Federica Scrascia

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.

Association between the c. 2495 A>G ATP7B Polymorphism and Sporadic Alzheimer's Disease

Nonceruloplasmin-bound copper (“free”) is reported to be elevated in Alzheimers disease (AD). In Wilsons disease (WD) Cu-ATPase 7B protein tightly controls free copper body levels. To explore whether the ATP7B gene harbours susceptibility loci for AD, we screened 180 AD chromosomes for sequence changes in exons 2, 5, 8, 10, 14, and 16, where most of the Mediterranean WD-causing mutations lie. No WD mutation, but sequence changes corresponding to c.1216 T>G Single-Nucleotide Polymorphism (SNP) and c.2495 A>G SNP were found. Thereafter, we genotyped 190 AD patients and 164 controls for these SNPs frequencies estimation. Logistic regression analyses revealed either a trend for the c.1216 SNP (P = .074) or a higher frequency for c.2495 SNP of the GG genotype in patients, increasing the probability of AD by 74% (P = .028). Presence of the GG genotype in ATP7B c.2495 could account for copper dysfunction in AD which has been shown to raise the probability of the disease.

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.

Alpha and beta EEG power reflects L-dopa acute administration in parkinsonian patients

Aim: To evaluate the effect of an acute L-dopa administration on eye-closed resting state electroencephalographic (EEG) activity of cognitively preserved Parkinsonian patients. Methods: We examined 24 right-handed patients diagnosed as uncomplicated probable Parkinson’s disease (PD). Each patient underwent Unified Parkinson’s Disease Rating Scale (UPDRS)-part-III evaluation before and 60 min after an oral load of L-dopa-methyl-ester/carbidopa 250/25 mg. Resting condition eyes-closed EEG data were recorded both pre- and post L-dopa load. Absolute EEG power values were calculated at each scalp derivation for Delta, Theta, Alpha and Beta frequency bands. UPDRS scores (both global and subscale scores) and EEG data (power values of different frequency bands for each scalp derivation) were submitted to a statistical analysis to compare Pre and Post L-Dopa conditions. Finally, a correlation analysis was carried out between EEG spectral content and UPDRS scores. Results: Considering EEG power spectral analysis, no statistically significant differences arose on Delta and Theta bands after L-dopa intake. Conversely, Alpha and Beta rhythms significantly increased on centro-parietal scalp derivations, as a function of L-dopa administration. Correlation analysis indicated a significant negative correlation between Beta power increase on centro-parietal areas and UPDRS subscores (Rigidity of arms and Bradykinesia). A minor significant negative correlation was also found between Alpha band increase and resting tremor. Conclusions: Assuming that a significant change in EEG power spectrum after L-dopa intake may be related to dopaminergic mechanisms, our findings are consistent with the hypothesis that dopaminergic defective networks are implicated in cortical oscillatory abnormalities at rest in non-demented PD patients.

An improved I-FAST system for the diagnosis of Alzheimer's disease from unprocessed electroencephalograms by using robust invariant features

OBJECTIVE This paper proposes a new, complex algorithm for the blind classification of the original electroencephalogram (EEG) tracing of each subject, without any preliminary pre-processing. The medical need in this field is to reach an early differential diagnosis between subjects affected by mild cognitive impairment (MCI), early Alzheimers disease (AD) and the healthy elderly (CTR) using only the recording and the analysis of few minutes of their EEG. METHODS AND MATERIAL This study analyzed the EEGs of 272 subjects, recorded at Romes Neurology Unit of the Policlinico Campus Bio-Medico. The EEG recordings were performed using 19 electrodes, in a 0.3-70Hz bandpass, positioned according to the International 10-20 System. Many powerful learning machines and algorithms have been proposed during the last 20 years to effectively resolve this complex problem, resulting in different and interesting outcomes. Among these algorithms, a new artificial adaptive system, named implicit function as squashing time (I-FAST), is able to diagnose, with high accuracy, a few minutes of the subjects EEG track; whether it manifests an AD, MCI or CTR condition. An updating of this system, carried out by adding a new algorithm, named multi scale ranked organizing maps (MS-ROM), to the I-FAST system, is presented, in order to classify with greater accuracy the unprocessed EEGs of AD, MCI and control subjects. RESULTS The proposed system has been measured on three independent pattern recognition tasks from unprocessed EEG tracks of a sample of AD subjects, MCI subjects and CTR: (a) AD compared with CTR; (b) AD compared with MCI; (c) CTR compared with MCI. While the values of accuracy of the previous system in distinguishing between AD and MCI were around 92%, the new proposed system reaches values between 94% and 98%. Similarly, the overall accuracy with best artificial neural networks (ANNs) is 98.25% for the distinguishing between CTR and MCI. CONCLUSIONS This new version of I-FAST makes different steps forward: (a) avoidance of pre-processing phase and filtering procedure of EEG data, being the algorithm able to directly process an unprocessed EEG; (b) noise elimination, through the use of a training variant with input selection and testing system, based on naïve Bayes classifier; (c) a more robust classification phase, showing the stability of results on nine well known learning machine algorithms; (d) extraction of spatial invariants of an EEG signal using, in addition to the unsupervised ANN, the principal component analysis and the multi scale entropy, together with the MS-ROM; a more accurate performance in this specific task.

The Italian Alzheimer's Disease Neuroimaging Initiative (I-ADNI): Validation of Structural MR Imaging

BACKGROUND The North American Alzheimers Disease Neuroimaging Initiative (NA-ADNI) was the first program to develop standardized procedures for Alzheimers disease (AD) imaging biomarker collection. OBJECTIVE We describe the validation of acquisition and processing of structural magnetic resonance imaging (MRI) in different Italian academic AD clinics following NA-ADNI procedures. METHODS 373 patients with subjective memory impairment (n = 12), mild cognitive impairment (n = 92), Alzheimers dementia (n = 253), and frontotemporal dementia (n = 16) were enrolled in 9 Italian centers. 22 cognitively healthy elderly controls were also included. MRI site qualification and MP-RAGE quality assessment was applied following the NA-ADNI procedures. Indices of validity were: (i) NA-ADNI phantoms signal-to-noise and contrast-to-noise ratio, (ii) proportion of images passing quality control, (iii) comparability of automated intracranial volume (ICV) estimates across scanners, and (iv) known-group validity of manual hippocampal volumetry. RESULTS Results on Phantom and Volunteers scans showed that I-ADNI acquisition parameters were comparable with those one of the ranked-A ADNI scans. Eighty-seven percent of I-ADNI MPRAGE images were ranked of high quality in comparison of 69% of NA-ADNI. ICV showed homogeneous variances across scanners except for Siemens scanners at 3.0 Tesla (p = 0.039). A significant difference in hippocampal volume was found between AD and controls on 1.5 Tesla scans (p < 0.001), confirming known group validity test. CONCLUSION This study has provided standardization of MRI acquisition and imaging marker collection across different Italian clinical units and equipment. This is a mandatory step to the implementation of imaging biomarkers in clinical routine for early and differential diagnosis.

Dyskinesias during levodopa–carbidopa intestinal gel (LCIG) infusion: Management inclinical practice

The continuous levodopaecarbidopa intestinal gel (LCIG) infusion is a valid alternative for motor control in advanced Parkinsons disease (PD). It has been demonstrated to improve motor fluctuation with a global increase in ON-time, generally without the outbreak of troublesome hyperkinesias [1]. However both peakdose and biphasic dyskinesias are observed in patients undergoing LCIG treatment. Here is reported our experience with a PD patient, whose LCIG treatment was challenged by the outbreak of peculiar dyskinesiasfollowingthe PEG-J-tube bedtime flushing. A 73 yearsold woman was affected by advanced PD with motor fluctuations. Because of her extreme susceptibility to develop dyskinesias even with very small doses of levodopa (otherwise defined as “brittle response” [2]), the maximum acceptable oral treatment was of 475 mg fractionated in 9 small doses a day. APEG-J was inserted and LCIG therapy was started in order to obtain a lower and more stable therapeutic regimen. A significant reduction of the OFFperiods and of the dyskinesias were obtained through a LCIG titration of the morning dose to1.5 ml (30 mg of levodopa), of the continuous dose to 1.0 ml (20 mg) per hour per 16 h a day (total dose of 350mg) and of the extra-doses to 1.0 ml (20mg). Nevertheless, at the end of the daily treatment, the mandatory operation of flushing the PEG-J-tube after pump disconnection [3] resulted in stereotypical violent peak-dose choreo-dystonic hyperkinesias that required patient protections to prevent disastrous falls. The tube cleaning led to the immediate delivery of the 3 ml (60 mg) of levodopa-gel contained in the device. Unfortunately the patient was highly sensitive to levodopa; so much that extra-doses have to be set at 1 ml (20mg) per dose. LCIG pump turning off may result in biphasic dyskinesias due to the incipient discontinuation of the levodopa effect; in this case the simple interruption of the infusion did not lead to any dyskinesia contrary to what was observed after bedtime tube cleaning. In fact through the flushing the patient received extra 60 mg of levodopa gel, that is three times the dose needed to overcome OFF-period, resulting in violent peak-dose dyskinesias. Levodopa gel is contained in a reservoir bag inside a hard plastic cassette. A used reservoir bag was cleaned out from residual gel through a solution of diluted ethyl alcohol delivered through a syringe connected to the cassette tube, and later rinsed with room temperature tap water. Then, the cassette was connected to the tube and the water was administered at usual maintenance dose (1 ml/h), so that it could slowly push the column of levodopa gel contained in the tube. After 3 h, water completely replaced the gel in the tube, and cleaning operations could be easily performed without the risk of delivering a high bolus of levodopa

Relationship among Diffusion Tensor Imaging, EEG Activity, and Cognitive Status in Mild Cognitive Impairment and Alzheimer's Disease Patients

Magnetic resonance (MR) diffusion tensor imaging (DTI) can detect microstructural alterations by means of fractional anisotropy (FA) in patients with dementia, also in relation to cognitive status. The present study aimed at investigating the possible relation among white matter damage in DTI, quantitative electroencephalography (EEG) spectral power, and cognitive status in Alzheimers disease (AD) and mild cognitive impairment (MCI) patients. Forty-seven subjects (8 moderate AD, 18 mild AD, 12 MCI, and 9 healthy controls) underwent brain MR, neuropsychological evaluation, and resting EEG recording. A progressive increase of EEG delta and theta spectral power was observed from controls to patients, mainly in more anterior areas, with a parallel widespread decrease of beta power. Moreover, a progressive decrease of FA from controls to patients in frontal areas and in the corpus callosum (genu) was observed. Correlation analyses indicated convergence among EEG rhythms changes, DTI values, and cognitive status mainly over anterior areas. The decrease of FA values and EEG spectral power changes might represent markers of neurodegenerative dysfunction, possibly preceding macrostructural atrophy.

Dorsolateral medullary ischemic infarction causing autonomic dysfunction and headache: a case report

Stroke can present, among other signs, with headache. Here, we describe the case of a man suffering from severe orbitary pain and autonomic dysfunction secondary to dorsolateral medullary ischemia. The anatomical relationship between lesion and symptomatology could be an indirect sign of hypothalamospinal tract involvement in the genesis of autonomic dysfunction and headache resembling a trigeminal autonomic cephalalgia.