Relationship between default mode network and resting-state electroencephalographic alpha rhythms in cognitively unimpaired seniors and patients with dementia due to Alzheimer's disease.

Here we tested the hypothesis of a relationship between the cortical default mode network (DMN) structural integrity and the resting-state electroencephalographic (rsEEG) rhythms in patients with Alzheimer's disease with dementia (ADD). Clinical and instrumental datasets in 45 ADD patients and 40 normal elderly (Nold) persons originated from the PDWAVES Consortium (www.pdwaves.eu). Individual rsEEG delta, theta, alpha, and fixed beta and gamma bands were considered. Freeware platforms served to derive (1) the (gray matter) volume of the DMN, dorsal attention (DAN), and sensorimotor (SMN) cortical networks and (2) the rsEEG cortical eLORETA source activities. We found a significant positive association between the DMN gray matter volume, the rsEEG alpha source activity estimated in the posterior DMN nodes (parietal and posterior cingulate cortex), and the global cognitive status in the Nold and ADD participants. Compared with the Nold, the ADD group showed lower DMN gray matter, lower rsEEG alpha source activity in those nodes, and lower global cognitive status. This effect was not observed in the DAN and SMN. These results suggest that the DMN structural integrity and the rsEEG alpha source activities in the DMN posterior hubs may be related and predict the global cognitive status in ADD and Nold persons.

Resting State Alpha Electroencephalographic Rhythms Are Affected by Sex in Cognitively Unimpaired Seniors and Patients with Alzheimer's Disease and Amnesic Mild Cognitive Impairment: A Retrospective and Exploratory Study.

In the present retrospective and exploratory study, we tested the hypothesis that sex may affect cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms recorded in normal elderly (Nold) seniors and patients with Alzheimer's disease and mild cognitive impairment (ADMCI). Datasets in 69 ADMCI and 57 Nold individuals were taken from an international archive. The rsEEG rhythms were investigated at individual delta, theta, and alpha frequency bands and fixed beta (14-30 Hz) and gamma (30-40 Hz) bands. Each group was stratified into matched females and males. The sex factor affected the magnitude of rsEEG source activities in the Nold seniors. Compared with the males, the females were characterized by greater alpha source activities in all cortical regions. Similarly, the parietal, temporal, and occipital alpha source activities were greater in the ADMCI-females than the males. Notably, the present sex effects did not depend on core genetic (APOE4), neuropathological (Aß42/phospho-tau ratio in the cerebrospinal fluid), structural neurodegenerative and cerebrovascular (MRI) variables characterizing sporadic AD-related processes in ADMCI seniors. These results suggest the sex factor may significantly affect neurophysiological brain neural oscillatory synchronization mechanisms underpinning the generation of dominant rsEEG alpha rhythms to regulate cortical arousal during quiet vigilance.

Retinal and Choriocapillaris Vascular Changes in Early Alzheimer Disease Patients Using Optical Coherence Tomography Angiography.

BACKGROUND: Alzheimer disease (AD) is a neurodegenerative disorder characterized by ß-amyloid accumulation in the brain. A simple and reliable biomarker for AD that is not invasive is urgently needed, particularly in the preclinical and early stages of the disease. The retina shares with the brain, the same embryologic origins and it is affected by similar vascular changes. The aim of this study was to analyze the characteristics of the retinal and choriocapillaris vascular structure through optical coherence tomography-angiography (OCTA) evaluation in patients with early AD. METHODS: Eighteen patients with early AD (study group) and 18 healthy age-matched subjects (control group) were enrolled in the study. All patients underwent full neurologic and ophthalmologic examination, and OCTA scans. RESULTS: We found a significant reduction in flow area of choriocapillaris in the study group compared with the control group (P-value: 0.006), suggesting an impairment of choriocapillaris circulation in patients with early AD. CONCLUSION: OCTA provides accumulative evidence on the microvasculature changes of the retina and choriocapillaris in patients with AD. Further studies and improved OCTA software are necessary to better evaluate the role of vascular changes shown with OCTA as potential biomarkers in early disease.

Abnormalities of Cortical Sources of Resting State Alpha Electroencephalographic Rhythms are Related to Education Attainment in Cognitively Unimpaired Seniors and Patients with Alzheimer's Disease and Amnesic Mild Cognitive Impairment.

In normal old (Nold) and Alzheimer's disease (AD) persons, a high cognitive reserve (CR) makes them more resistant and resilient to brain neuropathology and neurodegeneration. Here, we tested whether these effects may affect neurophysiological oscillatory mechanisms generating dominant resting state electroencephalographic (rsEEG) alpha rhythms in Nold and patients with mild cognitive impairment (MCI) due to AD (ADMCI). Data in 60 Nold and 70 ADMCI participants, stratified in higher (Edu+) and lower (Edu-) educational attainment subgroups, were available in an Italian-Turkish archive. The subgroups were matched for age, gender, and education. RsEEG cortical sources were estimated by eLORETA freeware. As compared to the Nold-Edu- subgroup, the Nold-Edu+ subgroup showed greater alpha source activations topographically widespread. On the contrary, in relation to the ADMCI-Edu- subgroup, the ADMCI-Edu+ subgroup displayed lower alpha source activations topographically widespread. Furthermore, the 2 ADMCI subgroups had matched cerebrospinal AD diagnostic biomarkers, brain gray-white matter measures, and neuropsychological scores. The current findings suggest that a high CR may be related to changes in rsEEG alpha rhythms in Nold and ADMCI persons. These changes may underlie neuroprotective effects in Nold seniors and subtend functional compensatory mechanisms unrelated to brain structure alterations in ADMCI patients.

Caregivers' Profiles Based on the Canadian Occupational Performance Measure for the Adoption of Assistive Technologies.

The COPM (Canadian Occupational Performance Measure) is a tool that is based on the identification of self-perceived performance and satisfaction problems in the performance of occupations, allowing the creation of a hierarchy in the order of the interventions to be carried out, and speeding up the identification of the necessary AT (Assistive Technologies). Given the importance of the caregiver's perception about their own performance in the design of AT, this research examines the caregiver's profile through the COPM. A sample of 40 caregivers volunteered to participate in the study. A cluster analysis was carried out on the COPM scores. Two caregiver profiles were found in relation to the COPM measure, one with low scores on performance and satisfaction and another with high scores on both of these two variables. The main predictor was found to be the self-perception of performance. The structure was replicated through a hierarchical cluster analysis, where the role of caregivers was of interest. These results are relevant on both a theoretical and practical level.

Circulating U13 Small Nucleolar RNA as a Potential Biomarker in Huntington's Disease: A Pilot Study.

Plasma small RNAs have been recently explored as biomarkers in Huntington's disease (HD). We performed an exploratory study on nine HD patients, eight healthy subjects (HS), and five psychiatric patients (PP; to control for iatrogenic confounder effects) through an Affymetrix-Gene-Chip-miRNA-Array. We validated the results in an independent population of 23 HD, 15 pre-HD, 24 PP, 28 Alzheimer's disease (AD) patients (to control the disease-specificity) and 22 HS through real-time PCR. The microarray results showed higher levels of U13 small nucleolar RNA (SNORD13) in HD patients than controls (fold change 1.54, p = 0.003 HD vs. HS, and 1.44, p = 0.0026 HD vs. PP). In the validation population, a significant increase emerged with respect to both pre-HD and the control groups (p < 0.0001). SNORD13 correlated with the status of the mutant huntingtin carrier (r = 0.73; p < 0.001) and the disease duration (r = 0.59; p = 0.003). The receiver operating characteristic (ROC) curve analysis showed the high accuracy of SNORD13 in discriminating HD patients from other groups (AUC = 0.963). An interactome and pathway analysis on SNORD13 revealed enrichments for factors relevant to HD pathogenesis. We report the unprecedented finding of a potential disease-specific role of SNORD13 in HD. It seems to peripherally report a 'tipping point' in the pathogenic cascade at the neuronal level.

Neurocognitive Assessment and Retinal Thickness Alterations in Alzheimer Disease: Is There a Correlation?

BACKGROUND: The relation of retinal thickness to neuropsychological indexes of cognitive impairment in patients with Alzheimer disease (AD) remains an area of investigation. The scope of this investigation was to compare volume and thickness changes of neuronal retinal layers in subjects with AD with those of age-matched healthy controls and to estimate the relation between cognitive functioning evaluated by neuropsychological assessment and thickness changes of the retina. METHODS: This was a prospective single-site study where we evaluated 25 subjects with probable AD matched for age, sex, and education to 17 healthy control subjects (HC). All participants underwent a full medical evaluation, neuropsychological assessment, and optical coherence tomography (OCT) to evaluate the peripapillary retinal nerve fiber layer (pRNFL) thickness, ganglion cell complex (GCC) thickness, and macular volume. RESULTS: The pRNFL thickness of AD patients showed a significant overall reduction compared with healthy controls (P = <0.0001). Furthermore, pRNFL was reduced in each retinal quadrant, particularly the inferior, nasal, and superior quadrants. GCC thickness and macular volume were reduced in AD patients in comparison with HC (P = 0.004; P = 0.001). Of particular interest was the correlation between OCT findings and neuropsychological assessment; we did not find a significant association of retinal thinning with worse MMSE score, but reduction of macular volume was associated with worse constructional praxis performance. Impairment of semantic-lexical and processing speed was associated with attenuation of macular GCC thickness. CONCLUSIONS: OCT can show early thickness changes in AD patients with subtle memory disturbances. These results suggest that correlations between retinal thinning and cognitive performance warrant further investigation.

Neurovascular Dysfunction in Alzheimer Disease: Assessment of Cerebral Vasoreactivity by Ultrasound Techniques and Evaluation of Circulating Progenitor Cells and Inflammatory Markers.

AIMS: The aims of this study were to assess vascular dysfunction in patients with Alzheimer disease (AD) by investigating cerebral vasomotor reactivity using transcranial Doppler ultrasound (TCD) and to evaluate any correlations between cerebral vasoreactivity and endothelium dysfunction. Moreover, the frequency of circulating progenitor cells (CPCs) and the blood concentration of vascular/inflammatory markers were evaluated. MATERIALS AND METHODS: We recruited 35 AD subjects and 17 age-matched, sex-matched, and education-matched healthy control subjects. Cerebral vasomotor reactivity was assessed by means of the TCD-based breath-holding index test (BHI). The level of CPCs was evaluated by means of flow cytometry from venous blood samples, while blood vascular/inflammatory markers were measured by means of enzyme-linked immunosorbent assay. RESULTS: Both cerebral assay blood flow velocity in the middle cerebral artery (MCAFV) and BHI values were significantly lower in AD subjects than in healthy controls (P<0.05). A positive trend was found between MCAFV and BHI values and Mini-Mental State Evaluation (MMSE) scores. Moreover, the hematopoietic progenitor cells' count was found to be lower in patients with AD than in controls (P<0.05). Finally, a significantly higher expression of the plasma chemokine CCL-2 was observed in AD patients than in healthy controls. CONCLUSIONS: Our results confirm that cerebral hemodynamic deterioration may be a critical marker of cognitive decline. Further studies are needed to investigate the role of circulating CPCs and chemokines as potential contributors to neurovascular dysfunction.

Emerging Biomarkers in Vascular Cognitive Impairment and Dementia: From Pathophysiological Pathways to Clinical Application.

Vascular pathology is the second most common neuropathology of dementia after Alzheimer's disease (AD), with small vessels disease (SVD) being considered the major cause of vascular cognitive impairment and dementia (VCID). This review aims to evaluate pathophysiological pathways underlying a diagnosis of VCID. Firstly, we will discuss the role of endothelial dysfunction, blood-brain barrier disruption and neuroinflammation in its pathogenesis. Then, we will analyse different biomarkers including the ones of inflammatory responses to central nervous system tissue injuries, of coagulation and thrombosis and of circulating microRNA. Evidences on peripheral biomarkers for VCID are still poor and large-scale, prospectively designed studies are needed to translate these findings into clinical practice, in order to set different combinations of biomarkers to use for differential diagnosis among types of dementia.

Cognitive profiles in degenerative dementia without evidence of small vessel pathology and small vessel vascular dementia.

Although a large number of studies have examined possible differences in cognitive performance between Alzheimer's disease (AD) and vascular dementia (VaD), the data in the literature are conflicting. The aims of this study were to analyze the neuropsychological pattern of subjects affected by degenerative dementia without evidence of small vessel pathology (DD) and small vessel VaD subjects in the early stages and to investigate differences in the progression of cognitive impairment. Seventy-five patients with probable VaD and 75 patients with probable DD were included. All the subjects underwent a standard neuropsychological evaluation, including the following test: Visual Search, Attentional matrices, Story Recall, Raven's Coloured Progressive Matrices, Phonological and Semantic Verbal Fluency, Token, and Copying Drawings. The severity of cognitive impairment was stratified according to the MMSE score. Fifteen subjects with probable DD and 10 subjects with probable VaD underwent a 12-month cognitive re-evaluation. No significant difference was found between DD and VaD subjects in any of the neuropsychological tests except Story Recall in the mild cognitive impairment (P < 0.001). The re-test value was significantly worse than the baseline value in the MMSE (P = 0.037), Corsi (P = 0.041), Story Recall (P = 0.032), Phonological Verbal Fluency (P = 0.02), and Copying Drawings (P = 0.043) in DD patients and in the Visual Search test (P = 0.036) in VaD subjects. These results suggest that a neuropsychological evaluation might help to differentiate degenerative dementia without evidence of small vessel pathology from small vessel VaD in the early stages of these diseases.

Resting state electroencephalographic alpha rhythms are sensitive to Alzheimer's disease mild cognitive impairment progression at a 6-month follow-up.

Are posterior resting-state electroencephalographic (rsEEG) alpha rhythms sensitive to the Alzheimer's disease mild cognitive impairment (ADMCI) progression at a 6-month follow-up? Clinical, cerebrospinal, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 Healthy old seniors (equivalent groups for demographic features) were available from an international archive (www.pdwaves.eu). The ADMCI patients were arbitrarily divided into two groups: REACTIVE and UNREACTIVE, based on the reduction (reactivity) in the posterior rsEEG alpha eLORETA source activities from the eyes-closed to eyes-open condition at ≥ -10% and -10%, respectively. 75% of the ADMCI patients were REACTIVE. Compared to the UNREACTIVE group, the REACTIVE group showed (1) less abnormal posterior rsEEG source activity during the eyes-closed condition and (2) a decrease in that activity at the 6-month follow-up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD. Such a biomarker might reflect abnormalities in cortical arousal in quiet wakefulness to be used for clinical studies in ADMCI patients using 6-month follow-ups.

Poor reactivity of posterior electroencephalographic alpha rhythms during the eyes open condition in patients with dementia due to Parkinson's disease.

Here, we hypothesized that the reactivity of posterior resting-state electroencephalographic (rsEEG) alpha rhythms during the transition from eyes-closed to -open condition might be lower in patients with Parkinson's disease dementia (PDD) than in patients with Alzheimer's disease dementia (ADD). A Eurasian database provided clinical-demographic-rsEEG datasets in 73 PDD patients, 35 ADD patients, and 25 matched cognitively unimpaired (Healthy) persons. The eLORETA freeware was used to estimate cortical rsEEG sources. Results showed substantial (greater than -10%) reduction (reactivity) in the posterior alpha source activities from the eyes-closed to the eyes-open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients. In these alpha-reactive participants, there was lower reactivity in the parietal alpha source activities in the PDD group than in the healthy control seniors and the ADD patients. These results suggest that PDD patients show poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. That neurophysiological biomarker may provide an endpoint for (non) pharmacological interventions for improving vigilance regulation in those patients.

Resting state cortical electroencephalographic rhythms are related to gray matter volume in subjects with mild cognitive impairment and Alzheimer's disease.

Cortical gray matter volume and resting state cortical electroencephalographic rhythms are typically abnormal in subjects with amnesic mild cognitive impairment (MCI) and Alzheimer's disease (AD). Here we tested the hypothesis that in amnesic MCI and AD subjects, abnormalities of EEG rhythms are a functional reflection of cortical atrophy across the disease. Eyes-closed resting state EEG data were recorded in 57 healthy elderly (Nold), 102 amnesic MCI, and 108 AD patients. Cortical gray matter volume was indexed by magnetic resonance imaging recorded in the MCI and AD subjects according to Alzheimer's disease neuroimaging initiative project (http://www.adni-info.org/). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). These rhythms were indexed by LORETA. Compared with the Nold, the MCI showed a decrease in amplitude of alpha 1 sources. With respect to the Nold and MCI, the AD showed an amplitude increase of delta sources, along with a strong amplitude reduction of alpha 1 sources. In the MCI and AD subjects as a whole group, the lower the cortical gray matter volume, the higher the delta sources, the lower the alpha 1 sources. The better the score to cognitive tests the higher the gray matter volume, the lower the pathological delta sources, and the higher the alpha sources. These results suggest that in amnesic MCI and AD subjects, abnormalities of resting state cortical EEG rhythms are not epiphenomena but are strictly related to neurodegeneration (atrophy of cortical gray matter) and cognition.

Rivastigmine patch ameliorates depression in mild AD: preliminary evidence from a 6-month open-label observational study.

Here we investigated the effect of the rivastigmine patch alone on depression in 50 mild Alzheimer's disease (AD) patients with comorbid major depressive episode (MDE). First diagnosis acetyl-cholinesterase inhibitor and psychoactive drug-free outpatients (n=50) were recruited in memory clinics and reassessed after 3 and 6 months. Global cognitive functioning, depressive symptoms and MDE frequency were evaluated with the Mini Mental State Examination, the CERAD Dysphoria scale and the modified DSM-IV criteria for MDE in AD. MDE frequency reduced significantly from the first diagnostic visit (100%) to the 6-month follow-up (62%). We also found a significant reduction in CERAD Dysphoria scores that decreased from 6.2±3.9 mean±standard deviation to 4.9±4.5 at the 6-month follow-up. In AD patients with MDE rivastigmine alone can have a positive impact on depressive phenomena. Thus, future controlled study are justified to definitively verify if rivastigmine alone may improve depression in AD.

Heterogeneous pathologies associated with dementia in Parkinsonism share a prion-like spreading mechanism.

Cognitive alterations accompany or follow motor disorders in subjects with Parkinsonism. The canonical phenotypeof the Parkinson's disease Dementia (PD-D) or Lewy Body Dementia (LBD) includes deficit of attention, executiveand visuospatial functions, and presents often with apathy, hallucinations, delusions, excessive daytime sleepiness,or sleep disorders. However, the clinical expression may overlap with other neurodegenerative diseases associatedwith cognitive disorders. Thus, while clinicians rely on phenomenological patterns to infer the disease causing thecognitive impairment, the inference is weakened by the heterogeneous clinical expression of the disease. In addition,recent post-mortem studies seem to undermine the supposed pathology-phenotype coherence, making it moreand more unreliable the diagnosis based on symptoms. The lack of coherence between phenotype and pathologymay support the speculation about a common mechanism underlying the progression of the disease. While it is verylikely that a distinct, specific causal event determines the disease itself, the progression might well follow commonpatterns. A number of observations suggest that progressive diseases, which cause cognitive impairment, share aprion-like mechanism. A seeding process is supposed to account for the spreading of the lesion.

What a Single Electroencephalographic (EEG) Channel Can Tell us About Alzheimer's Disease Patients With Mild Cognitive Impairment.

Abnormalities in cortical sources of resting-state eyes closed electroencephalographic (rsEEG) rhythms recorded by hospital settings (10-20 montage) with 19 scalp electrodes characterized Alzheimer's disease (AD) from preclinical to dementia stages. An intriguing rsEEG application is the monitoring and evaluation of AD progression in large populations with few electrodes in low-cost devices. Here we evaluated whether the above-mentioned abnormalities can be observed from fewer scalp electrodes in patients with mild cognitive impairment due to AD (ADMCI). Clinical and rsEEG data acquired in hospital settings (10-20 montage) from 75 ADMCI participants and 70 age-, education-, and sex-matched normal elderly controls (Nold) were available in an Italian-Turkish archive (PDWAVES Consortium; www.pdwaves.eu). Standard spectral fast fourier transform (FFT) analysis of rsEEG data for individual delta, theta, and alpha frequency bands was computed from 6 monopolar scalp electrodes to derive bipolar C3-P3, C4-P4, P3-O1, and P4-O2 markers. The ADMCI group showed increased delta and decreased alpha power density at the C3-P3, C4-P4, P3-O1, and P4-O2 bipolar channels compared to the Nold group. Increased theta power density for ADMCI patients was observed only at the C3-P3 bipolar channel. Best classification accuracy between the ADMCI and Nold individuals reached 81% (area under the receiver operating characteristic curve) using Alpha2/Theta power density computed at the C3-P3 bipolar channel. Standard rsEEG power density computed from six posterior bipolar channels characterized ADMCI status. These results may pave the way toward diffuse clinical applications in health monitoring of dementia using low-cost EEG systems with a strict number of electrodes in lower- and middle-income countries.

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.

Resting state EEG rhythms in different stages of chronic kidney disease with mild cognitive impairment.

Here, we tested that standard eyes-closed resting-state electroencephalographic (rsEEG) rhythms may characterize patients with mild cognitive impairment due to chronic kidney disease at stages 3-4 (CKDMCI-3&4) in relation to CKDMCI patients under hemodialysis (CKDMCI-H) and mild cognitive impairment (MCI) patients with cerebrovascular disease (CVMCI). Clinical and rsEEG data in 22 CKDMCI-3&4, 15 CKDMCI-H, 18 CVMCI, and 30 matched healthy control (HC) participants were available in a national archive. Spectral rsEEG power density was calculated from delta to gamma frequency bands at scalp electrodes. Results showed that (1) all MCI groups over the HC group showed decreased occipital rsEEG alpha power density; (2) compared to the HC and CVMCI groups, the 2 CKDMCI groups had higher rsEEG delta-theta power density; and (3) the CKDMCI-3&4 group showed the lowest parietal rsEEG alpha power density. The present rsEEG measures may be useful to monitor the impact of circulating uremic toxins on brain regulation of cortical arousal for quiet vigilance in CKDMCI patients.

Quantitative magnetization transfer provides information complementary to grey matter atrophy in Alzheimer's disease brains.

Preliminary studies, based on a region-of-interest approach, suggest that quantitative magnetization transfer (qMT), an extension of magnetization transfer imaging, provides complementary information to conventional magnetic resonance imaging (MRI) in the characterisation of Alzheimer's disease (AD). The aim of this study was to extend these findings to the whole brain, using a voxel-wise approach. We recruited 19AD patients and 11 healthy subjects (HS). All subjects had an MRI acquisition at 3.0T including a T(1)-weighted volume, 12 MT-weighted volumes for qMT, and data for computing T(1) and B(1) maps. The T(1)-weighted volumes were processed to yield grey matter (GM) volumetric maps, while the other sequences were used to compute qMT parametric maps of the whole brain. qMT maps were warped to standard space and smoothed, and subsequently compared between groups. Of all the qMT parameters considered, only the forward exchange rate, RM(0)(B), showed significant group differences. These images were therefore retained for the multimodal statistical analysis, designed to locate brain regions of RM(0)(B) differences between AD and HS groups, adjusting for local GM atrophy. Widespread areas of reduced RM(0)(B) were found in AD patients, mainly located in the hippocampus, in the temporal lobe, in the posterior cingulate and in the parietal cortex. These results indicate that, among qMT parameters, RM(0)(B) is the most sensitive to AD pathology. This quantity is altered in the hippocampus of patients with AD (as found by previous works) but also in other brain areas, that PET studies have highlighted as involved with both, reduced glucose metabolism and amyloid ß deposition. RM(0)(B) might reflect, through the measurement of the efficiency of MT exchange, some information with a specific pathological counterpart. Given previous evidence of a strict relationship between RM(0)(B) and intracellular pH, an intriguing speculation is that our findings might reflect metabolic changes related to mitochondrial dysfunction, which has been proposed as a contributor to neurodegeneration in AD.

Damage to the cingulum contributes to Alzheimer's disease pathophysiology by deafferentation mechanism.

This study investigates the differential contribution of gray matter (GM) atrophy and deafferentation through white matter (WM) damage in the clinical progression of Alzheimer's disease (AD). Thirty-one patients with probable AD, 23 with amnestic mild cognitive impairment (a-MCI), and 14 healthy subjects underwent MRI scanning at 3T. Voxel-based morphometry was used to assess regional GM atrophy in AD and a-MCI patients. Diffusion tensor-MRI tractography was used to reconstruct the cingulum bilaterally, and to quantify, voxel-by-voxel, its fractional anisotropy (FA) and mean diffusivity (MD) (measures of microscopic WM integrity). Atrophy of the cinguli was also assessed by means of jacobian determinants (JD) of local transformations. In AD patients, four clusters of reduced GM were found nearby the cinguli, in the posterior (PCC) and anterior cingulate cortex, and in the hippocampal/parahippocampal areas. Widespread areas of reduced FA and increased MD were found in the cinguli of both, AD and a-MCI patients. A region of macroscopic atrophy was detectable in AD patients only. Strong associations were found between local GM densities in the four identified clusters, and measures of micro- and (to a lesser extent) macroscopic damage of patients' cinguli. Linear regression analyses revealed that MD in the cinguli predicts patients' measures of episodic memory in combination with GM density of hippocampal/parahippocampal areas, and measures of global cognition in combination with GM density of the PCC. This study indicates that brain deafferentation though the cingulum is likely to play a remarkable role in progressive development of cognitive impairment in AD.