Patients with Alzheimer's disease dementia show partially preserved parietal 'hubs' modeled from resting-state alpha electroencephalographic rhythms.

Introduction: Graph theory models a network by its nodes (the fundamental unit by which graphs are formed) and connections. 'Degree' hubs reflect node centrality (the connection rate), while 'connector' hubs are those linked to several clusters of nodes (mainly long-range connections). Methods: Here, we compared hubs modeled from measures of interdependencies of between-electrode resting-state eyes-closed electroencephalography (rsEEG) rhythms in normal elderly (Nold) and Alzheimer's disease dementia (ADD) participants. At least 5 min of rsEEG was recorded and analyzed. As ADD is considered a 'network disease' and is typically associated with abnormal rsEEG delta (<4 Hz) and alpha rhythms (8-12 Hz) over associative posterior areas, we tested the hypothesis of abnormal posterior hubs from measures of interdependencies of rsEEG rhythms from delta to gamma bands (2-40 Hz) using eLORETA bivariate and multivariate-directional techniques in ADD participants versus Nold participants. Three different definitions of 'connector' hub were used. Results: Convergent results showed that in both the Nold and ADD groups there were significant parietal 'degree' and 'connector' hubs derived from alpha rhythms. These hubs had a prominent outward 'directionality' in the two groups, but that 'directionality' was lower in ADD participants than in Nold participants. Discussion: In conclusion, independent methodologies and hub definitions suggest that ADD patients may be characterized by low outward 'directionality' of partially preserved parietal 'degree' and 'connector' hubs derived from rsEEG alpha rhythms.

Cortical network modularity changes along the course of frontotemporal and Alzheimer's dementing diseases.

Cortical network modularity underpins cognitive functions, so we hypothesized its progressive derangement along the course of frontotemporal (FTD) and Alzheimer's (AD) dementing diseases. EEG was recorded in 18 FTD, 18 AD, and 20 healthy controls (HC). In the FTD and AD patients, the EEG recordings were performed at the prodromal stage of dementia, at the onset of dementia, and three years after the onset of dementia. HC underwent three EEG recordings at 2-3-year time interval. Information flows underlying EEG activity recorded at electrode pairs were estimated by means of Mutual Information (MI) analysis. The functional organization of the cortical network was modelled by means of the Graph theory analysis on MI adjacency matrices. Graph theory analysis showed that the main hub of HC (Parietal area) was lost in FTD patients at onset of dementia, substituted by provincial hubs in frontal leads. No changes in global network organization were found in AD. Despite a progressive cognitive impairment during the FTD and AD progression, only the FTD patients showed a derangement in the cortical network modularity, possibly due to dysfunctions in frontal functional connectivity.

Anterior EEG slowing in dementia with Lewy bodies: a multicenter European cohort study.

Electroencephalography (EEG) slowing with prealpha dominant frequency (DF) in posterior derivations is a biomarker for dementia with Lewy bodies (DLB) diagnosis, in contrast with Alzheimer's disease (AD). However, an intrasubject re-evaluation of the original data, which contributed to the identification of EEG DLB biomarker, showed that DF was slower in anterior than posterior derivations. We suppose this anterior-posterior gradient of DF slowing could arise in DLB from a thalamocortical dysrhythmia, differently involving the anterior and posterior cortical areas, and correlating with cognitive impairment (Mini-Mental State Examination). EEG was recorded in 144 DLB, 116 AD, and 65 controls from 7 Centers of the European DLB Consortium. Spectra were divided into delta, theta, prealpha, alpha frequency bands. In DLB, mean DF was prealpha both anteriorly and posteriorly, but lower anteriorly (p < 0.001). In 14% of DLB, DF was prealpha anteriorly, whereas alpha posteriorly. In AD and controls, DF was constantly alpha. EEG slowing in DLB correlated with cognitive impairment. Thalamocortical dysrhythmia gives rise to prealpha rhythm with an anterior-posterior gradient and correlates with impaired cognition.

Two-Year Longitudinal Monitoring of Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease Using Topographical Biomarkers Derived from Functional Magnetic Resonance Imaging and Electroencephalographic Activity.

Auditory "oddball" event-related potentials (aoERPs), resting state functional magnetic resonance imaging (rsfMRI) connectivity, and electroencephalographic (rsEEG) rhythms were tested as longitudinal functional biomarkers of prodromal Alzheimer's disease (AD). Data were collected at baseline and four follow-ups at 6, 12, 18, and 24 months in amnesic mild cognitive impairment (aMCI) patients classified in two groups: "positive" (i.e., "prodromal AD"; n = 81) or "negative" (n = 63) based on a diagnostic marker of AD derived from cerebrospinal samples (Aß42/P-tau ratio). A linear mixed model design was used to test functional biomarkers for Group, Time, and Group×Time effects adjusted by nuisance covariates (only data until conversion to dementia was used). Functional biomarkers that showed significant Group effects ("positive" versus "negative", p < 0.05) regardless of Time were 1) reduced rsfMRI connectivity in both the default mode network (DMN) and the posterior cingulate cortex (PCC), both also giving significant Time effects (connectivity decay regardless of Group); 2) increased rsEEG source activity at delta (<4 Hz) and theta (4-8 Hz) rhythms and decreased source activity at low-frequency alpha (8-10.5 Hz) rhythms; and 3) reduced parietal and posterior cingulate source activities of aoERPs. Time×Group effects showed differential functional biomarker progression between groups: 1) increased rsfMRI connectivity in the left parietal cortex of the DMN nodes, consistent with compensatory effects and 2) increased limbic source activity at theta rhythms. These findings represent the first longitudinal characterization of functional biomarkers of prodromal AD relative to "negative" aMCI patients based on 5 serial recording sessions over 2 years.

Increase of EEG Alpha3/Alpha2 Power Ratio Detects Inferior Parietal Lobule Atrophy in Mild Cognitive Impairment.

OBJECTIVE: The inferior parietal lobule (IPL) has been implicate in many higher cognitive processes, as visuo-motor transformations, tool use or tool making. In subjects with mild cognitive impairment (MCI) at major risk to develop Alzheimer' Disease (AD) an impairment of subtle visuomotor or praxic abilities is a well-known clinical feature. Enhance of the ratio of EEG alpha3/alpha2 frequency power was detected in subjects with MCI who will transform in Alzheimer's disease (AD). METHODS: We explored of the association of alpha3/alpha2 power ratio with cortical size of IPL in patients with MCI. 74 subjects with MCI undergone EEG recording and MRI scans. Alpha3/alpha2 power ratio in addition to cortical size had been computed for each patient. Three MCI groups had been acquired in keeping with growing tertile values of alpha3/alpha2 ratio. Huge difference of cortical thickness among the groups was calculated. Higher alpha3/alpha2 power ratio group had broader cortical loss compared to other teams on the IPL, particularly in the Supramarginal Gyrus, and Precuneus on both hemispheres. RESULTS: Our results unveil the possible part that the IPL could play in determining the classic alterations of early Alzheimer's disease (AD). CONCLUSION: Finally, the rise of alpha3/alpha2 power ratio detected a focused anatomo-functional association that could be a reliable marker of incipient AD.

Progranulin Mutations Affects Brain Oscillatory Activity in Fronto-Temporal Dementia.

BACKGROUND: Mild cognitive impairment (MCI) is a clinical stage indicating a prodromal phase of dementia. This practical concept could be used also for fronto-temporal dementia (FTD). Progranulin (PGRN) has been recently recognized as a useful diagnostic biomarker for fronto-temporal lobe degeneration (FTLD) due to GRN null mutations. Electroencephalography (EEG) is a reliable tool in detecting brain networks changes. The working hypothesis of the present study is that EEG oscillations could detect different modifications among FTLD stages (FTD-MCI versus overt FTD) as well as differences between GRN mutation carriers versus non-carriers in patients with overt FTD. MATERIALS AND METHODS: EEG in all patients and PGRN dosage in patients with a clear FTD were detected. The cognitive state has been investigated through mini mental state examination (MMSE). RESULTS: MCI-FTD showed a significant lower spectral power in both alpha and theta oscillations as compared to overt FTD. GRN mutations carriers affected by FTLD show an increase in high alpha and decrease in theta oscillations as compared to non-carriers. CONCLUSION: EEG frequency rhythms are sensible to different stage of FTD and could detect changes in brain oscillatory activity affected by GRN mutations.

Are there treatments for atypical parkinsonism? An update on actual options.

Success in treating patients with atypical parkinsonism remains exceedingly low. It is particularly important for both neurologists and general practicians to have a guideline in the actual possible cure options. This study reviews the limited available literature reporting treatment trials about treatment in parkinsonism. Various therapeutical approaches have been tried with rasagiline, immunoglobulin, autologous mesenchymal stem cells, davunetide, lithium, and tideglusib. Recently, the transdermal rotigotine has been proposed for the treatment of atypical parkinsonism, as well as deep brain stimulation (DBS) of the peduncolopontine nucleus alone or combined with globus pallidus internus stimulation. The outcomes reviewed here highlight the need for the development of randomized, placebo-controlled trials to validate outcomes about rotigotine, DBS, and all other new therapies directed at altering the underlying biological mechanisms involved in the disease process.

Theta and alpha EEG frequency interplay in subjects with mild cognitive impairment: evidence from EEG, MRI, and SPECT brain modifications.

BACKGROUND: Temporo-parietal and medial temporal cortex atrophy are associated with mild cognitive impairment (MCI) due to Alzheimer disease (AD) as well as the reduction of regional cerebral blood perfusion in hippocampus. Moreover, the increase of EEG alpha3/alpha2 power ratio has been associated with MCI due to AD and with an increase in theta frequency power in a group of subjects with impaired cerebral perfusion in hippocampus. METHODS: Seventy four adult subjects with MCI underwent clinical and neuropsychological evaluation, electroencephalogram (EEG) recording and high resolution 3D magnetic resonance imaging (MRI). Among the patients, a subset of 27 subjects underwent also perfusion single-photon emission computed tomography and hippocampal atrophy evaluation. Alpha3/alpha2 power ratio as well as cortical thickness was computed for each subject. Three MCI groups were detected according to increasing tertile values of alpha3/alpha2 power ratio and difference of cortical thickness among the groups estimated. RESULTS: Higher alpha3/alpha2 power ratio group had wider cortical thinning than other groups, mapped to the Supramarginal and Precuneus bilaterally. Subjects with higher alpha3/alpha2 frequency power ratio showed a constant trend to a lower perfusion than lower alpha3/alpha2 group. Moreover, this group correlates with both a bigger hippocampal atrophy and an increase of theta frequency power. CONCLUSION: Higher EEG alpha3/alpha2 power ratio was associated with temporo-parietal cortical thinning, hippocampal atrophy and reduction of regional cerebral perfusion in medial temporal cortex. In this group an increase of theta frequency power was detected inMCI subjects. The combination of higher EEG alpha3/alpha2 power ratio, cortical thickness measure and regional cerebral perfusion reveals a complex interplay between EEG cerebral rhythms, structural and functional brain modifications.

Alpha rhythm oscillations and MMSE scores are differently modified by transdermal or oral rivastigmine in patients with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in older patients. Rivastigmine, a reversible cholinesterase inhibitor, has been shown to improve the clinical manifestations of AD by delaying the breakdown of acetylcholine (ACh) released into synaptic clefts. Moreover, there is evidence that ACh modulates EEG alpha frequency. OBJECTIVES: the objectives of this pilot study in patients with AD were to determine the effects of two formulations of RV (transdermal and oral) on Mini-Mental State Examination (MMSE) scores and on alpha frequency in particular the posterior dominant rhythm. METHODS: twenty subjects with AD were randomly assigned to receive either RV transdermal patch (RV-TDP, n=10) or RV capsules (RV-CP, n=10) according to the standard recommended dosage regimen. All patients were driven to the maximum drug dosage. Diagnosis of AD was made according to NINCDS-ADRDA criteria and the Diagnostic and Statistical Manual of Mental Disorders IV. All patients underwent EEG recordings at the beginning and at the end of the 18-month study period using P3, P4, O1 and O2 electrodes each at high (10.5-13.0 Hz) and low (8.0-10.5 Hz) frequency. MMSE scores were determined at the start of the study and at three successive 6-month intervals (T0, T1, T2, and T3). RESULTS: administration of RV-DP increases the spectral power of alpha waves in the posterior region and is associated with improved cognitive function as evidenced by significant changes in MMSE scores. CONCLUSION: RV-DP provides an effective and long-term management option in patients with AD.

Comparison of the effects of transdermal and oral rivastigmine on cognitive function and EEG markers in patients with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in older patients. Rivastigmine (RV, Exelon, Novartis), a reversible cholinesterase inhibitor, improves clinical manifestations of AD and may enhance ACh-modulated electroencephalogram (EEG) alpha frequency. This pilot study aimed to determine the effects of two formulations of RV [transdermal patch (RV-TDP) and oral capsules (TV-CP)] on alpha frequency, in particular the posterior dominant rhythm, and cognitive function [assessed by the Mini-Mental State Examination (MMSE)] in patients with AD. METHODS: Subjects with AD were assigned to receive either RV-TDP 10 cm(2) or RV-CP 12 mg/day. All patients underwent EEG recordings at the beginning and end of the 18-month study period using P3, P4, O1, and O2 electrodes, each at high (10.5-13.0 Hz) and low (8.0-10.5 Hz) frequency. MMSE scores were determined at the start of the study (T0) and at three successive 6-month intervals (T1, T2, and T3). RESULTS: RV-TDP administration (n = 10) maintained cognitive function as evidenced by stable MMSE scores from baseline to 18 months (21.07 ± 2.4-21.2 ± 3.1) compared with a decrease in MMSE score with RV-CP (n = 10) over 18 months [18.3 ± 3.6-13.6 ± 5.06 (adjusted for covariates p = 0.006)]. MMSE scores were significantly different between treatment groups from 6 months (p = 0.04). RV-TDP also increased the spectral power of alpha waves in the posterior region measured with electrode P3 in a significantly great percentage of patients than TV-CP from baseline to 18 months; 80% vs 30%, respectively [p = 0.025 (χ (2) test)]. CONCLUSIONS: RV-TDP was associated with a greater proportion of patients with increased posterior region alpha wave spectral power and significantly higher cognitive function at 18 months, compared with RV-CP treatment. Our findings suggest that RV-TDP provides an effective long-term management option in patients with AD compared with oral RV-CP. This study is a pilot, open-label study with a clear explorative purpose and with a small number of patients. Further randomized, double-blind, placebo-controlled trial studies with a bigger sample size as well as healthy controls are needed to support these initial results.

EEG upper/low alpha frequency power ratio and the impulsive disorders network in subjects with mild cognitive impairment.

The ventral striatum-nucleus accumbens network has been associated with impulsive behavior in subjects with early cognitive impairment; in Alzheimer's disease (AD) modifications of basal ganglia have been also demonstrated. Moreover, the increase of EEG alpha3/alpha2 frequency power ratio has been investigated as EEG marker in subjects with mild cognitive impairment (MCI) who will develop AD. In the present study we have detected the relationship between upper alpha/low alpha ferquency power ratio and specific gray matter (GM) changes in the basal ganglia in subjects with MCI. Electroencefalographic (EEG) recording and high resolution 3D magnetic resonance imaging (MRI) were taken in 74 MCI subjects. In each subject the alpha3/alpha2 EEG frequency power ratio was estimated as EEG biomarker. Three groups were obtained according to increasing tertiles values of the biomarker. Through the Voxel Based Morphometry (VBM) technique, GM density differences between groups were evaluated. Results show that subjects with lower a3/a2 and middle a3/a2 ratio ratio showed greater gray matter reduction in the Nucleus Accumbens and the head of Caudate Nucleus as compared to subjects with higher a3/a2 ratio. Our study indicates that the a3/a2 frequency power ratio was associated with increase of grey matter density inside the impulsivity network of MCI patients more likely develop AD.

Increase of theta frequency is associated with reduction in regional cerebral blood flow only in subjects with mild cognitive impairment with higher upper alpha/low alpha EEG frequency power ratio.

BACKGROUND: Several biomarkers have been proposed for detecting Alzheimer's disease (AD) in its earliest stages, that is, in the predementia stage. In an attempt to find noninvasive biomarkers, researchers have investigated the feasibility of neuroimaging tools, such as MRI, SPECT as well as neurophysiological measurements using EEG. Moreover, the increase of EEG alpha3/alpha2 frequency power ratio has been associated with AD-converters subjects with mild cognitive impairment (MCI). OBJECTIVE: To study the association of alpha3/alpha2 frequency power ratio with regional cerebral blood flow (rCBF) changes in subjects with MCI. METHODS: Twenty-seven adult subjects with MCI underwent EEG recording and perfusion single-photon emission computed tomography (SPECT) evaluation. The alpha3/alpha2 frequency power ratio was computed for each subject. Two groups were obtained according to the median values of alpha3/alpha2, at a cut-off of 1.17. Correlation between brain perfusion and EEG markers were detected. RESULTS: Subjects with higher alpha3/alpha2 frequency power ratio showed a constant trend to a lower perfusion than low alpha3/alpha2 group. The two groups were significantly different as about the hippocampal volume and correlation with the theta frequency activity. CONCLUSION: There is a complex interplay between cerebral blood flow, theta frequency activity, and hippocampal volume in MCI patients with prodromal Alzheimer's disease, characterized by higher EEG alpha3/alpha2 frequency power ratio.

EEG upper/low alpha frequency power ratio relates to temporo-parietal brain atrophy and memory performances in mild cognitive impairment.

OBJECTIVE: Temporo-parietal cortex thinning is associated to mild cognitive impairment (MCI) due to Alzheimer disease (AD). The increase of EEG upper/low alpha power ratio has been associated with AD-converter MCI subjects. We investigated the association of alpha3/alpha2 ratio with patterns of cortical thickness in MCI. MATERIALS AND METHODS: Seventy-four adult subjects with MCI underwent clinical and neuropsychological evaluation, electroencephalogram (EEG) recording and high resolution 3D magnetic resonance imaging. Alpha3/alpha2 power ratio as well as cortical thickness was computed for each subject. Three MCI groups were detected according to increasing tertile values of upper/low alpha power ratio. Difference of cortical thickness among the groups was estimated. Pearson's r was used to assess the topography of the correlation between cortical thinning and memory impairment. RESULTS: High upper/low alpha power ratio group had total cortical gray matter volume reduction of 471 mm(2) than low upper/low alpha power ratio group (p < 0.001). Upper/low alpha group showed a similar but less marked pattern (160 mm(2)) of cortical thinning when compared to middle upper/low alpha power ratio group (p < 0.001). Moreover, high upper/low alpha group had wider cortical thinning than other groups, mapped to the Supramarginal and Precuneus bilaterally. Finally, in high upper/low alpha group temporo-parietal cortical thickness was correlated to memory performance. No significant cortical thickness differences was found between middle and low alpha3/alpha2 power ratio groups. CONCLUSION: High EEG upper/low alpha power ratio was associated with temporo-parietal cortical thinning and memory impairment in MCI subjects. The combination of EEG upper/low alpha ratio and cortical thickness measure could be useful for identifying individuals at risk for progression to AD dementia and may be of value in clinical context.

Predictors of comprehensive stimulation program efficacy in patients with cognitive impairment. Clinical practice recommendations.

BACKGROUND: The aim of the present study was to identify which factors may predict the best response to a comprehensive stimulation program in patients with dementia and mild cognitive impairment (MCI) as well as in their caregivers. METHODS: A six-month longitudinal study has been performed on 145 patients (55 with MCI and 90 with dementia), participating to a cognitive motor rehabilitation program, and their 131 caregivers, attending informational/psychoeducational interventions. Mini mental state examination, Alzheimer's Disease Assessment Scale-Cognition, and Clinician's Interview-Based Impression of Change-plus were used as primary outcome measures. RESULTS: Sixty-eight (46.9%) of the 145 subjects were classified as clinical responders. At baseline, responders had a significant less insight impairment, larger functional ability as well as less delusions, euphoria, and aberrant motor behaviors than the non-responder. After 6 months along with an improvement in cognition, responders showed decrease in behavioral disturbances and severity of the disturbances. During the 6 months of analysis, stability has been observed in caregiver's burden distress. After 6 months, the caregivers of MCI responders have their burden reduced. CONCLUSIONS: The high level of insight, the preserved functional abilities as well as the lack of severe delusions, euphoria, and aberrant motor behaviors are significant predictors of responsiveness to stimulation program.

Analysis of grey matter in thalamus and basal ganglia based on EEG α3/α2 frequency ratio reveals specific changes in subjects with mild cognitive impairment.

GM (grey matter) changes of thalamus and basal ganglia have been demonstrated to be involved in AD (Alzheimer's disease). Moreover, the increase of a specific EEG (electroencephalogram) marker, α3/α2, have been associated with AD-converters subjects with MCI (mild cognitive impairment). To study the association of prognostic EEG markers with specific GM changes of thalamus and basal ganglia in subjects with MCI to detect biomarkers (morpho-physiological) early predictive of AD and non-AD dementia. Seventy-four adult subjects with MCI underwent EEG recording and high-resolution 3D MRI (three-dimensional magnetic resonance imaging). The α3/α2 ratio was computed for each subject. Three groups were obtained according to increasing tertile values of α3/α2 ratio. GM density differences between groups were investigated using a VBM (voxel-based morphometry) technique. Subjects with higher α3/α2 ratios when compared with subjects with lower and middle α3/α2 ratios showed minor atrophy in the ventral stream of basal ganglia (head of caudate nuclei and accumbens nuclei bilaterally) and of the pulvinar nuclei in the thalamus; The integrated analysis of EEG and morpho-structural markers could be useful in the comprehension of anatomo-physiological underpinning of the MCI entity.

Anatomical Substrate and Scalp EEG Markers are Correlated in Subjects with Cognitive Impairment and Alzheimer's Disease.

Dementia is a syndromic diagnosis, encompassing various stage of severity and different anatomo-physiological substrates. The hippocampus is one of the first and most affected brain regions affected by both Alzheimer's disease (AD) and mild cognitive impairment (MCI). Moreover, chronic cerebrovascular disease (CVD) is one of the major risk factor for developing dementia. Recent studies have demonstrated different relationship between the anatomical substrate and scalp electroencephalography (EEG) markers. Indeed, modifications of EEG rhythmicity is not proportional to the hippocampal atrophy, whereas changes in EEG activity are directly proportional to the load of subcortical CVD. The computation of the EEG spectral power and the analysis of the functional coupling of brain areas, through linear coherence, are two of the most known processing methods in EEG research. Two specific EEG markers, theta/gamma and alpha3/alpha2 frequency ratio have been reliable associated to the atrophy of amygdalo-hippocampal complex. Moreover, theta/gamma ratio has been related to MCI conversion in dementia and alpha3/alpha2 ratio has been specifically related to MCI conversion in AD. The functional coupling of brain areas is also modulated by hippocampal atrophy. In the MCI subjects, hippocampal atrophy is linked to an increase of interhemispheric coherence seen on frontal and temporal regions whereas subcortical CVD is linked to a decrease of coherence in fronto-parietal regions. In the present study the most significant results of recent studies on correlation between scalp EEG, cognitive decline, and anatomical substrate have been reviewed, with particular attention to the relationships between EEG changes and hippocampal atrophy. The following review is not intended to provide a comprehensive summary of the literature. Rather it identifies and discusses selected studies that are designed to find the specific correlation between scalp EEG markers and anatomo-pathological substrate. The principal aim is to propose a plausible neurophysiological theoretical model of the cognitive decline as mirrored by both structural and functional tools of research.

Progranulin Leu271LeufsX10 is one of the most common FTLD and CBS associated mutations worldwide.

Mutations in the progranulin gene (PGRN) are a major cause of frontotemporal lobar degeneration (FTLD). Herein we estimated the contribution of the PGRN Leu271LeufsX10 mutation to FTLD and related disorders in the Brescia cohort. The PGRN Leu271LeufsX10 mutation was found in 31% of corticobasal syndrome (CBS), 29% of frontotemporal dementia with motorneuron disease (FTD-MND), 15% of behavioral variant frontotemporal dementia (FTD), 9.5% of primary progressive aphasia (PPA), 2% dementia with Lewy bodies and 0% of progressive supranuclear palsy and multiple system atrophy cases. The prevalence strongly increased in familial forms (75% CBS, 50% FTD-MND, 27% FTD, 18% PPA): in our cohort this mutation is a major disease determinant for FTLD-related disorders with a prominent motor component. MAPT haplotype was demonstrated to be a disease modifier in PGRN Leu271LeufsX10 carriers: in H1H2 subjects the disease onset was earlier than in H2H2 individuals. Sequencing of the whole PGRN gene disclosed a previously described mutation (c.2T>C, Met1X) and three novel ones (c.709-3; c.1011delG, His340ThrfsX21; c.1021C>T, Gln341X) in single families. In the Brescia cohort, while MAPT mutations have low prevalence, mutations in PGRN were shown in 28% of familial FTLD and 75% of familial CBS cases. The PGRN Leu271LeufsX10 mutation becomes one of the most common mutations worldwide, since it was identified in 38 patients belonging to 27 unrelated families.

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.

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.