Alzheimer Disease: Rossini PM

Rossi L, Squitti R, Calabrese L, Rotilio G, Rossini PM. · Department of Biology Tor Vergata University of Rome, Via della Ricerca Scientifica, 00133 Rome, Italy. · J Nutr Health Aging. · Pubmed #17657362 No free full text.

Abstract: Alzheimer's disease represents a growing health problem because of the ongoing increase in life expectancy. Therefore understanding the molecular alterations responsible for neurodegeneration has become imperative in order to develop efficient strategies for the therapy. Mounting evidence suggests that the essential metal ion copper is intriguingly connected with the established molecular markers of Alzheimer's disease and that copper homeostasis is disturbed in affected individuals, leading to oxidative stress and neurodegeneration. This review summarizes the mechanisms of copper trafficking in cells and describes the relationship between copper, the amyloid precursor protein and beta-amyloid. Since one of the main goals of the research on Alzheimer's disease is the identification of blood markers to aid diagnosis and monitor the effects of therapeutic approaches, the results obtained in a series of studies on copper in the blood of Alzheimer's disease patients recently carried out in our laboratories are described.

Babiloni C, Cassetta E, Dal Forno G, Del Percio C, Ferreri F, Ferri R, Lanuzza B, Miniussi C, Moretti DV, Nobili F, Pascual-Marqui RD, Rodriguez G, Luca Romani G, Salinari S, Zanetti O, Rossini PM. · Dip. Fisiologia Umana e Farmacologia, Univ. La Sapienza, Rome, Italy. · Neuroimage. · Pubmed #16600641 No free full text.

Abstract: Acetylcholinesterase inhibitors (AChEI) such as donepezil act in mild Alzheimer's disease (AD) by increasing cholinergic tone. Differences in the clinical response in patients who do or do not benefit from therapy may be due to different functional features of the central neural systems. We tested this hypothesis using cortical electroencephalographic (EEG) rhythmicity. Resting eyes-closed EEG data were recorded in 58 mild AD patients (Mini Mental State Examination [MMSE] range 17-24) before and approximately 1 year after standard donepezil treatment. Based on changes of MMSE scores between baseline and follow-up, 28 patients were classified as "Responders" (MMSEvar >or=0) and 30 patients as "Non-Responders" (MMSEvar <0). 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). Cortical EEG sources were studied with low-resolution brain electromagnetic tomography (LORETA). Before treatment, posterior sources of delta, alpha 1 and alpha 2 frequencies were greater in amplitude in Non-Responders. After treatment, a lesser magnitude reduction of occipital and temporal alpha 1 sources characterized Responders. These results suggest that Responders and Non-Responders had different EEG cortical rhythms. Donepezil could act by reactivating existing yet functionally silent cortical synapses in Responders, restoring temporal and occipital alpha rhythms.

Babiloni C, Binetti G, Cassetta E, Cerboneschi D, Dal Forno G, Del Percio C, Ferreri F, Ferri R, Lanuzza B, Miniussi C, Moretti DV, Nobili F, Pascual-Marqui RD, Rodriguez G, Romani GL, Salinari S, Tecchio F, Vitali P, Zanetti O, Zappasodi F, Rossini PM. · Dipartimento di Fisiologia Umana e Farmacologia, Sezione di EEG ad Alta Risoluzione, Universita degli Studi di Roma La Sapienza, Rome, Italy. · Neuroimage. · Pubmed #15109997 No free full text.

Abstract: The study aimed at mapping (i) the distributed electroencephalographic (EEG) sources specific for mild Alzheimer's disease (AD) compared to vascular dementia (VaD) or normal elderly people (Nold) and (ii) the distributed EEG sources sensitive to the mild AD at different stages of severity. Resting EEG (10-20 electrode montage) was recorded from 48 mild AD, 20 VaD, and 38 Nold subjects. Both AD and VaD patients had 24-17 of mini mental state examination (MMSE). EEG rhythms 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). Cortical EEG sources were modeled by low resolution brain electromagnetic tomography (LORETA). Regarding issue i, there was a decline of central, parietal, temporal, and limbic alpha 1 (low alpha) sources specific for mild AD group with respect to Nold and VaD groups. Furthermore, occipital alpha 1 sources showed a strong decline in mild AD compared to VaD group. Finally, distributed theta sources were largely abnormal in VaD but not in mild AD group. Regarding issue ii, there was a lower power of occipital alpha 1 sources in mild AD subgroup having more severe disease. Compared to previous field studies, this was the first investigation that illustrated the power spectrum profiles at the level of cortical (macroregions) EEG sources in mild AD patients having different severity of the disease with respect to VaD and normal subjects. Future studies should evaluate the clinical usefulness of this approach in early differential diagnosis, disease staging, and therapy monitoring.

Rossi L, Squitti R, Pasqualetti P, Marchese E, Cassetta E, Forastiere E, Rotilio G, Rossini PM, Finazzi-Agró A. · Department of Biology, Tor Vergata University of Rome, Via della Ricerca Scientifica, 00133 Rome, Italy. · Neurosci Lett. · Pubmed #12165396 No free full text.

Abstract: Copper, zinc superoxide dismutase (Cu, Zn SOD) activity was measured in red blood cells (RBC) of 32 patients affected by Alzheimer's disease (AD), eight other AD patients treated with the copper-chelating agent D-penicillamine, 13 first-degree relatives and 22 controls. All AD patients enrolled in our study showed a higher level of Cu, Zn SOD activity early in the disease. No correlation between apolipoprotein E genotype and SOD activity was found in AD patients. D-penicillamine treatment of AD patients for 24 weeks lowered the enzyme activity even below the control value. These results support the hypothesis that a higher level of Cu, Zn SOD activity in RBC can be an early diagnostic peripheral marker of this disease and a sensor to monitor treatments with copper-chelating drugs.

Squitti R, Rossini PM, Cassetta E, Moffa F, Pasqualetti P, Cortesi M, Colloca A, Rossi L, Finazzi-Agró A. · AFaR, Ospedale Fatebenefratelli, Rome, Italy. · Eur J Clin Invest. · Pubmed #11851727 No free full text.

Abstract: BACKGROUND: Several lines of evidence address the emerging role for copper in Alzheimer's disease (AD) for sustaining oxidative mechanisms. Studies indicate that peripheral markers of oxidative stress in AD patients could be informative about the pathophysiology of this brain condition. Here, we present a pilot study examining the efficacy of the copper-chelating agent d-penicillamine in reducing oxidative stress in AD patients. DESIGN: Serum levels of copper sampled in AD patients and healthy controls indicate a copper homeostasis imbalance in AD. On this basis, 34 AD patients were enrolled in a 6-month, double-blind, placebo-controlled trial with the copper d-penicillamine-chelating agent. Nine patients for each group completed the trial. Oxidative stress, trace metals and clinical parameters were evaluated. RESULTS: At the start of the study (t0) total peroxides and copper serum content of AD patients were higher (P < 0.0001, P < 0.0001, respectively) and antioxidants were lower (P < 0.05) than in healthy controls. Copper and peroxides were correlated in the AD population (Pearson's r = 0.61, P < 0.001). After treatment with d-penicillamine, the extent of oxidative stress (P < 0.05) was decreased, but no difference was observed in the rate of cognitive decline. CONCLUSION: Data from this pilot study suggest that copper could play a role in the production of peroxides in AD, and that d-penicillamine has an effect in reducing oxidative damage, however, results are still inconclusive in terms of drug efficacy on the clinical progression of AD. Studies with larger cohorts are needed to elucidate the real effectiveness of d-penicillamine treatment in AD.

Babiloni C, Babiloni F, Carducci F, Cincotti F, Del Percio C, De Pino G, Maestrini S, Priori A, Tisei P, Zanetti O, Rossini PM. · Ist. Fisiologia umana, University "La Sapienza,", Rome, Italy. · Neuroimage. · Pubmed #10913320 No free full text.

Abstract: 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.

Pasqualetti P, Bonomini C, Dal Forno G, Paulon L, Sinforiani E, Marra C, Zanetti O, Rossini PM. · Medical Statistics & Information Technology, Fatebenefratelli Association for Research, Isola Tiberina, Rome, Italy. · Aging Clin Exp Res. · Pubmed #19448381 No free full text.

Abstract: BACKGROUND AND AIMS: Epidemiological studies have examined the association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of Alzheimer's disease (AD). Recently, a variety of experimental studies indicates that a subset of NSAIDs, such as ibuprofen or flurbiprofen, also have Abeta-lowering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. In this trial, we evaluated whether the non-selective NSAID ibuprofen slows disease progression in patients with mild to moderate AD. METHODS: This was a 12-month multicenter, randomized, double-blind, placebo-controlled, parallel group trial. Participants with mild-moderate AD (Mini-Mental State Examination score >15, <26; Clinical Dementia Rating= 0.5-1), 65 years or older, with reliable caregivers, were recruited between April 2003 and September 2004. Seven AD Outpatient Treatment Centers screened 530 patients, 132 of whom were enrolled. Intervention consisted of 400 mg ibuprofen twice a day or placebo, together with 20 mg once a day of esomeprazol, or placebo. The primary measure was any one-year change in the Alzheimer Disease Assessment Scale- Cognitive (ADAS-Cog) subscale score. Secondary measures included changes in MMSE, CDR, Basic and Instrumental Activities of Daily Living scales, and Neuropsychiatric Inventory (NPI). RESULTS: Fifty-one patients (77%) in the ibuprofen vs 46 (70%) in the placebo group completed the protocol (p>0.20). In intention-to- treat analysis, ADAS-Cog score worsening was similar in the two groups (p=0.951, treatment difference= 0.1, CI -2.7; 2.9). No differences were found for any secondary outcomes. In a subsample of genotyped patients, ApoE epsilon4 carriers treated with ibuprofen (n=27) were the only group without significant cognitive decline. CONCLUSIONS: Ibuprofen, if used for relatively short periods of time and although well tolerated thanks to gastroprotection, does not seem to be effective in tertiary prevention of mild-moderate AD. Our results suggest the need to examine whether differences in the response to NSAIDs exist, based on ApoE epsilon4 carrier status.

Babiloni C, Frisoni GB, Del Percio C, Zanetti O, Bonomini C, Cassetta E, Pasqualetti P, Miniussi C, De Rosas M, Valenzano A, Cibelli G, Eusebi F, Rossini PM. · Department of Biomedical Sciences, University of Foggia, Viale Pinto 7, Foggia I-71100, Italy. · Clin Neurophysiol. · Pubmed #19324592 No free full text.

Abstract: OBJECTIVE: Non-steroidal anti-inflammatory drugs such as ibuprofen have a protective role on risk of Alzheimer's disease (AD). Here we evaluated the hypothesis that long-term ibuprofen treatment affects cortical sources of resting electroencephalographic (EEG) rhythms in mild AD patients. METHODS: Twenty-three AD patients (13 treated AD IBUPROFEN; 10 untreated AD PLACEBO) were enrolled. Resting EEG data were recorded before and 1 year after the ibuprofen/placebo treatment. EEG rhythms 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). LORETA was used for EEG source analysis. RESULTS: In the AD PLACEBO group, amplitude of delta sources was globally greater at follow-up than baseline. Instead, amplitude of delta sources remained stable or decreased in the majority of the AD IBUPROFEN patients. Clinical (CDR) but not global cognitive status (MMSE) reflected EEG results. CONCLUSIONS: These results suggest that in mild AD patients, a long-term ibuprofen treatment slightly slows down the progressive increment of delta rhythms as a sign of contrast against the neurodegenerative processes. SIGNIFICANCE: They motivate future investigations with larger population and extended neuropsychological testing, to study the relationships among ibuprofen treatment, delta cortical sources, and higher order functions.

Squitti R, Quattrocchi CC, Salustri C, Rossini PM. · AfaR, Department of Neuroscience, Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy. · Prion. · Pubmed #19164917 links to  free full text

Abstract: A dysfunction in copper homeostasis seems to occur in Alzheimer's disease (AD). We recently demonstrated that an excess of non-ceruloplasmin-copper (i.e., 'free' copper) correlates with the main functional and anatomical deficits as well as the cerebrospinal markers of the disease, thus suggesting that copper contributes to AD neurodegeneration. Aim of this study was to investigate the profile of serum ceruloplasmin isoforms immunoreactive protein in relation to copper dysfunction in AD. Twenty-five AD patients and 25 controls were included in the study. All subjects underwent individual measurements of serum ceruloplasmin and copper concentrations, and the amount of 'free' copper was computed for each copper and ceruloplasmin pair. Serum samples were also pooled and analyzed by two dimensional polyacrylamide gel electrophoresis (2-D PAGE) and western blot analysis. The mean concentration of 'free' copper resulted higher in AD patients than in controls. Ceruloplasmin 2-D PAGE western blot analysis of pooled sera showed in the AD samples low-molecular-weight spots in the <50 kDa range that were not detected in controls' pooled sera (p < 0.029). Our data indicate a ceruloplasmin fragmentation in the serum of AD patients, possibly related to 'free' copper deregulation in this disease.

Squitti R, Bressi F, Pasqualetti P, Bonomini C, Ghidoni R, Binetti G, Cassetta E, Moffa F, Ventriglia M, Vernieri F, Rossini PM. · Department of Neuroscience, AFaR-Osp. Fatebenefratelli, 00186, Rome, Italy. · Neurology. · Pubmed #19122030 No free full text.

Abstract: BACKGROUND: Serum copper not bound to ceruloplasmin ("free") appears slightly elevated in patients with Alzheimer disease (AD). We explored whether a deregulation of the free copper pool can predict AD clinical worsening. METHODS: We assessed levels of copper, iron, zinc, transferrin, ceruloplasmin, peroxides, total antioxidant capacity, free copper, and apolipoprotein E genotype in 81 patients with mild or moderate AD, mean age 74.4, SD = 7.4 years, clinically followed up after 1 year. The association among biologic variables under study and Mini-Mental State Examination (MMSE) (primary outcome), activities of daily living (ADL), and instrumental activities of daily living (IADL) (secondary outcomes) performed at study entry and after 1 year were analyzed by multiple regression. RESULTS: Free copper predicted the annual change in MMSE, adjusted for the baseline MMSE by means of a linear regression model: it raised the explained variance from 2.4% (with only sex, age, and education) to 8.5% (p = 0.026). When the annual change in MMSE was divided into < 3 or > or = 3 points, free copper was the only predictor of a more severe decline (predicted probability of MMSE worsening 23%: odds ratio = 1.23; 95% confidence interval = 1.03-1.47; p = 0.022). Hyperlipidemic patients with higher levels of free copper seemed more prone to worse cognitive impairment. Free copper at baseline correlated with the ADL and IADL clinical scales scores at 1 year. CONCLUSIONS: These results show an association between copper deregulation and unfavorable evolution of cognitive function in Alzheimer disease. Further research is needed to establish whether copper is an independent risk factor for cognitive decline.

Babiloni C, Frisoni GB, Pievani M, Vecchio F, Lizio R, Buttiglione M, Geroldi C, Fracassi C, Eusebi F, Ferri R, Rossini PM. · Department of Biomedical Sciences, University of Foggia, Foggia, Italy. · Neuroimage. · Pubmed #18805495 No free full text.

Abstract: Atrophy of hippocampus and alteration of resting eyes-closed electroencephalographic (EEG) rhythms represent important features of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Here we evaluated linear and non-linear aspects of the relationship between these features in the continuum along MCI and AD conditions, as a reflection of neurodegenerative processes. Eyes-closed resting EEG data were recorded in 60 healthy elderly (Nold), 88 MCI, and 35 Alzheimer's disease (AD) patients. Hippocampal volume was measured in magnetic resonance imaging of the MCI and AD subjects. Based on the normalized hippocampal volume, selected MCI subjects could be divided into two demographically paired sub-groups: those with larger hippocampal volume (MCI +h; N=40; mini mental state evaluation - MMSE - score=27.5+/-0.26 SE) and those with smaller hippocampal volume (MCI -h; N=40; h; MMSE=26.5+/-0.34 SE); the normalized hippocampal volume was statistically greater in the MCI +h than in the MCI -h and AD subjects (p<0.0001). 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). Cortical EEG generators were estimated by LORETA software. Results showed that the power of occipital, parietal, and temporal alpha 1 sources was maximum in MCI +h, intermediate in MCI -h, and low in AD patients. Furthermore, the power of these sources was linearly and non-linearly correlated with the normalized hippocampal volume. These 3 EEG sources were given as input for evaluating correlations (linear, exponential, logarithmic and power) with hippocampal volume. When subjects were considered as a unique group, there was a significant linear correlation of hippocampal volume with the magnitude of alpha 1 sources in the parietal, occipital and temporal areas. In general, the EEG sources showing significant linear correlation with hippocampal volume also supported a non-linear correlation with hippocampal volume strongly for the logarithmic one. The present results suggest that progressive atrophy of hippocampus correlates with decreased cortical alpha power, as estimated by using LORETA source modeling, in the continuum along MCI and AD conditions.

Frisoni GB, Henneman WJ, Weiner MW, Scheltens P, Vellas B, Reynish E, Hudecova J, Hampel H, Burger K, Blennow K, Waldemar G, Johannsen P, Wahlund LO, Zito G, Rossini PM, Winblad B, Barkhof F, Anonymous00039. · IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy. · Alzheimers Dement. · Pubmed #18631976 links to  free full text

Abstract: BACKGROUND: In North America, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has established a platform to track the brain changes of Alzheimer's disease. A pilot study has been carried out in Europe to test the feasibility of the adoption of the ADNI platform (pilot E-ADNI). METHODS: Seven academic sites of the European Alzheimer's Disease Consortium (EADC) enrolled 19 patients with mild cognitive impairment (MCI), 22 with AD, and 18 older healthy persons by using the ADNI clinical and neuropsychological battery. ADNI compliant magnetic resonance imaging (MRI) scans, cerebrospinal fluid, and blood samples were shipped to central repositories. Medial temporal atrophy (MTA) and white matter hyperintensities (WMH) were assessed by a single rater by using visual rating scales. RESULTS: Recruitment rate was 3.5 subjects per month per site. The cognitive, behavioral, and neuropsychological features of the European subjects were very similar to their U.S. counterparts. Three-dimensional T1-weighted MRI sequences were successfully performed on all subjects, and cerebrospinal fluid samples were obtained from 77%, 68%, and 83% of AD patients, MCI patients, and controls, respectively. Mean MTA score showed a significant increase from controls (left, right: 0.4, 0.3) to MCI patients (0.9, 0.8) to AD patients (2.3, 2.0), whereas mean WMH score did not differ among the three diagnostic groups (between 0.7 and 0.9). The distribution of both MRI markers was comparable to matched US-ADNI subjects. CONCLUSIONS: Academic EADC centers can adopt the ADNI platform to enroll MCI and AD patients and older controls with global cognitive and structural imaging features remarkably similar to those of the US-ADNI.

Zappasodi F, Salustri C, Babiloni C, Cassetta E, Del Percio C, Ercolani M, Rossini PM, Squitti R. · Istituto di Scienze e Tecnologie della Cognizione-CNR, Rome, Italy. · Brain Res. · Pubmed #18486114 No free full text.

Abstract: Since many years the apolipoprotein E epsilon4 allele (APOE-epsilon4) is known to be associated with Alzheimer disease (AD) but the mechanisms of these associations remained unclear. In the last years, the potential pathogenetic role of 'free' copper (i.e. non-ceruloplasmin bound copper) has been evidenced in AD. Recently, elevated 'free' copper was found to be correlated with slowing of cortical electroencephalographic (EEG) rhythms. The present work aimed to check the hypothesis that the strength of the correlations between free-copper and alterations of cortical rhythms might be different in carriers and non-carriers of the APOE-epsilon4 allele. Fifty-four AD patients and 20 healthy controls were included in the study. In all of them 1) APOE genotyping was performed; 2) total serum copper and ceruloplasmin was determined in order to calculate the serum 'free' copper; and 3) resting eyes-closed EEG rhythms were recorded and spectral brain activity was estimated via LORETA. A 'two correlation coefficients comparison' test was used to test the strength of the correlation in APOE-epsilon4 carriers and non-carriers. 'Free' copper levels were higher in patients than in controls and correlated positively with parietal-temporal delta and negatively with parieto-temporal alpha-1 activities. The correlation between 'free' copper and temporal alpha-1 activity was stronger in APOE-epsilon4 carriers than in non-carriers. Peroxide levels correlated with higher temporal delta in the AD group. APOE-epsilon4 appears to modulate the effect of copper on the altered AD brain activities, suggesting that modulation of oxidative stress related to copper dysfunction may be one of the mechanisms that make APOE-epsilon4 a risk factor for AD.

Rossini PM, Buscema M, Capriotti M, Grossi E, Rodriguez G, Del Percio C, Babiloni C. · Associazione Fatebenefratelli per la ricerca, S. Giovanni Calibita-Isola Tiberina, Rome, Italy. · Clin Neurophysiol. · Pubmed #18485814 No free full text.

Abstract: OBJECTIVE: It has been shown that a new procedure (implicit function as squashing time, IFAST) based on artificial neural networks (ANNs) is able to compress eyes-closed resting electroencephalographic (EEG) data into spatial invariants of the instant voltage distributions for an automatic classification of mild cognitive impairment (MCI) and Alzheimer's disease (AD) subjects with classification accuracy of individual subjects higher than 92%. METHODS: Here we tested the hypothesis that this is the case also for the classification of individual normal elderly (Nold) vs. MCI subjects, an important issue for the screening of large populations at high risk of AD. Eyes-closed resting EEG data (10-20 electrode montage) were recorded in 171 Nold and in 115 amnesic MCI subjects. The data inputs for the classification by IFAST were the weights of the connections within a nonlinear auto-associative ANN trained to generate the instant voltage distributions of 60-s artifact-free EEG data. RESULTS: The most relevant features were selected and coincidently the dataset was split into two halves for the final binary classification (training and testing) performed by a supervised ANN. The classification of the individual Nold and MCI subjects reached 95.87% of sensitivity and 91.06% of specificity (93.46% of accuracy). CONCLUSIONS: These results indicate that IFAST can reliably distinguish eyes-closed resting EEG in individual Nold and MCI subjects. SIGNIFICANCE: IFAST may be used for large-scale periodic screening of large populations at risk of AD and personalized care.

Babiloni C, Frisoni GB, Pievani M, Toscano L, Del Percio C, Geroldi C, Eusebi F, Miniussi C, Rossini PM. · Department of Biomedical Sciences, University of Foggia, Foggia, Italy; Casa di Cura San Raffaele Cassino, IRCCS San Raffaele Pisana, Rome, Italy. · Neuropsychologia. · Pubmed #18440574 No free full text.

Abstract: It is an open issue if vascular and Alzheimer's disease (AD) lesions represent additive factors in the development of mild cognitive impairment (MCI), as a preclinical stage of Alzheimer's disease (AD) at group level. In the present study, we tested the hypothesis that electroencephalographic (EEG) alpha rhythms, which are affected (i.e. decreased in amplitude) by AD processes, are relatively preserved in MCI subjects in whom the cognitive decline is mainly explained by white-matter vascular load. Resting EEG was recorded in 40 healthy elderly (Nold), 80 MCI, and 40 AD subjects. In the MCI subjects, white-matter vascular load was quantified based on MRI (0-30 Wahlund visual rating scale). 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), and beta 2 (20-30Hz). Low resolution electromagnetic source tomography (LORETA) was used for EEG source analysis. As expected, we observed that alpha 1 sources in parietal, occipital, and temporal areas were lower in amplitude in the AD and MCI subjects than in the Nold subjects, whereas the amplitude of wide delta sources was higher in the AD than in the Nold and MCI subjects. As novel results, the amplitude of parietal, occipital, and temporal alpha 1 sources was higher in the MCI V+ (high vascular load; N=42; MMSE=26) than MCI V- group (low vascular load; N=37; MMSE=26.7). Furthermore, a weak but significant (p<0.05) positive statistical correlation was found between the parietal alpha 1 sources and the score of Wahlund scale across all MCI subjects (i.e. the more severe white-matter lesions, the higher parietal alpha source power). The present results are in line with the additive model of cognitive impairment postulating that this arises as the sum of neurodegenerative and cerebrovascular lesions.

Alberici A, Bonato C, Calabria M, Agosti C, Zanetti O, Miniussi C, Padovani A, Rossini PM, Borroni B. · Department of Neurological Sciences, University of Brescia, Italy. · Acta Neurol Scand. · Pubmed #18397363 No free full text.

Abstract: OBJECTIVE: Frontotemporal lobar degeneration (FTLD) includes different heterogeneous conditions mainly characterized by personality changes and cognitive deficits in language and executive functions; movement disorders have also been associated with FTLD. The present study aimed to measure the primary motor cortex (M1) inhibitory and facilitatory functions in patients affected by FTLD. MATERIALS AND METHODS: The study included 17 FTLD patients, 8 age-matched healthy controls and 8 Alzheimer's disease (AD) patients. Transcranial magnetic stimulation (TMS) was used to study intracortical inhibition (ICI) and facilitation (ICF) by using a double-pulse paradigm. RESULTS: FTLD patients were comparable with controls and AD patients for ICI and ICF. Corticobasal degeneration (CBD) patients presented significant reduced inhibition at ISI3; moreover two out of seven CBD patients had only ipsilateral responses. DISCUSSION: The present study reveals a selective impairment of M1 ICI inhibitory response in CBD, which may help in distinguishing among the FTLD clinical spectrum.

Capo CR, Arciello M, Squitti R, Cassetta E, Rossini PM, Calabrese L, Rossi L. · Department of Biology, "Tor Vergata" University of Rome, Via della Ricerca Scientifica, 00133 Rome, Italy. · Biometals. · Pubmed #18060472 No free full text.

Abstract: The level of the apo-form of the copper enzyme ceruloplasmin (CP) is an established peripheral marker in diseases associated with copper imbalance. In view of the proposal that disturbances of copper homeostasis may contribute to neurodegeneration associated with Alzheimer's disease (AD), the present work investigates, by Western blot and non-reducing SDS-PAGE followed by activity staining, the features of CP protein, and the copper/CP relationship in cerebrospinal fluid (CSF) and serum of AD patients. Results show that only a fraction of total copper is associated with CP in the CSF, at variance with serum, both in affected and in healthy individuals. Furthermore, a conspicuous amount of apo-ceruloplasmin and a decrease of CP oxidase activity characterize the CSF of the affected individuals, and confirm that an impairment of copper metabolism occurs in their central nervous system. In the CSF of AD patients the decrease of active CP, associated with the increase in the pool of copper not sequestered by this protein, may play a role in the neurodegenerative process.

Babiloni C, Frisoni GB, Pievani M, Vecchio F, Infarinato F, Geroldi C, Salinari S, Ferri R, Fracassi C, Eusebi F, Rossini PM. · Dip. Fisiologia Umana e Farmacologia, University La Sapienza, Rome, Italy. · Hum Brain Mapp. · Pubmed #17979121 No free full text.

Abstract: Do cerebrovascular and Alzheimer's disease (AD) lesions represent additive factors in the development of mild cognitive impairment (MCI) as a putative preclinical stage of AD? Here we tested the hypothesis that directionality of fronto-parietal functional coupling of electroencephalographic (EEG) rhythms is relatively preserved in amnesic MCI subjects in whom the cognitive decline is mainly explained by white-matter vascular load. Resting EEG was recorded in 40 healthy elderly (Nold) and 78 amnesic MCI. In the MCI subjects, white-matter vascular load was quantified based on magnetic resonance images (0-30 visual rating scale). 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). Directionality of fronto-parietal functional coupling of EEG rhythms was estimated by directed transfer function software. As main results, (i) fronto-parietal functional coupling of EEG rhythms was higher in magnitude in the Nold than in the MCI subjects; (ii) more interestingly, that coupling was higher at theta, alpha1, alpha2, and beta1 in MCI V+ (high vascular load; N = 42; MMSE = 26) than in MCI V- group (low vascular load; N = 36; MMSE= 26.7). These results are interpreted as supporting the additive model according to which MCI state would result from the combination of cerebrovascular and neurodegenerative lesions.

Squitti R, Ventriglia M, Barbati G, Cassetta E, Ferreri F, Dal Forno G, Ramires S, Zappasodi F, Rossini PM. · Department of Neuroscience, AFaR - Ospedale Fatebenefratelli, Rome, Italy. · J Neural Transm. · Pubmed #17641816 No free full text.

Abstract: Non-ceruloplasmin bound copper ('free') seems slightly elevated in Alzheimer's disease (AD) patients. To test the hypothesis of a correlation between 'free' copper and liver function in AD. We evaluated 51 AD patients and 53 controls through typical tests for chronic liver disease (AST, ALT, gamma-GT, Albumin, prothrombin time - PT-, bilirubins), along with copper, ceruloplasmin, iron, cholesterol in the serum and apolipoprotein E epsilon4 (APOE4) genotype. Absolute serum copper and 'free' copper were higher, albumin was lower and PT longer in AD patients than in controls. 'Free' copper correlated negatively with markers of liver function, in that albumin and albumin/PT ratio (r = -0.43, p = 0.004), and positively with direct bilirubin. Copper and 'free' copper were higher in the APOE4 carriers. These results suggest that abnormalities in copper metabolism might have an effect on liver function in AD.

Babiloni C, Cassetta E, Binetti G, Tombini M, Del Percio C, Ferreri F, Ferri R, Frisoni G, Lanuzza B, Nobili F, Parisi L, Rodriguez G, Frigerio L, Gurzì M, Prestia A, Vernieri F, Eusebi F, Rossini PM. · Dip. Fisiologia Umana e Farmacologia, Università degli Studi di Roma La Sapienza, P.le Aldo Moro 5, 00185 Rome, Italy. · Eur J Neurosci. · Pubmed #17610594 No free full text.

Abstract: Previous evidence has shown that resting delta and alpha electroencephalographic (EEG) rhythms are abnormal in patients with Alzheimer's disease (AD) and its potential preclinical stage (mild cognitive impairment, MCI). Here, we tested the hypothesis that these EEG rhythms are correlated with memory and attention in the continuum across MCI and AD. Resting eyes-closed EEG data were recorded in 34 MCI and 53 AD subjects. 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). These sources were correlated with neuropsychological measures such as Rey list immediate recall (word short-term memory), Rey list delayed recall (word medium-term memory), Digit span forward (immediate memory for digits probing focused attention), and Corsi span forward (visuo-spatial immediate memory probing focused attention). A statistically significant negative correlation (Bonferroni corrected, P < 0.05) was observed between Corsi span forward score and amplitude of occipital or temporal delta sources across MCI and AD subjects. Furthermore, a positive correlation was shown between Digit span forward score and occipital alpha 1 sources (Bonferroni corrected, P < 0.05). These results suggest that cortical sources of resting delta and alpha rhythms correlate with neuropsychological measures of immediate memory based on focused attention in the continuum of MCI and AD subjects.

Babiloni C, Ferri R, Binetti G, Vecchio F, Frisoni GB, Lanuzza B, Miniussi C, Nobili F, Rodriguez G, Rundo F, Cassarino A, Infarinato F, Cassetta E, Salinari S, Eusebi F, Rossini PM. · Department of Human Physiology and Pharmacology, University La Sapienza, Rome, Italy. · Neurobiol Aging. · Pubmed #17573161 No free full text.

Abstract: Is directionality of electroencephalographic (EEG) synchronization abnormal in amnesic mild cognitive impairment (MCI) and Alzheimer's disease (AD)? EEG data were recorded in 64 normal elderly (Nold), 69 amnesic MCI, and 73 mild AD subjects at rest condition (closed eyes). Direction of information flux within EEG functional coupling at electrode pairs was performed by directed transfer function (DTF) at delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10 Hz), alpha 2 (10-12 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz). Parietal to frontal direction of the information flux within EEG functional coupling was stronger in Nold than in MCI and/or AD subjects, namely for alpha and beta rhythms. In contrast, the directional flow within inter-hemispheric EEG functional coupling did not discriminate among the three groups. These results suggest that directionality of parieto-to-frontal EEG synchronization is abnormal not only in AD but also in amnesic MCI.

Altamura C, Squitti R, Pasqualetti P, Tibuzzi F, Silvestrini M, Ventriglia MC, Cassetta E, Rossini PM, Vernieri F. · Department of Neuroscience, Università Campus Bio-Medico, Rome, Italy. · Eur J Neurol. · Pubmed #17539949 No free full text.

Abstract: Evidence suggests the important role of vascular factors both in vascular dementia (VaD) and Alzheimer disease (AD) pathogenesis. However, the relationship between apolipoprotein E (APOE) polymorphism and markers of atherosclerosis is still controversial. The aim of the study was to investigate the interplay between APOE polymorphisms and atherosclerosis in patients with AD and VaD. In this cross-sectional study, 101 demented (68 AD and 33 VaD) patients underwent APOE genotyping and neck vessel ultrasound to evaluate carotid artery disease [intima-media thickness (IMT) and plaques]. Patients with AD carrying epsilon4 allele presented increased IMT values with respect to non-epsilon4 carriers and VaD patients, whereas no relation was found between APOE polymorphisms and the presence or grade of carotid plaques both in AD and VaD patients. The epsilon4 APOE allele may promote intima-media thickening, interacting with other factors contributing to AD development.

Babiloni C, Squitti R, Del Percio C, Cassetta E, Ventriglia MC, Ferreri F, Tombini M, Frisoni G, Binetti G, Gurzi M, Salinari S, Zappasodi F, Rossini PM. · Dip Fisiologia Umana e Farmacologia, Univ La Sapienza, Rome, Italy. · Clin Neurophysiol. · Pubmed #17462944 No free full text.

Abstract: OBJECTIVE: The present study tested the hypothesis that the serum copper abnormalities were correlated with alterations of resting electroencephalographic (EEG) rhythms across the continuum of healthy elderly (Hold), mild cognitive impairment (MCI), and AD subjects. METHODS: Resting eyes-closed EEG rhythms 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), estimated by LORETA, were recorded in 17 Hold, 19 MCI, 27 AD- (MMSE< or =20), and 27 AD+ (MMSE20) individuals and correlated with copper biological variables. RESULTS: Across the continuum of Hold, MCI and AD subjects, alpha sources in parietal, occipital, and temporal areas were decreased, while the magnitude of the delta and theta EEG sources in parietal, occipital, and temporal areas was increased. The fraction of serum copper unbound to ceruloplasmin positively correlated with temporal and frontal delta sources, regardless of the effects of age, gender, and education. CONCLUSIONS: These results sustain the hypothesis of a toxic component of serum copper that is correlated with functional loss of AD, as revealed by EEG indexes. SIGNIFICANCE: The present study represents the first demonstration that the fraction of serum copper unbound to ceruloplasmin is correlated with cortical delta rhythms across Hold, MCI, and AD subjects, thus unveiling possible relationships among the biological parameter, advanced neurodegenerative processes, and synchronization mechanisms regulating the relative amplitude of selective EEG rhythms.

Babiloni C, Bosco P, Ghidoni R, Del Percio C, Squitti R, Binetti G, Benussi L, Ferri R, Frisoni G, Lanuzza B, Cassetta E, Anello G, Gurzì M, Bartesaghi S, Lizio R, Tombini M, Rossini PM. · Dipartimento di Fisiologia Umana e Farmacologia, Università degli Studi di Roma La Sapienza, Rome, Italy. <> · Neuroscience. · Pubmed #17321055 No free full text.

Abstract: 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.

Cotelli M, Manenti R, Cappa SF, Geroldi C, Zanetti O, Rossini PM, Miniussi C. · Istituto di Recovero e Cura a Carattere Scientifico San Giovanni di Dio Fatebenefratelli, University of Brescia, Brescia, Italy. · Arch Neurol. · Pubmed #17101829 links to  free full text

Abstract: OBJECTIVE: To assess the effect of repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) on picture naming in patients with Alzheimer disease (AD). DESIGN: Experimental study. Patients with AD underwent rTMS in real and control conditions during picture-naming tasks. SETTING: San Giovanni di Dio Fatebenefratelli Scientific Institute in Brescia, Italy. Patients Fifteen patients with probable AD. Intervention High-frequency rTMS was applied to the left and right DLPFC during object and action naming. MAIN OUTCOME MEASURES: Language ability was assessed by accuracy of verbal response during online rTMS. RESULTS: Stimulation to the left and right DLPFC improved accuracy in action naming. CONCLUSIONS: These findings indicate that rTMS to the DLPFC, which speeds up action naming in normal controls, improves performance in patients with AD. While the mechanisms of rTMS-induced naming facilitation in these patients are unknown, the procedure may be worth testing as a novel approach to the treatment of language dysfunction.