Francesca Ursini

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 Alzheimers 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 Alzheimers 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. Hum Brain Mapp, 2013.

Hyperhomocysteinemia, intima-media thickness and C677T MTHFR gene polymorphism: A correlation study in patients with cognitive impairment

OBJECTIVE Intima-media thickness (IMT) seems associated with risk of Alzheimer disease (AD). Homocysteine (hcy) is a risk factor for vascular diseases and dementia. This study aimed at investigating the possible relationship among IMT, plasma hcy and C677T methylentetrahydrofolate reductase (MTHFR) polymorphism in relation to cognitive status. METHODS Sixty-three patients with cognitive impairment and 64 controls underwent biochemical, neuropsychological and carotid ultrasound assessment. RESULTS After age and folate adjustment, plasma hcy correlated with both Mini Mental State Examination (MMSE) score (r=-0.7, p<0.01) and IMT (r=0.7, p<0.01). Among patients with cognitive impairment, carriers of TT677 MTHFR genotype had plasma hcy (p<0.001) and IMT (p<0.01) values higher than non carriers. Furthermore, multiple regression analysis showed that MMSE scores were associated with plasma hcy (beta=-0.3, p=0.01), IMT (beta=-0.3, p=0.01) and TT677 MTHFR genotype (beta=-0.3, p=0.02). Structural equation modelling showed that the relation between hcy levels and MMSE score was partly direct (parameter estimate=-0.6; p=0.01) and partly mediated by IMT values (parameter estimate=-0.4; p=0.03). Finally, IMT resulted associated with hypertension (parameter estimate=0.8; p<0.0001). CONCLUSION Our findings suggest that TT677 MTHFR genotype promotes plasma homocysteine increase which in turn may favour intima-media thickening in patients with cognitive impairment. Hcy may promote neuronal damage through multiple mechanisms, including a micro-vascular damage, mediated by IMT increase, and a direct neuro-toxic effect.

Motor cortex excitability in Alzheimer's disease: a transcranial magnetic stimulation follow-up study

Transient cognitive and behavioral stabilization of patients with Alzheimers disease (AD) is the main goal of acetylcholinesterase inhibitor (AChEI) therapy. Response to treatment is variable and it is usually assessed clinically via neuropsychological scales. Functional neuroimaging could ideally permit the objective evaluation of the topographic correlates of therapy on brain functioning, but is expensive and little available on a large scale. On the other hand, neurophysiological methods such as transcranial magnetic stimulation (TMS) could offer an alternative, low-cost and risk free tool of assessing response to treatment in AD. Previous TMS studies have demonstrated hyperexcitability and asymptomatic motor cortex reorganization in the early stages of AD in patients with normal motor function. The aim of this study was to compare motor cortex functionality in 10 AD patients before and after long-term AchEIs therapy in order to monitor potential drug-related changes in cortical excitability and organization. Examined parameters of motor cortex physiology were found to be unchanged in patients with stabilized cognitive performance during the therapy. TMS, along with clinical, neuropsychological, and neuroimaging data, could be an inexpensive measure of biological progression in AD and it might supplement traditional methods to assess the effects of therapy.

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

Cortical sources of resting state electroencephalographic (EEG) rhythms are abnormal in subjects with Alzheimers disease (AD). Here we tested the hypothesis that these sources are also sensitive to the progression of early stage AD over the course of one year. The resting state eyes-closed EEG data were recorded in 88 mild AD patients at baseline (Mini Mental State Evaluation, MMSE I = 21.7 ± 0.2 standard error, SE) and at approximately one-year follow up (13.3 months ± 0.5 SE; MMSE II = 20 ± 0.4 SE). All patients received standard therapy with acetylcholinesterase inhibitors. EEG recordings were also performed in 35 normal elderly (Nold) subjects as controls. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz). Cortical EEG sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Compared to the Nold subjects, the mild AD patients were characterized by a power increase of widespread delta sources and by a power decrease of posterior alpha sources. In the mild AD patients, the follow-up EEG recordings showed increased power of widespread delta sources as well as decreased power of widespread alpha and posterior beta 1 sources. These results suggest that the resting state EEG sources were sensitive, at least at group level, to the cognitive decline occurring in the mild AD group over a one-year period, and might represent cost-effective and non-invasive markers with which to enrich cohorts of AD patients that decline faster for clinical studies.

Transcranial Magnetic Stimulation Studies in Alzheimer's Disease

Although motor deficits affect patients with Alzheimers disease (AD) only at later stages, recent studies demonstrated that primary motor cortex is precociously affected by neuronal degeneration. It is conceivable that neuronal loss is compensated by reorganization of the neural circuitries, thereby maintaining motor performances in daily living. Effectively several transcranial magnetic stimulation (TMS) studies have demonstrated that cortical excitability is enhanced in AD and primary motor cortex presents functional reorganization. Although the best hypothesis for the pathogenesis of AD remains the degeneration of cholinergic neurons in specific regions of the basal forebrain, the application of specific TMS protocols pointed out a role of other neurotransmitters. The present paper provides a perspective of the TMS techniques used to study neurophysiological aspects of AD showing also that, based on different patterns of cortical excitability, TMS may be useful in discriminating between physiological and pathological brain aging at least at the group level. Moreover repetitive TMS might become useful in the rehabilitation of AD patients. Finally integrated approaches utilizing TMS together with others neuro-physiological techniques, such as high-density EEG, and structural and functional imaging as well as biological markers are proposed as promising tool for large-scale, low-cost, and noninvasive evaluation of at-risk populations.

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

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

Sensorimotor cortex excitability and connectivity in Alzheimer's disease: A TMS-EEG Co-registration study.

Several studies have shown that, in spite of the fact that motor symptoms manifest late in the course of Alzheimers disease (AD), neuropathological progression in the motor cortex parallels that in other brain areas generally considered more specific targets of the neurodegenerative process. It has been suggested that motor cortex excitability is enhanced in AD from the early stages, and that this is related to diseases severity and progression. To investigate the neurophysiological hallmarks of motor cortex functionality in early AD we combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). We demonstrated that in mild AD the sensorimotor system is hyperexcitable, despite the lack of clinically evident motor manifestations. This phenomenon causes a stronger response to stimulation in a specific time window, possibly due to locally acting reinforcing circuits, while network activity and connectivity is reduced. These changes could be interpreted as a compensatory mechanism allowing for the preservation of sensorimotor programming and execution over a long period of time, regardless of the diseases progression. Hum Brain Mapp 37:2083–2096, 2016.

Intronic rs2147363 Variant in ATP7B Transcription Factor-Binding Site Associated with Alzheimer's Disease

Copper homeostasis abnormalities have been shown to be associated with Alzheimers disease (AD), possibly by accelerating amyloid-β toxicity and plaque formation. The ATP7B gene plays a key role in controlling body copper balance. Our previous studies showed an association between ATP7B variants and AD risk. Among these variants, an intronic single nucleotide polymorphism, rs2147363, was associated with AD risk. In order to understand this intronic association, we screened a population of 286 AD patients and 283 healthy controls, and verified the presence of other functional coding variants in linkage disequilibrium (LD). Then we searched for a regulatory function region close to rs2147363. An LD analysis revealed the presence of an LD between rs2147363 and a Wilsons disease-causing variant, rs7334118. However, this mutation did not explain the observed genetic association. Conversely, in silico analyses of rs2147363 functionality highlighted that this variant is located in a binding site of a transcription factor, and is, consequently, associated with regulatory function. These data suggest that the genetic variation in cis-regulatory elements located in non-coding regions can have a role in determining ATP7B functionality and account for some of the AD missing hereditability.

Regional MRI Diffusion, White-Matter Hyperintensities, and Cognitive Function in Alzheimer's Disease and Vascular Dementia

Background and Purpose An increase in brain water diffusivity as measured using magnetic resonance imaging (MRI) has been recently reported in normal-appearing white matter (NAWM) in patients affected by cognitive impairment. However, it remains to be clarified if this reflects an overt neuronal tissue disruption that leads to degenerative or microvascular lesions. This question was addressed by comparing the regional MRI apparent diffusion coefficients (ADCs) of NAWM in patients affected by Alzheimers disease (AD) or vascular dementia (VaD). The relationships of ADCs with the white-matter hyperintensity (WMH) burden, carotid atherosclerosis, and cognitive performance were also investigated. Methods Forty-nine AD and 31 VaD patients underwent brain MRI to assess the WMH volume and regional NAWM ADCs, neuropsychological evaluations, and carotid ultrasound to assess the plaque severity and intima-media thickness (IMT). Results Regional ADCs in NAWM did not differ between VaD and AD patients, while the WMH volume was greater in VaD than in AD patients. The ADC in the anterior corpus callosum was related to the WMH volume, while a greater carotid IMT was positively correlated with the temporal ADC and WMH volume. The memory performance was worse in patients with higher temporal ADCs. Constructional praxis scores were related to ADCs in the frontal, and occipital lobes, in the anterior and posterior corpus callosum as well as to the WMH volume. Abstract reasoning was related to frontal, parietal, and temporal ADCs. Conclusions Our data show that higher regional ADCs in NAWM are associated with microcirculatory impairment, as depicted by the WMH volume. Moreover, regional ADCs in NAWM are differently associated with the neuropsychological performances in memory, constructional praxia, and abstract reasoning domains.

Global functional coupling of resting EEG rhythms is abnormal in mild cognitive impairment and Alzheimer's disease: A multicenter EEG study

Alzheimer’s disease (AD) is typically associated with an impairment of brain networks and global cognitive function in aging. In this vein, the present study tested the hypothesis that the functional coupling of resting cortical electroencephalographic (EEG) rhythms is progressively abnormal in amnesic mild cognitive impairment (MCI) and AD subjects. Eyes-closed resting EEG data were recorded (10–20 system) in 33 mild AD, 52 amnesic MCI, and 47 normal elderly subjects (Nold). EEG rhythms of interest were delta (2–4 Hz), theta (4–8 Hz), alpha1 (8–10 Hz), alpha2 (10–13 Hz), beta1 (13–20 Hz), beta2 (20–30 Hz), and gamma (30–40 Hz). The global functional coupling of the EEG rhythms was indexed by means of spectral coherence for all combinations of electrode pairs (i.e., total coherence). The main results showed that the total coherence of delta rhythms was higher in the AD than the MCI group. It was also higher in the MCI than the Nold group. Furthermore, the delta total coherence was negatively correlated wi...