTS Two variants and haplotypes were strongly associated with hypertension and stroke, independent of methylenetetrahydrofolate reductase (MTHFR) variants. Homozygotes of the MAT1A d18777A (rs3851059) allele had a significantly greater likelihood of stroke (odds ratio: 4.30; 95% CI: 1.34, 12.19; P = 0.006), whereas 3U1510A (rs7087728) homozygotes had a lower likelihood of hypertension (odds ratio: 0.67; 95% CI: 0.48, 0.95; P = 0.022) and stroke (odds ratio: 0.35; 95% CI: 0.15, 0.82; P = 0.015). A similar trend of association was observed in a second elderly population. Furthermore, strong interactions between MAT1A genotypes and vitamin B-6 status were found. Carriers of the nonrisk allele 3U1510A had a lower 8-hydroxydeoxyguanosine concentration--a biomarker of oxidative DNA damage--when plasma vitamin B-6 was high, whereas homozygotes for the risk-allele 3U1510G had higher 8-hydroxydeoxyguanosine concentrations, regardless of vitamin B-6 status. CONCLUSIONS MAT1A variants were strongly associated with hypertension and stroke. Improving folate and vitamin B-6 status might decrease the CVD risk of only a subset of the population, depending on genotype. These findings suggest that impairments in methylation activity, independent of homocysteine, have an effect on CVD risk.