Searching for Primary Predictors of Conversion from Mild Cognitive Impairment to Alzheimer's Disease: A Multivariate Follow-Up Study.

Recent proposals of diagnostic criteria within the healthy aging-Alzheimer's disease (AD) continuum stressed the role of biomarker information. More importantly, such information might be critical to predict those mild cognitive impairment (MCI) patients at a higher risk of conversion to AD. Usually, follow-up studies utilize a reduced number of potential markers although the conversion phenomenon may be deemed as multifactorial in essence. In addition, not only biological but also cognitive markers may play an important role. Considering this background, we investigated the role of cognitive reserve, cognitive performance in neuropsychological testing, hippocampal volumes, APOE genotype, and magnetoencephalography power sources to predict the conversion to AD in a sample of 33 MCI patients. MCIs were followed up during a 2-year period and divided into two subgroups according to their outcome: The "stable" MCI group (sMCI, 21 subjects) and the "progressive" MCI group (pMCI, 12 subjects). Baseline multifactorial information was submitted to a hierarchical logistic regression analysis to build a predictive model of conversion to AD. Results indicated that the combination of left hippocampal volume, occipital cortex theta power, and clock drawing copy subtest scores predicted conversion to AD with a 100% of sensitivity and 94.7% of specificity. According to these results it might be suggested that anatomical, cognitive, and neurophysiological markers may be considered as "first order" predictors of progression to AD, while APOE or cognitive reserve proxies might play a more secondary role.

Source analysis of spontaneous magnetoencephalograpic activity in healthy aging and mild cognitive impairment: influence of apolipoprotein E polymorphism.

The apolipoprotein E (APOE) ε4 allele is a genetic risk factor for the development of late-onset Alzheimer's disease (AD), which affects cholinergic system functioning. The association between reduced cholinergic levels and increase of magnetoencephalographic (MEG) low-frequency has been used to explain spectral changes found in AD patients. However, the investigation in predementia stages is scarce. We obtained MEG recordings from 25 aged controls and 36 mild cognitive impairment (MCI) patients during a resting-state condition. According to their APOE genotype, MCIs and controls were subdivided in carriers and non-carriers of the ε4 allele. Sources of spectral variations in these groups were calculated through beamforming. MCI patients exhibited a significant increase of relative power within the low-frequency domain, accompanied by a power decrease within the high-frequency range. APOEε4 carriers showed an increased relative power in the 4.5-6.5 Hz frequency range over frontal lobes. The power increase observed in controls carrying ε4 was significantly higher as compared with MCI non-carriers, while MCI carriers exhibited the highest relative power within the 4.5-6.5 Hz range. Higher power values within the low-frequency ranges correlated with a poorer cognitive performance in MCIs and controls. Our investigation demonstrates that APOEε4 affects resting-state activity to an extent that makes it more proximate to the pattern observed in early stages of AD. Therefore, a combination of genetic and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD, and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration.

Influence of the APOE ε4 allele and mild cognitive impairment diagnosis in the disruption of the MEG resting state functional connectivity in sources space.

The apolipoprotein E (APOE) ε4 allele constitutes the major genetic risk for the development of late onset Alzheimer's disease (AD). However, its influence on the neurodegeneration that occurs in early AD remains unresolved. In this study, the resting state magnetoencephalography(MEG) recordings were obtained from 27 aged healthy controls and 36 mild cognitive impairment (MCI) patients. All participants were divided into carriers and non-carriers of the ε4 allele. We have calculated the functional connectivity (FC) in the source space along brain regions estimated using the Harvard-Oxford atlas and in the classical bands. Then, a two way ANOVA analysis (diagnosis and APOE) was performed in each frequency band. The diagnosis effect consisted of a diminished FC within the high frequency bands in the MCI patients, affecting medial temporal and parietal regions. The APOE effect produced a decreased long range FC in delta band in ε4 carriers. Finally, the interaction effect showed that the FC pattern of the right frontal-temporal region could be reflecting a compensatory/disruption process within the ε4 allele carriers. Several of these results correlated with cognitive decline and neuropsychological performance. The present study characterizes how the APOE ε4 allele and MCI status affect the brain's functional organization by analyzing the FC patterns in MEG resting state in the sources space. Therefore a combination of genetic, neuropsychological, and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration.

No effect of polymorphisms in the non-duplicated region of the CHRNA7 gene on sensory gating P50 ratios in patients with schizophrenia and bipolar disorder.

Previous research has reported that bipolar disorder and schizophrenic patients evidence sensory gating deficits. The use of intermediate phenotypes may facilitate genetic studies. Four single nucleotide polymorphisms (SNPs) located on the non-duplicated region of the alpha-7 nicotinic receptor gene (CHRNA7) were genotyped in 95 healthy subjects, 127 bipolar disorder and 153 schizophrenic patients. We evaluated the association of these polymorphisms with P50 evoked potential measures. Our results do not support a role for the candidate gene in this neurophysiological disturbance.

Sensory gating deficit is associated with catechol-O-methyltransferase polymorphisms in bipolar disorder.

OBJECTIVES. Recent studies have evidenced that bipolar patients show a sensory gating deficit (P50). Among the neural systems that could be influencing this electrophysiological phenotype, dopamine seems to play an important role. We hypothesize that catechol-O-methyltransferase (COMT), the main metabolizer of dopamine in prefrontal cortex, is related to this deficit. METHODS. We selected three polymorphisms in COMT gene: rs2075507 (Promoter 2 region), Val158Met (rs4680) and rs165599 (3' region). A case-control study was performed in 784 controls and 238 bipolar patients. Besides, 122 euthymic bipolar subjects and 95 healthy subjects carried out a sensory gating task (P50). RESULTS. Polymorphism rs165599 in the COMT gene was associated with susceptibility to bipolar disorder (BD), mainly in women (AG: OR = 1.46; GG: OR = 1.84; P = 0.03). In the female group, haplotype AAG was associated with an OR = 7.6. Subjects who carried Val158 allele evidenced a deficit in suppression (P = 0.046) and rs165599 allele G carriers (mainly in homozygosis) had a bigger S2 amplitude and a higher S2/S1 ratio (1.6(e-5) < P < 0.01). Not a single association was proven in the control group. CONCLUSIONS. Our results support the association of the COMT gene with BD and with one of its potential endophenotypes, auditory sensory gating deficit, measured by the P50 paradigm.

The effect of MAPT H1 and APOE ε4 on transition from mild cognitive impairment to dementia.

Microtubule-associated protein tau (MAPT) and apolipoprotein E (APOE) are involved in the pathogenic mechanisms of Alzheimer's disease (AD). We prospectively followed three longitudinal independent samples (total n=319) with amnestic mild cognitive impairment (MCI) and analyzed whether MAPT H1/H2 haplotypes and APOE ε4 polymorphisms accelerated the rate of progression from MCI to dementia. At the end of the study, 172 subjects remained cognitively stable, whereas 147 progressed to dementia. APOE ε4 and MAPT H1/H1 were independently associated with an increased rate of progression to dementia in the combined sample. Cox regression models of the combined MCI sample showed that MAPT H1/H1 carriers had an increased rate of progression to dementia compared with non carriers (Hazard Ratio =1.45; 95% CI=1.04-2.02; p=0.028) and time-to-progression was shortened by 1.37 years. APOE ε4 allele also accelerated progression to dementia (Hazard Ratio=1.47; 95% CI= 1.06-2.04; p=0.020) and reduced the time-to-progression by 0.87 years. Additionally, MAPT H1/H1 genotype and APOE ε4 allele had an additive effect in progression to dementia, increasing progression rate to dementia (Hazard Ratio=2.24, 95% CI =1.40-3.58; p=0.001) and shortening time-to-progression to dementia by 2.92 years. Similar results were obtained when only considering progression to AD-type dementia. Our results suggest that both MAPT H1/H1 genotype and APOE ε4 allele lead to a more rapid progression to dementia among MCI subjects, probably mediating an increased rate of amyloid-ß and tau brain deposition.

Neuropsychological markers of progression from mild cognitive impairment to Alzheimer's disease.

To find early clinical markers that may predict a likely progression to Alzheimer's disease (AD), the authors performed neuropsychological tests on 82 mild cognitive impairment (MCI) subjects. After 3 years, 38 patients developed AD while 44 retained the diagnosis of MCI. The cognitive differences between the groups were studied. Patients who developed AD showed significantly lower values than did MCI subjects in some neuropsychological scores (P = .02-.001), with sensitivities and specificities higher than 84% and 64%, respectively, for detecting early-onset AD, with a 7.9-fold increased risk of converting to AD (P < .001). Regarding the logistic regression model, the CAMCOG Memory and Perception cognitive screening items were the optimum independent tools to classify the patients who will progress to AD, showing a relative risk of progression of 10.5 (P = .002), 5.5 (P = .008), and 3.9 times (P = .05), respectively, with a sensibility of of 92.1% and a specificity 72.7%.

Regional cerebral blood flow assessed with 99mTc-ECD SPET as a marker of progression of mild cognitive impairment to Alzheimer's disease.

Patients diagnosed with mild cognitive impairment (MCI) have a higher risk of developing Alzheimer's disease (AD). However, not all such patients develop this kind of dementia. The purpose of this prospective study was to assess whether regional cerebral blood flow (rCBF) patterns measured with technetium-99m ethyl cysteinate dimer single-photon emission tomography ((99m)Tc-ECD SPET) in patients suffering from MCI are useful in predicting progression to AD. The study group comprised 42 patients who fulfilled MCI criteria according to the International Psychogeriatric Association and the Alzheimer's Disease Cooperative Study. rCBF was calculated in 16 regions of interest (ROIs). All patients were clinically assessed for 1-3 years. Twenty-one developed AD (group I) while the initial diagnosis of MCI was retained in the other 21 (group II). ROC curves were designed, and sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were determined for each ROI. Compared with group II (MCI), group I (AD) showed a significant reduction of relative blood flow (RBF), ranging from 7% to 10%, in the following areas: right and left prefrontal, right and left frontal, right and left parietal, right and left temporal, right and left frontoparietotemporal and left posterior lateral temporal. Left prefrontal, left frontal and left parietal areas showed sensitivities and specificities higher than 75% and areas below the ROC curve close to 80%. This study shows that RBF patterns in the right and left prefrontal, right and left frontal and left parietal areas are sensitive early markers of progression towards AD. Reduction of rCBF in the medial temporal and anterior lateral temporal cortex has no value as a predictor since it also occurs in patients with MCI who remain stable.