Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.

BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

Functional coupling of parietal α rhythms is enhanced in athletes before visuomotor performance: a coherence electroencephalographic study.

It has been shown that elite pistol shooters are characterized by a power increase of wide cortical electroencephalographic (EEG) alpha (about 8-12 Hz) and beta (about 14-35 Hz) rhythms during the preparation of air pistol shots, possibly related to selective attentional and "neural efficiency" processes [Del Percio C, Babiloni C, Bertollo M, Marzano N, Iacoboni M, Infarinato F, Lizio R, Stocchi M, Robazza C, Cibelli G, Comani S, Eusebi F (2009a) Hum Brain Mapp 30(11):3527-3540; Del Percio C, Babiloni C, Marzano N, Iacoboni M, Infarinato F, Vecchio F, Lizio R, Aschieri P, Fiore A, Toràn G, Gallamini M, Baratto M, Eusebi F (2009b) Brain Res Bull 79(3-4):193-200]. Here, we tested the hypothesis that such processes are associated with an enhanced functional coupling of posterior cortical regions involved in task-relevant attentional processes and visuo-motor transformations. To this aim, between-electrodes spectral coherence was computed from spatially enhanced EEG data collected during a previous study (i.e. right handed 18 elite air pistol shooters and 10 matched non-athletes; augmented 10-20 system; surface Laplacian estimation). Theta (about 4-6 Hz), low-frequency alpha (about 8-10 Hz), high-frequency alpha (about 10-12 Hz), low-frequency beta (14-22 Hz), high-frequency beta (23-35 Hz), and gamma (36-44 Hz) bands were considered. Statistical results showed that intra-hemispheric low-frequency alpha (parietal-temporal and parietal-occipital regions), high-frequency alpha (parietal-temporal and parietal-occipital regions), high-frequency beta, and gamma (parietal-temporal regions) coherence values were stable in amplitude in the elite athletes but not in the non-athletes during the preparation of pistol shots. The same applies to inter-hemispheric low-frequency alpha (parietal regions), high-frequency alpha (parietal regions), high-frequency beta and gamma coherence values. These findings suggest that under the present experimental conditions, elite athletes are characterized by the stabilization of functional coupling of preparatory EEG rhythms between "visuo-spatial" parietal area and other posterior cortical areas.

Effects of tiredness on visuo-spatial attention processes in elite karate athletes and non-athletes.

"Attentional" adaptations are fundamental effects for sport performance. We tested the hypothesis that tiredness and muscular fatigue poorly affect visuo-spatial attentional processes in elite karate athletes. To this aim, 14 elite karate athletes and 11 non-athletes were involved in an isometric contraction exercise protocol up to muscular fatigue. Blood lactate and attention measurements were taken. Posner's test probed "endogenous" (i.e., internally planned allocation of spatial attention) and "reflexive" (i.e., brisk variation of endogenous spatial attention due to unexpected external stimuli) attention. Lactate and attentional measurements were performed before (Block 1, B1) and after the fatiguing exercise (B2) and at the end of a recovery period (B3). Compared to the non-athletes, the athletes showed a better performance in the fatigue protocol, confirmed by the higher absolute lactate values in B2. The correct responses in the "valid trials" probing "endogenous" attention were 92.4% (B1), 93.9% (B2), and 95.8% (B3) in the non-athletes, and 98.5%, 96.4%, 95.5% in the elite karate athletes. The correct responses in the "invalid trials" probing "reflexive" attention were 95.4%, 89.7%, 93.2% in the non-athletes, and 96.4%, 97.3%, 98.5% in the elite karate athletes. The percentage of correct responses in the "invalid" trials significantly decreased from B1 to B2 in the non-athletes but not in the elite karate athletes. In conclusion, tiredness and muscular fatigue do not affect "reflexive" attentional processes of elite karate athletes, which is crucial to contrast attacks coming from an unexpected spatial region.

Inhibitory effect of voluntary movement preparation on cutaneous heat pain and laser-evoked potentials.

In our study, preparation of voluntary movement was used to physiologically activate the motor cortex areas and the effect of this activation on CO(2) laser-evoked potentials (LEPs) was explored. LEPs were recorded from 31 scalp electrodes in 10 healthy subjects after painful stimulation of the right C6-C7 skin dermatomes. LEP stimuli were delivered in the time interval between a visual warning stimulus followed after 1 s. by an imperative stimulus. The imperative stimulus triggered: (i) no task in the baseline condition (Pain); (ii) flexion-extension movements of the second finger of the right hand in the movement condition (Pain + Movement); (iii) cognitive task (mathematic computation) in the distraction condition (Pain + Cognition). The experimental conditions were also repeated during application of laser stimuli on the left C6-C7 skin dermatomes. Compared with the baseline condition (no task required), during preparation of right-hand voluntary movement there was a significant reduction in LEP amplitude and subjective pain rating after right- but not after left-hand stimulation, which suggests that the observed effect cannot be attributed to a nonspecific reduction in attention toward painful stimulus. During preparation of a cognitive task, LEP amplitude was reduced compared to baseline. Our results represent the first neurophysiological suggestion that physiological activation of the motor cortex, occurring during movement preparation, inhibits cortical pain processing by a centrifugal mechanism.

Homocysteine and electroencephalographic rhythms in Alzheimer disease: a multicentric study.

High plasma concentration of homocysteine is an independent risk factor for Alzheimer's disease (AD), due to microvascular impairment and consequent neural loss [Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346(7):476-483]. Is high plasma homocysteine level related to slow electroencephalographic (EEG) rhythms in awake resting AD subjects, as a reflection of known relationships between cortical neural loss and these rhythms? To test this hypothesis, we enrolled 34 mild AD patients and 34 subjects with mild cognitive impairment (MCI). Enrolled people were then subdivided into four sub-groups of 17 persons: MCI and AD subjects with low homocysteine level (MCI- and AD-, homocysteine level <11 micromol/l); MCI and AD subjects with high homocysteine level (MCI+ and AD+, homocysteine level >or=11 micromol/l). Resting eyes-closed EEG data were recorded. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Results showed that delta (frontal and temporal), theta (central, frontal, parietal, occipital, and temporal), alpha 1 (parietal, occipital, and temporal), and alpha 2 (parietal and occipital) sources were stronger in magnitude in AD+ than AD- group. Instead, no difference was found between MCI- and MCI+ groups. In conclusion, high plasma homocysteine level is related to unselective increment of cortical delta, theta, and alpha rhythms in mild AD, thus unveiling possible relationships among that level, microvascular concomitants of advanced neurodegenerative processes, and synchronization mechanisms generating EEG rhythms.

Conversion from mild cognitive impairment to Alzheimer's disease is predicted by sources and coherence of brain electroencephalography rhythms.

Objective. Can quantitative electroencephalography (EEG) predict the conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD)? Methods. Sixty-nine subjects fulfilling criteria for MCI were enrolled; cortical connectivity (spectral coherence) and (low resolution brain electromagnetic tomography) sources of EEG rhythms (delta=2-4 Hz; theta=4-8 Hz; alpha 1=8-10.5 Hz; alpha 2=10.5-13 Hz: beta 1=13-20 Hz; beta 2=20-30 Hz; and gamma=30-40) were evaluated at baseline (time of MCI diagnosis) and follow up (about 14 months later). At follow-up, 45 subjects were still MCI (MCI Stable) and 24 subjects were converted to AD (MCI Converted). Results. At baseline, fronto-parietal midline coherence as well as delta (temporal), theta (parietal, occipital and temporal), and alpha 1 (central, parietal, occipital, temporal, limbic) sources were stronger in MCI Converted than stable subjects (P<0.05). Cox regression modeling showed low midline coherence and weak temporal source associated with 10% annual rate AD conversion, while this rate increased up to 40% and 60% when strong temporal delta source and high midline gamma coherence were observed respectively. Interpretation. Low-cost and diffuse computerized EEG techniques are able to statistically predict MCI to AD conversion.

Movement-related electroencephalographic reactivity in Alzheimer disease.

Event-related desynchronization/synchronization (ERD/ERS) of alpha and beta electroencephalographic (EEG) rhythms was investigated in normal subjects and mild Alzheimer Disease patients (AD), performing unilateral right finger movements (about 10 s intermovement interval). Electroencephalographic data were sampled based on 10-20 system electrode montage. Surface Laplacian estimate of the potential reduced the head-volume conductor effects and annulled electrode reference variations. Results showed that EEG reactivity (i.e., ERD/ERS) of modeled contralateral rolandic cortex and motor performance were preserved in mild to moderate AD. In contrast, modeled activity (i.e., ERD/ERS) of frontolateral, centromedial, and ipsilateral rolandic areas was abnormal. Furthermore, interrelatedness of cortical response and movement timing was abnormal in AD patients. These results would support the working hypothesis that mild to moderate AD is a global brain network disease, including processing of sensorimotor information (despite no overt movement disorder). Further investigations will ascertain the clinical relevance of these results.