Interaction between Cognitive Reserve and Biomarkers in Alzheimer Disease.

Patients with comparable degree of neuropathology could show different cognitive impairments. This could be explained with the concept of cognitive reserve (CR), which includes a passive and an active component. In particular, CR is used to explain the gap between tissue damage and clinical symptoms that has been observed in dementia and, in particular, in patients affected by Alzheimer disease (AD). Different studies confirm brain neuroplasticity. Our preliminary study demonstrated that AD patients with high education showed a CR inversely associated with glucose uptake measured in fluorodeoxyglucose positron emission tomography (FDG-PET), whereas the inverse correlation was observed in AD patients with low education. In other words, our findings suggest that CR compensates the neurodegeneration and allows the maintenance of patients' cognitive performance. Best understanding of the concept of CR could lead to interventions to slow cognitive aging or reduce the risk of dementia.

Neurophysiological assessment of Alzheimer's disease individuals by a single electroencephalographic marker.

Here we presented a single electroencephalographic (EEG) marker for a neurophysiological assessment of Alzheimer's disease (AD) patients already diagnosed by current guidelines. The ability of the EEG marker to classify 127 AD individuals and 121 matched cognitively intact normal elderly (Nold) individuals was tested. Furthermore, its relationship to AD patients' cognitive status and structural brain integrity was examined. Low-resolution brain electromagnetic tomography (LORETA) freeware estimated cortical sources of resting state eyes-closed EEG rhythms. The EEG marker was defined as the ratio between the activity of parieto-occipital cortical sources of delta (2-4 Hz) and low-frequency alpha (8-10.5 Hz) rhythms. Results showed 77.2% of sensitivity in the recognition of the AD individuals; 65% of specificity in the recognition of the Nold individuals; and 0.75 of area under the receiver-operating characteristic curve. Compared to the AD subgroup with the EEG maker within one standard deviation of the Nold mean (EEG-), the AD subgroup with EEG+ showed lower global cognitive status, as revealed by Mini-Mental State Evaluation score, and more abnormal values of white-matter and cerebrospinal fluid normalized volumes, as revealed by structural magnetic resonance imaging. We posit that cognitive and functional status being equal, AD patients with EEG+ should receive special clinical attention due to a neurophysiological "frailty". EEG+ label can be also used in clinical trials (i) to form homogeneous groups of AD patients diagnosed by current guidelines and (ii) as end-point to evaluate intervention effects.

Resting state Rolandic mu rhythms are related to activity of sympathetic component of autonomic nervous system in healthy humans.

We tested the hypothesis of a relationship between heart rate variability (HRV) and Rolandic mu rhythms in relaxed condition of resting state. Resting state eyes-closed electroencephalographic (EEG) and electrocardiographic (ECG) data were recorded (10-20 System) in 42 healthy adults. EEG rhythms of interest were high-frequency alpha (10.5-13Hz) and low-frequency beta (13-20Hz), which are supposed to form Rolandic mu rhythms. Rolandic and occipital (control) EEG sources were estimated by LORETA software. Results showed a statistically significant (p<0.05, corrected) negative correlation across all subjects between Rolandic cortical sources of low-frequency beta rhythms and the low-frequency band power (LF, 0.04-0.15Hz) of tachogram spectrum as an index of HRV. The lower the amplitude of Rolandic sources of low-frequency beta rhythms (as a putative sign of activity of somatomotor cortex), the higher the LF band power of tachogram spectrum (as a putative sign of sympathetic activity). This effect was specific as there was neither a similar correlation between these EEG rhythms and high-frequency band power of tachogram spectrum (as a putative sign of parasympathetic vagal activity) neither between occipital sources of low-frequency beta rhythms (as a putative sign of activity of visual cortex) and LF band power of tachogram spectrum. These results suggest that Rolandic low-frequency beta rhythms are related to sympathetic activity regulating heart rate, as a dynamic neurophysiologic oscillatory mechanism sub-serving the interaction between brain neural populations involved in somatomotor control and brain neural populations regulating ANS signals to heart for on-going homeostatic adaptations.

Fingolimod Treatment in Relapsing-Remitting Multiple Sclerosis Patients: A Prospective Observational Multicenter Postmarketing Study.

Objective. The aim of this prospective observational multicenter postmarketing study was to evaluate fingolimod efficacy in a real world clinical setting. Methods. One hundred forty-two subjects with relapsing-remitting multiple sclerosis (RRMS) were enrolled in three multiple sclerosis centers throughout Central and Southern Italy between January 2011 and September 2013. After enrollment, regular visits and EDSS assessment were scheduled every 3 months, and MRI scan was obtained every 12 months. Patients were followed up from 1 to 33 months (mean 14.95 ± 9.15 months). The main efficacy endpoints included the proportion of patients free from clinical relapses, from disability progression, from magnetic resonance imaging activity, and from any disease activity. Results. Out of 142 patients enrolled in the study, 88.1% were free from clinical relapse and 69.0% were free from disability progression; 68.5% of patients remained free from new or newly enlarging T2 lesions and 81.7% of patients were free from gadolinium enhancing lesions. Overall the proportion of patients free from any disease activity was 41.9%. Conclusions. Our data in a real world cohort are consistent with previous findings that yield convincing evidence for the efficacy of fingolimod in patients with RRMS.

Occipital sources of resting-state alpha rhythms are related to local gray matter density in subjects with amnesic mild cognitive impairment and Alzheimer's disease.

Occipital sources of resting-state electroencephalographic (EEG) alpha rhythms are abnormal, at the group level, in patients with amnesic mild cognitive impairment (MCI) and Alzheimer's disease (AD). Here, we evaluated the hypothesis that amplitude of these occipital sources is related to neurodegeneration in occipital lobe as measured by magnetic resonance imaging. Resting-state eyes-closed EEG rhythms were recorded in 45 healthy elderly (Nold), 100 MCI, and 90 AD subjects. Neurodegeneration of occipital lobe was indexed by weighted averages of gray matter density, estimated from structural MRIs. EEG rhythms of interest were alpha 1 (8-10.5 Hz) and alpha 2 (10.5-13 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography. Results showed a positive correlation between occipital gray matter density and amplitude of occipital alpha 1 sources in Nold, MCI, and AD subjects as a whole group (r = 0.3, p = 0.000004, N = 235). Furthermore, there was a positive correlation between the amplitude of occipital alpha 1 sources and cognitive status as revealed by Mini Mental State Examination score across all subjects (r = 0.38, p = 0.000001, N = 235). Finally, amplitude of occipital alpha 1 sources allowed a moderate classification of individual Nold and AD subjects (sensitivity: 87.8%; specificity: 66.7%; area under the receiver operating characteristic curve: 0.81). These results suggest that the amplitude of occipital sources of resting-state alpha rhythms is related to AD neurodegeneration in occipital lobe along pathologic aging.

Standardization and normative data obtained in the Italian population for a new verbal fluency instrument, the phonemic/semantic alternate fluency test.

The phonemic/semantic alternate fluency test seems to overcome some limits of the instruments currently used to assess set-shifting abilities. In particular, this test does not make high demands on motor systems because the subject is required to rapidly change mental set to generate words by continuously alternating between phonemic and semantic criteria. Thus, it is potentially feasible for use in individuals who have movement disorders. In this regard, some data support its sensitivity in revealing cognitive impairments in people suffering from frontal-striatal-related disorders. The first aim of this study was to provide standardization and normative data for the phonemic/semantic alternate fluency test. The second aim was to upgrade normative data for the single phonemic and semantic fluency tests. For these purposes, we administered to a sample of 335 healthy Italian subjects (ranging from 20 to 90 years), a test consisting of the following three subtests: (1) a single letter-cued (phonemic) fluency subtest; (2) a single category-cued (semantic) subtest; (3) a phonemic/semantic alternate fluency subtest. A composite shifting index was also derived to capture the shifting cost a subject pays passing from performance of the two single fluency subtests to performance of the alternate fluency subtest. We computed correction grids to adjust raw scores for age, literacy and gender according to the results of regression analyses. Moreover, we computed equivalent scores to permit direct and fast comparison of performance on the three fluency tests.

Cortical sources of resting state electroencephalographic alpha rhythms deteriorate across time in subjects with amnesic mild cognitive impairment.

Cortical sources of resting state electroencephalographic (EEG) rhythms are abnormal in subjects with mild cognitive impairment (MCI). Here, we tested the hypothesis that these sources in amnesic MCI subjects further deteriorate over 1 year. To this aim, the resting state eyes-closed EEG data were recorded in 54 MCI subjects at baseline (Mini Mental State Examination I = 26.9; standard error [SE], 0.2) and at approximately 1-year follow-up (13.8 months; SE, 0.5; Mini Mental State Examination II = 25.8; SE, 0.2). As a control, EEG recordings were also performed in 45 normal elderly and in 50 mild Alzheimer's disease subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), and beta2 (20-30 Hz). Cortical EEG sources were estimated using low-resolution brain electromagnetic tomography. Compared with the normal elderly and mild Alzheimer's disease subjects, the MCI subjects were characterized by an intermediate power of posterior alpha1 sources. In the MCI subjects, the follow-up EEG recordings showed a decreased power of posterior alpha1 and alpha2 sources. These results suggest that the resting state EEG alpha sources were sensitive-at least at the group level-to the cognitive decline occurring in the amnesic MCI group over 1 year, and might represent cost-effective, noninvasive and widely available markers to follow amnesic MCI populations in large clinical trials.

Mini mental Parkinson test: standardization and normative data on an Italian sample.

The mini mental Parkinson (MMP) is a test built to overcome the limits of the mini mental state examination (MMSE) in the short-time screening of cognitive disorders in individuals with Parkinson's disease (PD). In fact, in this scale, items tapping executive functioning are included to better capture PD-related cognitive changes. Some data sustain the sensitivity and validity of the MMP in the short neuropsychological screening of these individuals. Here, we report normative data on the MMP we collected on a sample of 307 Italian healthy subjects ranging from 40 to 91 years. The results document a detrimental effect of age and an ameliorative effect of education on the MMP total performance score. We provide for correction grids for age and literacy that derive from results of the regression analyses. Moreover, we also computed equivalent scores in order to allow a direct and fast comparison between the performance on the MMP and on other psychometric measures that can be administered to the subjects.

Poor desynchronisation of resting-state eyes-open cortical alpha rhythms in obese subjects without eating disorders.

OBJECTIVE: Obese subjects without eating disorders were characterised by poor electroencephalographic (EEG) alpha rhythms during resting-state eye-closed condition (Babiloni et al., 2011b). Is this true also for the desynchronisation of alpha rhythms during resting-state eyes opening? METHODS: EEG data were recorded in 15 underweight, 20 normal-weight, and 18 overweight/obese subjects during resting-state eyes-closed and -open conditions. EEG sources were estimated by LORETA for alpha 1 (8-10.5 Hz) and alpha 2 (10.5-13 Hz). The alpha desynchronisation was calculated as the difference eyes-open minus -closed condition. RESULTS: The occipital alpha 1 desynchronisation was lower in overweight/obese and underweight subjects compared with normal-weight subjects (p < 0.000005). The same was true for parietal, occipital and temporal alpha 2 (10.5-13 Hz) desynchronisation (p < 0.000002). The parietal and temporal alpha 1 desynchronisation was lower in overweight/obese than in normal-weight subjects (p < 0.00001). These effects spatially matched those observed in the resting-state eyes-closed condition. CONCLUSION: Subjects with abnormal weight and normal eating behaviour are characterised by poor alpha desynchronisation during resting-state eyes opening. SIGNIFICANCE: Obese subjects without eating disorders show abnormal mechanisms of cortical neural synchronisation and desynchronisation of alpha rhythms in the resting state condition.

Cortical sources of resting state EEG rhythms are sensitive to the progression of early stage Alzheimer's disease.

Cortical sources of resting state electroencephalographic (EEG) rhythms are abnormal in subjects with Alzheimer's disease (AD). Here we tested the hypothesis that these sources are also sensitive to the progression of early stage AD over the course of one year. The resting state eyes-closed EEG data were recorded in 88 mild AD patients at baseline (Mini Mental State Evaluation, MMSE I = 21.7 ± 0.2 standard error, SE) and at approximately one-year follow up (13.3 months ± 0.5 SE; MMSE II = 20 ± 0.4 SE). All patients received standard therapy with acetylcholinesterase inhibitors. EEG recordings were also performed in 35 normal elderly (Nold) subjects as controls. 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), beta 2 (20-30 Hz), and gamma (30-40 Hz). Cortical EEG sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Compared to the Nold subjects, the mild AD patients were characterized by a power increase of widespread delta sources and by a power decrease of posterior alpha sources. In the mild AD patients, the follow-up EEG recordings showed increased power of widespread delta sources as well as decreased power of widespread alpha and posterior beta 1 sources. These results suggest that the resting state EEG sources were sensitive, at least at group level, to the cognitive decline occurring in the mild AD group over a one-year period, and might represent cost-effective and non-invasive markers with which to enrich cohorts of AD patients that decline faster for clinical studies.

Frontal-parietal responses to "oddball" stimuli depicting "fattened" faces are increased in successful dieters: an electroencephalographic study.

Here we tested the hypothesis that compared with normal weight non dieting (control) subjects, normal weight successful dieters submitted to a rigorous and continuous monitoring of body weight (i.e. karate athletes) are characterized by an increase of cortical responses to oddball visual stimuli depicting the enlargement of faces or foods, as neural underpinning of attention processes related to the control of weight and eating. Electroencephalographic (EEG) data were recorded in 18 successful dieters (5 females) and 24 non dieting subjects (9 females). The subjects were given frequent (70%) and rare (30%) stimuli depicting faces (FACE), food (FOOD), and landscapes (CONTROL). The task was to click the mouse after the rare stimuli. The rare stimuli depicted the frequent stimuli graphically dilated by 25% along the horizontal axis. Cortical responses accompanying attention processes were probed by the difference between positive event-related potentials peaking around 400-500ms post-stimulus for the rare minus frequent stimuli (P300). The popular freeware LORETA estimated P300 cortical sources. The results showed that in the FACE condition, the amplitude of left frontal (BA 6) and medial parietal (BA 5) P300 sources was higher in the successful dieters (karate athletes) than non dieting subjects. These results disclose that frontal-parietal responses to "oddball" stimuli depicting enlarged faces (i.e. representing face fattening) are enhanced in successful dieters (karate athletes). Future studies should evaluate this effect in other populations of successful dieters (i.e. boxers, top models etc.).

Resting state cortical electroencephalographic rhythms in subjects with normal and abnormal body weight.

It is well known that resting state regional cerebral blood flow is abnormal in obese when compared to normal-weight subjects but the underlying neurophysiological mechanisms are poorly known. To address this issue, we tested the hypothesis that amplitude of resting state cortical electroencephalographic (EEG) rhythms differ among underweight, normal-weight, and overweight/obese subjects as a reflection of the relationship between cortical neural synchronization and regulation of body weight. Eyes-closed resting state EEG data were recorded in 16 underweight subjects, 25 normal-weight subjects, and 18 overweight/obese subjects. All subjects were psychophysically healthy (no eating disorders or major psychopathologies). EEG rhythms of interest were delta (2-4Hz), theta (4-8Hz), alpha 1 (8-10.5Hz), alpha 2 (10.5-13Hz), beta 1 (13-20Hz), beta 2 (20-30Hz), and gamma (30-40Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Statistical results showed that parietal and temporal alpha 1 sources fitted the pattern underweight>normal-weight>overweight/obese (p<0.004), whereas occipital alpha 1 sources fitted the pattern normal-weight>underweight>overweight/obese (p<0.00003). Furthermore, amplitude of the parietal, occipital, and temporal alpha 2 sources was stronger in the normal-weight subjects than in the underweight and overweight/obese subjects (p<0.0007). These results suggest that abnormal weight in healthy overweight/obese subjects is related to abnormal cortical neural synchronization at the basis of resting state alpha rhythms and fluctuation of global brain arousal.

Resting state cortical electroencephalographic rhythms and white matter vascular lesions in subjects with Alzheimer's disease: an Italian multicenter study.

Resting state electroencephalographic (EEG) rhythms do not deteriorate with the increase of white matter vascular lesion in amnesic mild cognitive impairment (MCI) subjects [1], although white matter is impaired along Alzheimer's disease (AD). Here we tested whether this is true even in AD subjects. Closed-eye resting state EEG data were recorded in 40 healthy elderly (Nold), 96 amnesic MCI, and 83 AD subjects. White matter vascular lesions were indexed by magnetic resonance imaging recorded in the MCI and AD subjects (about 42% of cases following ADNI standards). The MCI subjects were divided into two sub-groups based on the median of the white matter lesion, namely MCI+ (people with highest vascular load; n = 48) and MCI- (people with lowest vascular load; n = 48). The same was true for the AD subjects (AD+, n = 42; AD-, n = 41). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). LORETA software estimated cortical EEG sources. When compared to Nold group, MCI and AD groups showed well known abnormalities of delta and alpha sources. Furthermore, amplitude of occipital, temporal, and limbic alpha 1 sources were higher in MCI+ than MCI- group. As a novelty, amplitude of occipital delta sources was lower in AD+ than AD- group. Furthermore, central, parietal, occipital, temporal, and limbic alpha sources were higher in amplitude in AD+ than AD- group. Amplitude of these sources was correlated to global cognitive status (i.e., Mini Mental State Evaluation score). These results suggest that in amnesic MCI and AD subjects, resting state posterior delta and alpha EEG rhythms do not deteriorate with the increase of white-matter vascular lesion. These rhythms might be more sensitive to AD neurodegenerative processes and cognitive status rather than to concomitant lesions to white matter.

Attention cortical responses to enlarged faces are reduced in underweight subjects: an electroencephalographic study.

OBJECTIVE: A previous electroencephalographic (EEG) study has shown that obese subjects are characterized by reduced attention frontal responses to food images, thus raising the hypothesis of attention deficits associated with abnormal body weight (Babiloni et al., 2009a,b). In this line, here we tested the hypothesis of reduced attention cortical responses in underweight subjects. METHODS: EEG data were recorded in 16 normal-weight and 16 underweight subjects during an "oddball" paradigm. The subjects were given frequent (70%) and rare (30%) stimuli depicting faces (FACE), food (FOOD), and landscapes (CONTROL), and clicked the mouse after the rare stimuli. These stimuli depicted the same frequent stimuli graphically dilated by 25% along the horizontal axis. Cortical attention responses were probed by the difference between positive event-related potentials peaking around 400-500 ms post-stimulus for the rare minus frequent stimuli (P300). Low resolution electromagnetic source tomography (LORETA) estimated P300 sources. RESULTS: In the FACE condition, the amplitude of prefrontal (Brodmann area: BA10 and BA11) and tempo-parietal (BA19, BA20, BA21, BA22, BA36, BA37, BA39, BA40) sources was lower in the underweight than normal-weight subjects. CONCLUSIONS: These results suggest that anterior-posterior cortical attention processes to face images declined in underweight subjects. SIGNIFICANCE: The present study motivates future research evaluating if this mechanism is related to a poor judgment about body shape.

Frontal attentional responses to food size are abnormal in obese subjects: an electroencephalographic study.

OBJECTIVE: Are obese subjects characterized by a reduction of attentional cortical responses to the enlargement of food or body images? METHODS: Electroencephalographic data were recorded in 19 obese and 15 normal-weight adults during an "oddball" paradigm. The subjects were given frequent (70%) and rare (30%) stimuli depicting faces (FACE), food (FOOD), and landscapes (CONTROL), and clicked the mouse after the rare stimuli. These stimuli depicted the same frequent stimuli graphically dilated by 25% along the horizontal axis. Bioelectrical impedance indexed subjects' body fat percentage. Cortical attentional responses were probed by the difference between positive event-related potentials peaking around 400-500ms post-stimulus for the rare minus frequent stimuli (P300). Low resolution electromagnetic source tomography (LORETA) estimated P300 sources. RESULTS: In the FOOD condition, the amplitude of medial prefrontal P300 sources (Brodmann area 9) was lower in the obese than normal-weight subjects, and there was a negative correlation between the body fat percentage and the amplitude of these sources in all subjects as a single group. CONCLUSIONS: These results disclose that prefrontal attentional processes to food size are abnormal in obese subjects. SIGNIFICANCE: The present study motivates future research evaluating the effects of cognitive rehabilitation in obese subjects.

Attentional cortical responses to enlarged faces are related to body fat in normal weight subjects: an electroencephalographic study.

OBJECTIVE: Here we tested the hypothesis that in normal weight subjects, attentional cortical responses to the enlargement of faces are related to features of body weight, as a basis for future studies on the role of neurocognitive mechanisms in eating and weight disorders. METHODS: Electroencephalographic data were recorded in 15 normal weight adults during a visual "oddball" paradigm. The subjects were given frequent (70%) and rare (30%) stimuli depicting faces (FACE), food (FOOD), and landscapes (CONTROL). The task was to click the mouse after the rare stimuli. These stimuli depicted the same frequent stimuli graphically dilated by 25% along the horizontal axis. Analysis of bioelectrical impedance indexed subjects' body fat percentage. Cortical attentional responses were probed by the difference between positive event-related potentials peaking around 200-600 ms post-stimulus for the frequent minus rare stimuli (P300). LORETA estimated P300 cortical sources. RESULTS: Main results showed that in the FACE condition, there was a negative correlation between the body fat percentage and the reaction time to the rare stimuli, and a positive correlation between the body fat percentage and the amplitude of prefrontal P300 sources (p<0.05). CONCLUSIONS: These results disclose a relationship between body fat and prefrontal attentional processes to body image in normal weight adults. SIGNIFICANCE: The present study motivates future research testing the hypothesis that this relationship might be altered in patients with eating and weight disorders.