Genetic risk score predicting accelerated progression from mild cognitive impairment to Alzheimer's disease.

Aside from APOE, the genetic factors that influence the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) remain largely unknown. We assessed whether a genetic risk score (GRS), based on eight non-APOE genetic variants previously associated with AD risk in genome-wide association studies, is associated with either risk of conversion or with rapid progression from MCI to AD. Among 288 subjects with MCI, follow-up (mean 26.3 months) identified 118 MCI-converters to AD and 170 MCI-nonconverters. We genotyped ABCA7 rs3764650, BIN1 rs744373, CD2AP rs9296559, CLU rs1113600, CR1 rs1408077, MS4A4E rs670139, MS4A6A rs610932, and PICALM rs3851179. For each subject we calculated a cumulative GRS, defined as the number of risk alleles (range 0-16) with each allele weighted by the AD risk odds ratio. GRS was not associated with risk of conversion from MCI to AD. However, MCI-converters to AD harboring six or more risk alleles (second and third GRS tertiles) progressed twofold more rapidly to AD when compared with those with less than six risk alleles (first GRS tertile). Our GRS is a first step toward development of prediction models for conversion from MCI to AD that incorporate aggregate genetic factors.

Reduced serum progranulin level might be associated with Parkinson's disease risk.

BACKGROUND AND PURPOSE: Common genetic variants (rs5848 and rs646776) have been reported as regulators of blood progranulin (GRN) levels in healthy individuals. METHODS: To assess the influence of rs5848 and rs646776 polymorphisms in both serum GRN level and risk for common neurodegenerative diseases, we studied 304 patients with Parkinson's disease (PD), 217 individuals with Alzheimer's disease, 131 subjects with mild cognitive impairment, and 126 controls. RESULTS: The mean concentration of GRN in the serum of patients with PD (319.6 ng/ml) was significantly lower than that of controls (371.5 ng/ml; P = 0.009), whereas there were no significant differences between other groups. Rs646776 minor allele carriers had lower serum GRN levels in each of the four subgroups. There was no correlation between rs5848 genotypes and serum GRN concentrations. Genotype frequencies of both polymorphisms did not differ between groups. CONCLUSION: Reduced circulating GRN levels might be associated with PD risk by pathogenic factors different from rs5848 and rs646776 polymorphisms.

Serum heme oxygenase-1 levels are increased in Parkinson's disease but not in Alzheimer's disease.

OBJECTIVE: Oxidative stress is implicated in Parkinson's disease (PD) and Alzheimer's disease (AD), and heme oxygenase-1 (HO-1) is a potent antioxidant overexpressed in PD substantia nigra and AD cerebral cortex and hippocampus, indicating a possible up-regulation of antioxidant defenses in both neurodegenerative diseases. The role of HO-1 in peripheral blood of PD and AD patients remains unresolved. METHODS: We measured serum HO-1 levels in 107 patients with PD, 105 patients with AD, 104 controls for PD and 120 controls for AD. RESULTS: The median serum concentration of HO-1 was significantly higher in PD patients (2.04 ng/ml) compared with that of PD controls (1.69 ng/ml, P = 0.016), with PD patients predominating over controls in the upper tertile of serum HO-1 levels, whereas there was more PD controls than PD patients in the lower tertile (P = 0.006). Median serum levels of HO-1 did not differ significantly between AD patients and AD controls. CONCLUSION: The increase of serum HO-1 levels in PD patients could indicate a systemic antioxidant reaction related to a chronic oxidative stress state in PD brain.

Epistasis between tau phosphorylation regulating genes (CDK5R1 and GSK-3beta) and Alzheimer's disease risk.

OBJECTIVE: Glycogen synthase kinase-3beta (GSK-3beta) and cyclin-dependent kinase 5 (CDK5) have been implicated as two major protein kinases involved in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles. CDK5 regulatory subunit 1 (CDK5R1) encodes for p35, a protein required for activation of CDK5. As both CDK5R1 and GSK-3beta genes are related to phosphorylation of tau, we examined the combined contribution of these genes to the susceptibility for AD. METHODS: In a case-control study in 283 AD patients and 263 healthy controls, we examined the combined effects between CDK5R1 (3'-UTR, rs735555) and GSK-3beta (-50, rs334558) polymorphisms on susceptibility to AD. RESULTS: Subjects carrying both the CDK5R1 (3'-UTR, rs735555) AA genotype and the GSK-3beta (-50, rs334558) CC genotype had a 12.5-fold decrease in AD risk (adjusted by age, sex and APOE status OR = 0.08, 95% CI = 0.01-0.76, P = 0.03), suggesting synergistic effects (epistasis) between both genes. CONCLUSION: These data support a role for tau phosphorylation regulating genes in risk for AD.

[Molecular neuroimaging in the study of cognitive impairment: contribution of the cerebral blood flow SPECT with 99mTc-HMPAO and 18F-FDG PET/CT scan]. / La neuroimagen molecular en el estudio del deterioro cognitivo: contribución de la SPECT de perfusión cerebral con 99mTc-HMPAO y la 18F-FDG PET/TAC.

OBJECTIVE: The aim of this study was to analyze cerebral perfusion and glucose metabolism in patients with cognitive impairment using cerebral blood flow (99m)Tc-HMPAO SPECT and (18)F-FDG PET/CT scans. MATERIAL AND METHODS: Twenty-two patients with cognitive impairment were included: 4 subjective memory complaints (SMC), 8 amnestic mild cognitive impairment (MCI), 5 prodromic Alzheimer's disease (AD) and 5 AD. In each clinical group, (99m)Tc-HMPAO SPECT and (18)F-FDG PET/CT scans were performed. RESULTS: (99m)Tc-HMPAO SPECT showed regions of cerebral hypoperfusion in 15 patients and was normal in 7 of the 22 patients. (18)F-FDG PET/CT scan showed cerebral regional hypometabolism in 19 patients and was normal in the other 3 patients. The distribution of abnormalities on (99m)Tc-HMPAO SPECT and (18)F-FDG PET/CT scans was similar in 9 patients (2 SMC, 2 amnestic MCI, 2 prodromic AD, and 3 AD). In 6 patients (1 amnestic MCI, 2 prodromic AD, and 3 AD), FDG hypometabolism was more extensive than the cerebral hypoperfusion. Four patients (1SMC, 3 amnestic MCI) had an abnormal (18)F-FDG PET/CT scan and normal (99m)Tc-HMPAO SPECT. There were 3 patients (1 SMC 2, amnestic MCI) with normal (99m)Tc-HMPAO SPECT and (18)F-FDG PET/CT scans. CONCLUSION: (99m)Tc-HMPAO SPECT and (18)F-FDG PET/CT scans showed cerebral hypoperfusion and hypometabolism in patients with cognitive impairment, even in patients with clinical diagnosis of SMC. In patients with a normal cerebral blood flow SPECT, brain glucose cerebral hypometabolism can be detected. In some patients, the extension of FDG hypometabolism is more pronounced than that corresponding to the hypoperfusion area.

Aromatase and interleukin-10 genetic variants interactively modulate Alzheimer's disease risk.

A chronic inflammatory process with activation of microglial cells contribute to the neurodegeneration associated with Alzheimer's disease (AD). Estrogen could protect the brain from neurodegeneration by augmenting the secretion of the anti-inflammatory interleukin (IL)-10 from microglial cells. In a case-control study in 231 AD patients and 194 healthy controls, we examined whether the combined effects between the genes coding for aromatase (a critical enzyme in the peripheral synthesis of estrogens) and IL-10 might be responsible for susceptibility to AD. Subjects carrying both the aromatase (5 -UTR) GG and the IL-10 (-1082) GG genotypes had a six times lower risk of developing AD than subjects without these risk genotypes (OR = 0.17, 95% CI = 0.04-0.77, P = 0.02).