A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer's disease.

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.

The added value of neuropsychologic tests and structural imaging for the etiologic diagnosis of dementia in italian expert centers.

Aim of the study was to assess the added diagnostic value of neuropsychologic tests and structural neuroimaging (computed tomography or magnetic resonance) in the routine clinical assessment of demented patients in Italian expert centers. Nine centers were involved, located across the whole country (3 in Northern, 3 in Central, and 3 in Southern Italy). Diagnostic pathways were tracked for 474 patients with an expert diagnosis of neurodegenerative or vascular dementia (age 76+/-8; 62% females; Mini-Mental State Examination 17.70+/-5.7). The contribution of neuropsychology and structural neuroimaging to diagnosis was estimated as "number needed to test" (NNT), denoting the number of patients who need to undergo such procedures to improve expert diagnosis of 1 unit. Expert physicians reached their diagnosis without resorting to structural imaging examinations and neuropsychologic tests in 93% of Alzheimer disease (AD) and 76% of non-AD dementias. The completion of the extended assessment led to improvement of diagnostic accuracy in both cases: the NNT was 15.3 (95% confidence interval: 10.4-29.1) and 4.1 (3.0 to 6.5) for AD and non-AD diagnoses. The added value of structural imaging and neuropsychologic testing in the routine clinical assessment of demented patients is substantial in both AD and non-AD cases.

Association of adiposity status and changes in early to mid-adulthood with incidence of Alzheimer's disease.

Adiposity status and change are potential risk factors for Alzheimer's disease (AD). The authors used data on 2,322 participants in the Baltimore Longitudinal Study of Aging to analyze the relation between AD incidence and adiposity in Cox proportional hazards models, with adjustment for sociodemographic factors and smoking status. Body mass index (BMI; weight (kg)/height (m)(2)) and waist circumference at specific ages were predicted by empirical Bayes estimators from mixed-effects regression models. After a median of 23.4 years of follow-up between 1958 and 2006, 187 participants developed AD. Among men, being underweight (BMI or=30) at age 30, 40, or 45 years and jointly centrally obese (waist circumference >or=80th percentile) at age 30, 35, or 50 years increased AD risk (HR = 6.57, 95% CI: 1.96, 22.02). Women who lost weight (BMI change <10th percentile) between ages 30 and 45 years were also at increased risk (HR = 2.02, 95% CI: 1.06, 3.85). Weight gain among men (BMI change >90th percentile) between ages 30 and 50 years increased AD risk (HR = 3.70, 95% CI: 1.43, 9.56). Future studies should identify age- and gender-specific optimal weights and weight-loss strategies for preventing AD and investigate potential mechanisms.

Survival in Alzheimer's disease is shorter in women carrying heterozygosity at codon 129 of the PRNP gene and no APOE epsilon 4 allele.

We assessed the role of the APOE genotype and prion protein polymorphism at codon 129 in predicting the clinical duration of 92 neuropathologically confirmed sporadic Alzheimer's disease patients. Analyses of survival showed that the absence of the APOE epsilon 4 allele in heterozygous codon 129 PRNP carriers is a negative predictor of survival. When this subgroup of patients was stratified by sex, the effect of APOE was observed in women, but not in men.

Externalizing and oppositional behaviors and karate-do: the way of crime prevention. A pilot study.

Childhood disruptive behaviors can be precursors to later deviance. To verify the efficacy of karate, a complex psychomotor activity that enhances self-regulation and executive skills, as an intervention for externalizing behaviors, 16 children, ranging in age from 8 to 10 years, and meeting diagnostic criteria for oppositional defiant disorder were studied. Eight were randomly assigned to a 10-month Wa Do Ryu karate program, whereas 8 children received no intervention. The children were assigned to a larger karate class, composed of typically developing youngsters. Three domains of temperament--intensity, adaptability, and mood regulation--were measured at the beginning and the end of the training period in all 16 participants. A significant improvement in temperament scale scores was measured in the karate group for all tested items compared to controls. Karate, when properly taught, can be a useful adjunct in multimodal programs aimed at externalizing behavior reduction.

Areas of intervention for genetic counselling of dementia: cross-cultural comparison between Italians and Americans.

OBJECTIVE: Purposes of this study are: (1) to evaluate attitudes, beliefs and experiences towards dementia among relatives of Italian familial cases; (2) to perform a cross-cultural comparison between Italian and American samples; (3) to identify predictors of intentions to undergo hypothetical genetic testing. METHODS: Participants were 134 relatives of patients affected by familial forms of dementia. We administered tests measuring health psychological styles, social variables, illness perceptions, intentions regarding genetic testing, and perceptions of the pros and cons of genetic testing. RESULTS: Respondents had a poor Alzheimer's disease knowledge and a low perceived dementia threat. When compared to Americans, Italians reported greater willingness to undergo genetic testing and perceived a different subset of benefits and risks. The strongest predictors of test intention were decisional balance, homemaker status and two beliefs concerning dementia causes. CONCLUSIONS: Italians had a poor knowledge of the disease and a low awareness of personal risk of developing dementia. As compared to Americans, they expressed higher intentions to undergo genetic testing and they have a different perception of benefits and risks. PRACTICE IMPLICATIONS: Understanding of cultural differences in knowledge, attitudes and perception of the disease is important to design optimal health services and education programs for dementia.

Donepezil effects on sources of cortical rhythms in mild Alzheimer's disease: Responders vs. Non-Responders.

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.

Fronto-parietal coupling of brain rhythms in mild cognitive impairment: a multicentric EEG study.

Electroencephalographic (EEG) data were recorded in 69 normal elderly (Nold), 88 mild cognitive impairment (MCI), and 109 mild Alzheimer's disease (AD) subjects at rest condition, to test whether the fronto-parietal coupling of EEG rhythms is in line with the hypothesis that MCI can be considered as a pre-clinical stage of the disease at group level. Functional coupling was estimated by synchronization likelihood of Laplacian-transformed EEG data at electrode pairs, which accounts for linear and non-linear components of that coupling. Cortical 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). Compared to the Nold subjects, the AD patients presented a marked reduction of the synchronization likelihood (delta to gamma) at both fronto-parietal and inter-hemispherical (delta to beta 2) electrodes. As a main result, alpha 1 synchronization likelihood progressively decreased across Nold, MCI, and mild AD subjects at midline (Fz-Pz) and right (F4-P4) fronto-parietal electrodes. The same was true for the delta synchronization likelihood at right fronto-parietal electrodes (F4-P4). For these EEG bands, the synchronization likelihood correlated with global cognitive status as measured by the Mini Mental State Evaluation. The present results suggest that at group level, fronto-parietal coupling of the delta and alpha rhythms progressively becomes abnormal though MCI and mild AD. Future longitudinal research should evaluate whether the present EEG approach is able to predict the cognitive decline in individual MCI subjects.

Use of an Italian version of the telephone interview for cognitive status in Alzheimer's disease.

OBJECTIVES: Validation of an Italian version of the Telephone Interview for Cognitive Status (I-TICS). METHODS: Telephone administration of the I-TICS within 6 weeks of face-to-face testing with the Mini Mental State Examination (MMSE), in Probable Alzheimer's disease (AD) patients and healthy controls. Two hundred and seven consecutive outpatients with cognitive impairment were recruited from Dementia Clinic of University Campus BioMedico. Of these, 45 probable AD patients with complete data were analyzed. Other dementias, Mild Cognitive Impairment (MCI), and patients with incomplete data were excluded. The control sample consisted of 64 age- and sex-matched healthy subjects. For diagnosis, an extensive clinical evaluation, laboratory testing, brain imaging, EEG, neuropsychological battery and a depression scale were used. For I-TICS validation, telephone I-TICS and face-to-face MMSE were administered. RESULTS: The I-TICS correlated highly and linearly with the MMSE (Pearson's r=0.904). Conversion equations are provided. Sensitivity and specificity were similar between tests (area under curve=0.894 for the I-TICS; 0.966 for the MMSE). I-TICS sensitivity was 84% and specificity 86% at a cut-off score of 28. No significant difference in accuracy with the MMSE was present. Total agreement between I-TICS and MMSE was 'substantial' at 86% (Cohen's K=0.717). Repeated testing in a subset of patients showed a disease progression related decrease of 4.2 points/year (t=2.664; p=0.018) in I-TICS scores. CONCLUSION: The I-TICS is a valid instrument in clinical and research screening and monitoring of AD. Potential applications in other dementias and MCI are worth further studies.

Sources of cortical rhythms in adults during physiological aging: a multicentric EEG study.

This electroencephalographic (EEG) study tested whether cortical EEG rhythms (especially delta and alpha) show a progressive increasing or decreasing trend across physiological aging. To this aim, we analyzed the type of correlation (linear and nonlinear) between cortical EEG rhythms and age. Resting eyes-closed EEG data were recorded in 108 young (Nyoung; age range: 18-50 years, mean age 27.3+/-7.3 SD) and 107 elderly (Nold; age range: 51-85 years, mean age 67.3+/-9.2 SD) subjects. The 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). Statistical results showed that delta sources in the occipital area had significantly less magnitude in Nold compared to Nyoung subjects. Similarly, alpha 1 and alpha 2 sources in the parietal, occipital, temporal, and limbic areas had significantly less magnitude in Nold compared to Nyoung subjects. These nine EEG sources were given as input for evaluating the type (linear, exponential, logarithmic, and power) of correlation with age. When subjects were considered as a single group there was a significant linear correlation of age with the magnitude of delta sources in the occipital area and of alpha 1 sources in occipital and limbic areas. The same was true for alpha 2 sources in the parietal, occipital, temporal, and limbic areas. In general, the EEG sources showing significant linear correlation with age also supported a nonlinear correlation with age. These results suggest that the occipital delta and posterior cortical alpha rhythms decrease in magnitude during physiological aging with both linear and nonlinear trends. In conclusion, this new methodological approach holds promise for the prediction of dementia in mild cognitive impairment by regional source rather than surface EEG data and by both linear and nonlinear predictors.

Genotype (cystatin C) and EEG phenotype in Alzheimer disease and mild cognitive impairment: a multicentric study.

Previous findings demonstrated that haplotype B of CST3, the gene coding for cystatin C, is a recessive risk factor for late-onset Alzheimer's disease (AD; Finckh, U., von der Kammer, H., Velden, J., Michel, T., Andresen, B., Deng, A., Zhang, J., Muller-Thomsen, T., Zuchowski, K., Menzer, G., Mann, U., Papassotiropoulos, A., Heun, R., Zurdel, J., Holst, F., Benussi, L., Stoppe, G., Reiss, J., Miserez, A.R., Staehelin, H.B., Rebeck, G.W., Hyman, B.T., Binetti, G., Hock, C., Growdon, J.H., Nitsch, R.M., 2000. Genetic association of the cystatin C gene with late-onset Alzheimer disease. Arch. Neurol. 57, 1579-1583). In the present multicentric electroencephalographic (EEG) study, we analyzed the effects of CST3 haplotypes on resting cortical rhythmicity in subjects with AD and mild cognitive impairment (MCI) with the hypothesis that sources of resting EEG rhythms are more impaired in carriers of the CST3 B haplotype than non-carriers. We enrolled a population of 84 MCI subjects (42% with the B haplotype) and 65 AD patients (40% with the B haplotype). Resting eyes-closed EEG data were recorded in all 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). Results showed that the amplitude of alpha 1 (parietal, occipital, temporal areas) and alpha 2 (occipital area) was statistically lower in CST3 B carriers than non-carriers (P < 0.01). Whereas there was a trend towards statistical significance that amplitude of occipital delta sources was stronger in CST3 B carriers than in non-carriers. This was true for both MCI and AD subjects. The present findings represent the first demonstration of relationships between the AD genetic risk factor CST3 B and global neurophysiological phenotype (i.e., cortical delta and alpha rhythmicity) in MCI and AD subjects, prompting future genotype-EEG phenotype studies for the early prediction of AD conversion in individual MCI subjects.

Apolipoprotein E and alpha brain rhythms in mild cognitive impairment: a multicentric electroencephalogram study.

OBJECTIVE: Relationships between the apolipoprotein E epsilon4 allele and electroencephalographic (EEG) rhythmicity have been demonstrated in Alzheimer's disease (AD) patients but not in the preclinical stage prodromic to it, namely, mild cognitive impairment (MCI). The present multicentric EEG study tested the hypothesis that presence of epsilon4 affects sources of resting EEG rhythms in both MCI and AD subjects. METHODS: We enrolled 89 MCI subjects (34.8% with epsilon4) and 103 AD patients (50.4% with epsilon4). Resting eyes-closed EEG data were recorded for all subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). EEG cortical sources were estimated by low-resolution brain electromagnetic tomography. RESULTS: Results showed that amplitude of alpha 1 and 2 sources in occipital, temporal, and limbic areas was lower in subjects carrying the epsilon4 allele than in those not carrying the epsilon4 allele (p < 0.01). This was true for both MCI and AD. For the first time to our knowledge, a relationship was shown between ApoE genotype and global neurophysiological phenotype (ie, cortical alpha rhythmicity) in a preclinical AD condition, MCI, in addition to clinically manifest AD. INTERPRETATION: Such a demonstration motivates future genotype-EEG phenotype studies for the early prediction of AD conversion in individual MCI subjects.

Sources of cortical rhythms change as a function of cognitive impairment in pathological aging: a multicenter study.

OBJECTIVE: The present study tested the hypothesis that cortical electroencephalographic (EEG) rhythms. change across normal elderly (Nold), mild cognitive impairment (MCI), and Alzheimer's disease (AD) subjects as a function of the global cognitive level. METHODS: Resting eyes-closed EEG data were recorded in 155 MCI, 193 mild AD, and 126 age-matched Nold 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 LORETA. RESULTS: Occipital delta and alpha 1 sources in parietal, occipital, temporal, and 'limbic' areas had an intermediate magnitude in MCI subjects compared to mild AD and Nold subjects. These five EEG sources presented both linear and nonlinear (linear, exponential, logarithmic, and power) correlations with the global cognitive level (as revealed by mini mental state examination score) across all subjects. CONCLUSIONS: Cortical EEG rhythms change in pathological aging as a function of the global cognitive level. SIGNIFICANCE: The present functional data on large populations support the 'transitional hypothesis' of a shadow zone across normality, pre-clinical stage of dementia (MCI), and AD.

Depressive symptoms, sex, and risk for Alzheimer's disease.

Depression associates with increased risk for dementia and Alzheimer's disease (AD), although it is unclear whether it represents an actual risk factor or a prodrome. To determine the relative hazard of premorbid depressive symptomatology for development of dementia and AD, we studied risk for incident dementia and AD over a 14-year period in 1,357 community-dwelling men and women participating in the 40-year prospective Baltimore Longitudinal Study of Aging. Screening for depressive symptoms, comprehensive medical and neuropsychological evaluations were prospectively collected every 2 years. Time-dependent proportional hazards of development of AD or dementia were calculated separately for men and women, with symptoms of depression detected at 2-, 4-, and 6-year intervals before onset of dementia symptoms. Vascular risk factors were analyzed as covariates. Premorbid depressive symptoms significantly increased risk for dementia, particularly AD in men but not in women. Hazard ratios were approximately two times greater than for individuals without history of depressive symptoms, an effect independent of vascular disease. We conclude that the impact of depressive symptoms on risk for dementia and AD may vary with sex. Further studies assessing separately the role of depression as a risk factor in men and women are necessary.

Genotypes and haplotypes in the IL-1 gene cluster: analysis of two genetically and diagnostically distinct groups of Alzheimer patients.

Increased risk of Alzheimer's disease (AD) has been associated with polymorphisms in the IL-1 gene cluster, and in particular with the IL-1alpha-889 T/T genotype. However, this association is still unclear, and needs further investigation. In order to clarify the role of these polymorphisms in the complex pathogenesis of AD we examined genotype and haplotype frequencies of the two C-to-T SNPs at position -889 and -551 in the IL-1alpha and IL-1beta genes, respectively, and of the 86 bp VNTR intron-2 polymorphisms in the IL-1Ra gene. The analysis was performed in two genetically and diagnostically distinct groups of sporadic AD from Italy and the USA. In the Italian group a significant association between the IL-1alpha-889 T/T genotype and AD (OR=3.022, 95% CI: 1.001-9.119) was found, whereas no difference was found in the group from the USA. Results were also compared with previously published studies that analyzed the same IL-1 polymorphisms in AD. In both groups, the analysis of the estimated haplotypes shows that AD patients and controls who carry the IL-1beta-511 C allele, were also more frequently carriers of the IL-1Ra 1 allele (haplotypes -C-1). The total frequency of the two -C-1 haplotypes (C-C-1 plus T-C-1) was about one half of the total frequency of the eight estimated haplotypes. This was confirmed by significant linkage disequilibrium between these two loci in both the Italian and USA groups. In the Italian group a weak association of the T-C-2 haplotype with the disease (OR=1.648, 95% CI: 1.519-1.788) was also found, whereas in the USA group no difference was found. Although ours and other published data on different samples of Caucasian and non-Caucasian AD show a great heterogeneity in the frequencies of the IL-1alpha-889, the IL-1beta-511 and the IL-1Ra VNTR gene polymorphisms, we confirm the role of the IL-1alpha-889 T/T genotype as a risk factor for sporadic AD, and show the presence of an allelic association between IL-1beta C and IL-1Ra 1 alleles in both the Italian and the USA groups, confirmed by the presence of significant levels of linkage disequilibrium between these two loci.

Neuronal post-stroke plasticity in the adult.

Contrary to what previously believed, recent research advances have demonstrated that the adult brain has a certain capacity for plastic reorganization and self-repair after a lesion such as cerebrovascular accidents. The mechanisms subtending post-stroke recovery are probably complex and operating at different levels, from molecular to synaptic to anatomical reorganization. The integrated use of functional neuroimaging techniques, by overcoming the limitations of each specific methodology is likely to shed much light on plasticity mechanisms. In this review we discuss the neuroanatomy and neurophysiology possibly underlying reorganization of the central nervous system, as well as the experimental evidence of "in vivo" post-stroke plasticity. Better understanding of these mechanisms can provide neurorehabilitation with powerful tools in designing and implementing new therapeutic approaches to stroke patients both in the acute and the chronic stages after a brain tissue lesion has occurred and stabilized.

Copper perturbation in 2 monozygotic twins discordant for degree of cognitive impairment.

BACKGROUND: Recent evidence indicates that peripheral tissue markers can provide information regarding changes affecting cellular metabolism in Alzheimer disease (AD). We previously reported that serum copper levels can discriminate subjects with AD from normal control subjects (with 60% sensitivity and 95% specificity) and from patients with vascular dementia (with 63% sensitivity and 85% specificity). OBJECTIVE: To study the correlation between AD and serum levels of transition metals and markers of peripheral oxidative stress. DESIGN: Case study. SETTING: General hospital inpatient wards and outpatient clinics. Patients A pair of elderly monozygotic female twins discordant for AD. MAIN OUTCOME MEASURES: Biochemical analyses of peripheral-blood transition metals and indicators of oxidative stress and neurologic and neuropsychological assessments of clinical status for presence of cognitive impairment and AD. RESULTS: Serum copper and total peroxide levels were both 44% higher in the twin with greater cognitive impairment and a diagnosis of AD. CONCLUSIONS: The cases reported support the hypothesis of a major involvement of copper and oxidative abnormalities in AD.

Abnormal fronto-parietal coupling of brain rhythms in mild Alzheimer's disease: a multicentric EEG study.

Cholinergic deafferentation/recovery in rats mainly impinges on the fronto-parietal coupling of brain rhythms [D. P. Holschneider et al. (1999) Exp. Brain Res., 126, 270-280]. Is this reflected by the functional coupling of fronto-parietal cortical rhythms at an early stage of Alzheimer's disease (mild AD)? Resting electroencephalographic (EEG) rhythms were studied in 82 patients with mild AD and in control subjects, such as 41 normal elderly (Nold) subjects and 25 patients with vascular dementia (VaD). Patients with AD and VaD had similar mini-mental state evaluation scores of 17-24. The functional coupling was estimated by means of the synchronization likelihood (SL) of the EEG data at electrode pairs, accounting for linear and non-linear components of that coupling. Cortical 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). A preliminary data analysis (Nold) showed that surface Laplacian transformation of the EEG data reduced the values of SL, possibly because of the reduction of influences due to head volume conduction. Therefore, the final analysis was performed on Laplacian-transformed EEG data. The SL was dominant at alpha 1 band in all groups. Compared with the Nold subjects, patients with VaD and mild AD presented a marked reduction of SL at both fronto-parietal (delta-alpha) and inter-hemispherical (delta-beta) electrode pairs. The feature distinguishing the patients with mild AD with respect to patients with VaD groups was a more prominent reduction of fronto-parietal alpha 1 SL. These results suggest that mild AD is characterized by an abnormal fronto-parietal coupling of the dominant human cortical rhythm at 8-10.5 Hz.

Mapping distributed sources of cortical rhythms in mild Alzheimer's disease. A multicentric EEG study.

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.

Integrated technology for evaluation of brain function and neural plasticity.

The study of neural plasticity has expanded rapidly in the past decades and has shown the remarkable ability of the developing, adult, and aging brain to be shaped by environmental inputs in health and after a lesion. Robust experimental evidence supports the hypothesis that neuronal aggregates adjacent to a lesion in the sensorimotor brain areas can take over progressively the function previously played by the damaged neurons. It definitely is accepted that such a reorganization modifies sensibly the interhemispheric differences in somatotopic organization of the sensorimotor cortices. This reorganization largely subtends clinical recovery of motor performances and sensorimotor integration after a stroke. Brain functional imaging studies show that recovery from hemiplegic strokes is associated with a marked reorganization of the activation patterns of specific brain structures. To regain hand motor control, the recovery process tends over time to bring the bilateral motor network activation toward a more normal intensity/extent, while overrecruiting simultaneously new areas, perhaps to sustain this process. Considerable intersubject variability exists in activation/hyperactivation pattern changes over time. Some patients display late-appearing dorsolateral prefrontal cortex activation, suggesting the development of "executive" strategies to compensate for the lost function. The AH in stroke often undergoes a significant "remodeling" of sensory and motor hand somatotopy outside the "normal" areas, or enlargement of the hand representation. The UH also undergoes reorganization, although to a lesser degree. Although absolute values of the investigated parameters fluctuate across subjects, secondary to individual anatomic variability, variation is minimal with regards to interhemispheric differences, due to the fact that individual morphometric characters are mirrored in the two hemispheres. Excessive interhemispheric asymmetry of the sensorimotor hand areas seems to be the parameter with highest sensitivity in describing brain reorganization after a monohemispheric lesion, and mapping motor and somatosensory cortical areas through focal TMS, fMRI, PET, EEG, and MEG is useful in studying hand representation and interhemispheric asymmetries in normal and pathologic conditions. TMS and MEG allow the detection of sensorimotor areas reshaping, as a result of either neuronal reorganization or recovery of the previously damaged neural network. These techniques have the advantage of high temporal resolution but also have limitations. TMS provides only bidimensional scalp maps, whereas MEG, even if giving three-dimensional mapping of generator sources, does so by means of inverse procedures that rely on the choice of a mathematical model of the head and the sources. These techniques do not test movement execution and sensorimotor integration as used in everyday life. fMRI and PET may provide the ideal means to integrate the findings obtained with the other two techniques. This multitechnology combined approach is at present the best way to test the presence and amount of plasticity phenomena underlying partial or total recovery of several functions, sensorimotor above all. Dynamic patterns of recovery are emerging progressively from the relevant literature. Enhanced recruitment of the affected cortex, be it spared perilesional tissue, as in the case of cortical stroke, or intact but deafferented cortex, as in subcortical strokes, seems to be the rule, a mechanism especially important in early postinsult stages. The transfer over time of preferential activation toward contralesional cortices, as observed in some cases, seems, however, to reflect a less efficient type of plastic reorganization, with some aspects of maladaptive plasticity. Reinforcing the use of the affected side can cause activation to increase again in the affected side with a corresponding enhancement of clinical function. Activation of the UH MI may represent recruitment of direct (uncrossed) corticospinal tracts and relate more to mirror movements, but it more likely reflects activity redistribution within preexisting bilateral, large-scale motor networks. Finally, activation of areas not normally engaged in the dysfunctional tasks, such as the dorsolateral prefrontal cortex or the superior parietal cortex in motor paralysis, might reflect the implication of compensatory cognitive strategies. An integrated approach with technologies able to investigate functional brain imaging is of considerable value in providing information on the excitability, extension, localization, and functional hierarchy of cortical brain areas. Deepening knowledge of the mechanisms regulating the long-term recovery (even if partial), observed for most neurologic sequelae after neural damage, might prompt newer and more efficacious therapeutic and rehabilitative strategies for neurologic diseases.