Fabrizio De Carli

Quantitative Electroencephalography and Regional Cerebral Blood Flow: Discriminant Analysis between Alzheimer’s Patients and Healthy Controls

Forty-two patients with probable Alzheimer’s disease (AD) and 18 elderly healthy controls underwent quantitative EEG (qEEG) and regional cerebral blood flow (rCBF; 133Xe clearance) examinations. Correlations were sought between relative qEEG band powers and percent rCBF values in a posterior temporoparietal region of interest in either hemisphere. Moreover, stepwise discriminant analysis was applied to study the accuracy of the two techniques in differentiating AD from healthy ageing. rCBF and qEEG were correlated with one another, especially in the right hemisphere (p values ranging from <0.001 to <0.01). Significant correlations were found between Mini Mental State Examination (MMSE) and relative power of both the 2- to 6-Hz and the 6.5- to 12-Hz bands on either side (p < 0.001), and between MMSE and left rCBF (p < 0.005), while the correlation with right rCBF was poorer (p < 0.02). The statistical procedure identified the right values of both examinations for the discriminant analysis. Sensitivity of qEEG and rCBF employed together was 88% and specificity 89%, with a total accuracy of 88.3%. The unrecognized patients (n = 5) were affected by mild AD (4 scoring 3 at the Global Deterioration Scale and 1 scoring 4). qEEG alone showed an accuracy of 77% in the whole group and of 69% in mild AD, and rCBF alone an accuracy of 75% in the whole group and of 71% in mild AD. It is concluded that qEEG and rCBF examinations employed together are accurate tools to differentiate AD from normal ageing, although a lower degree of accuracy is achieved in mildly demented patients.

Quantitative analysis of sleep EEG microstructure in the time-frequency domain.

A number of phasic events influence sleep quality and sleep macrostructure. The detection of arousals and the analysis of cyclic alternating patterns (CAP) support the evaluation of sleep fragmentation and instability. Sixteen polygraphic overnight recordings were visually inspected for conventional Rechtscaffen and Kales scoring, while arousals were detected following the criteria of the American Sleep Disorders Association (ASDA). Three electroencephalograph (EEG) segments were associated to each event, corresponding to background activity, pre-arousal period and arousal. The study was supplemented by the analysis of time-frequency distribution of EEG within each subtype of phase A in the CAP. The arousals were characterized by the increase of alpha and beta power with regard to background. Within NREM sleep most of the arousals were preceded by a transient increase of delta power. The time-frequency evolution of the phase A of the CAP sequence showed a strong prevalence of delta activity during the whole A1, but high amplitude delta waves were found also in the first 2/3 s of A2 and A3, followed by desynchronization. Our results underline the strict relationship between the ASDA arousals, and the subtype A2 and A3 within the CAP: in both the association between a short sequence of transient slow waves and the successive increase of frequency and decrease of amplitude characterizes the arousal response.

Dissociated wake-like and sleep-like electro-cortical activity during sleep.

Sleep is traditionally considered a global process involving the whole brain. However, recent studies have shown that sleep depth is not evenly distributed within the brain. Sleep disorders, such as sleepwalking, also suggest that EEG features of sleep and wakefulness might be simultaneously present in different cerebral regions. In order to probe the coexistence of dissociated (wake-like and sleep-like) electrophysiological behaviors within the sleeping brain, we analyzed intracerebral electroencephalographic activity drawn from sleep recordings of five patients with pharmacoresistant focal epilepsy without sleep disturbances, who underwent pre-surgical intracerebral electroencephalographic investigation. We applied spectral and wavelet transform analysis techniques to electroencephalographic data recorded from scalp and intracerebral electrodes localized within the Motor cortex (Mc) and the dorso-lateral Prefrontal cortex (dlPFc). The Mc showed frequent Local Activations (lasting from 5 to more than 60s) characterized by an abrupt interruption of the sleep electroencephalographic slow waves pattern and by the appearance of a wake-like electroencephalographic high frequency pattern (alpha and/or beta rhythm). Local activations in the Mc were paralleled by a deepening of sleep in other regions, as expressed by the concomitant increase of slow waves in the dlPFc and scalp electroencephalographic recordings. These results suggest that human sleep can be characterized by the coexistence of wake-like and sleep-like electroencephalographic patterns in different cortical areas, supporting the hypothesis that unusual phenomena, such as NREM parasomnias, could result from an imbalance of these two states.

Quantitative EEG Changes in Alzheimer Patients during Long-Term Donepezil Therapy

Twenty patients affected with probable mild-to-moderate Alzheimer’s disease (AD; NINCDS-ADRDA criteria; 14 women and 6 men, mean age 75.2 ± 7.1 years) who regularly received an oral acetylcholinesterase inhibitor (AChEI; donepezil 5 mg/day; Dz group) were compared with a control group of 11 AD patients (6 women and 5 men, mean age 73.5 ± 6.0 years) diagnosed and followed up in the pre-AChEIs era (C group). At basal evaluation (t₀), the 2 groups were comparable for age, education, and severity of disease (Global Deterioration Scale). All patients underwent quantitative EEG (qEEG, average reference, 10–20 International System), and were reexamined about 1 year later (t1; i.e., after 12.3 ± 3.6 months the Dz group, and after 13.7 ± 3.9 months the C group). Log-transformed values of two qEEG bands, i.e. 2–6 and 6.5–12 Hz, were averaged between adjacent channels (frontal F3 and F7, F4 and F8; parietotemporal P3 and T7, P4 and T8) to obtain a qEEG ratio (6.5–12/2–6 Hz.) from one frontal and one temporoparietal region in each hemisphere. Neuropsychological impairment was summarized by the Mini-Mental Status Examination (MMSE). At t₀, both the MMSE score and the qEEG ratio values were somewhat higher in the C than in the Dz group, although nonsignificantly. Between t₀ and t1, the MMSE score decreased significantly (p < 0.01) more in the C group (–4.36 ± 2.25) than in the Dz group (–1.45 ± 2.16), as did the qEEG ratio in the right frontal region (p < 0.01), whereas in the left frontal region the significance level was not reached (p = 0.02). Between t₀ and t1, the qEEG ratio difference in both frontal regions and in the right temporoparietal region significantly correlated with the MMSE difference (p < 0.01), but neither with time between examinations nor with the difference on the Visual Search Test score. Long-term treatment with Dz led to a lesser deterioration of qEEG, paralleling a milder neuropsychological decline. The effect was significant in frontal regions, possibly because they are relatively spared during the mild-to-moderate phases of the disease.

Functional pattern of brain FDG-PET in amyotrophic lateral sclerosis

Objective: We investigated a large sample of patients with amyotrophic lateral sclerosis (ALS) at rest in order to assess the value of 18F-2-fluoro-2-deoxy-d-glucose (18F-FDG) PET as a biomarker to discriminate patients from controls. Methods: A total of 195 patients with ALS and 40 controls underwent brain 18F-FDG-PET, most within 5 months of diagnosis. Spinal and bulbar subgroups of ALS were also investigated. Twenty-five bilateral cortical and subcortical volumes of interest and cerebellum were taken into account, and 18F-FDG uptakes were individually normalized by whole-brain values. Group analyses investigated the ALS-related metabolic changes. Discriminant analysis investigating sensitivity and specificity was performed using the 51 volumes of interest as well as age and sex. Metabolic connectivity was explored by voxel-wise interregional correlation analysis. Results: Hypometabolism was found in frontal, motor, and occipital cortex and hypermetabolism in midbrain, temporal pole, and hippocampus in patients with ALS compared to controls. A similar metabolic pattern was also found in the 2 subgroups. Discriminant analysis showed a sensitivity of 95% and a specificity of 83% in separating patients from controls. Connectivity analysis found a highly significant positive correlation between midbrain and white matter in corticospinal tracts in patients with ALS. Conclusions: 18F-FDG distribution changes in ALS showed a clear pattern of hypometabolism in frontal and occipital cortex and hypermetabolism in midbrain. The latter might be interpreted as the neurobiological correlate of diffuse subcortical gliosis. Discriminant analysis resulted in high sensitivity and specificity in differentiating patients with ALS from controls. Once validated by diseased-control studies, the present methodology might represent a potentially useful biomarker for ALS diagnosis. Classificaton of evidence: This study provides Class III evidence that 18F-FDG-PET accurately distinguishes patients with ALS from normal controls (sensitivity 95.4%, specificity 82.5%).

CAP and arousals are involved in the homeostatic and ultradian sleep processes

There is growing evidence that cyclic alternating pattern (CAP) and arousals are woven into the basic mechanisms of sleep regulation. In the present study, the overnight sleep cycles (SC) of 20 normal subjects were analyzed according to their stage composition, CAP rate, phase A subtypes and arousals. Individual SC were then divided into 10 normalized temporal epochs. CAP parameters and arousals were measured in each epoch and averaged in relation to the SC order. Subtypes A2 and A3 of CAP in non‐rapid eye movement (NREM) sleep, and arousals, both in REM and NREM sleep when not coincident with a A2 or A3 phases, were lumped together as fast electroencephalographic (EEG) activities (FA). Subtypes A1 of CAP, characterized by slow EEG activities (SA), were analyzed separately. The time distribution of SA and FA was compared to the mathematical model of normal sleep structure including functions representing the homeostatic process S, the circadian process C, the ultradian process generating NREM/REM cycles and the slow wave activity (SWA) resulting from the interaction between homeostatic and ultradian processes. The relationship between SA and FA and the sleep‐model components was evaluated by multiple regression analysis in which SA and FA were considered as dependent variables while the covariates were the process S, process C, SWA, REM‐on and REM‐off activities and their squared values. Regression was highly significant (P < 0.0001) for both SA and FA. SA were prevalent in the first three SC, and exhibited single or multiple peaks immediately before and in the final part of deep sleep (stages 3 + 4). The peaks of FA were delayed and prevailed during the pre‐REM periods of light sleep (stages 1 + 2) and during REM sleep. SA showed an exponential decline across the successive SC, according to the homeostatic process. In contrast, the distribution of FA was not influenced by the order of SC, with periodic peaks of FA occurring before the onset of REM sleep, in accordance with the REM‐on switch. The dynamics of CAP and arousals during sleep can be viewed as an intermediate level between cellular activities and macroscale EEG phenomena as they reflect the decay of the homeostatic process and the interaction between REM‐off and REM‐on mechanisms while are slightly influenced by circadian rhythm.

Brain SPECT in subtypes of mild cognitive impairment Findings from the DESCRIPA multicenter study

The Development of Screening Guidelines and Clinical Criteria of Predementia Alzheimer’s Disease (DESCRIPA) multicenter study enrolled patients with MCI or subjective cognitive complaints (SUBJ), a part of whom underwent optional brain perfusion SPECT. These patients were classified as SUBJ (n = 23), nonamnestic MCI (naMCI; n = 17) and amnestic MCI (aMCI; n = 40) based on neuropsychology. Twenty healthy subjects formed the control (CTR) group. Volumetric regions of interest (VROI) analysis was performed in six associative cortical areas in each hemisphere. ANOVA for repeated measures, corrected for age and center, showed significant differences between groups (p = 0.01) and VROI (p < 0.0001) with a significant group-region interaction (p = 0.029). In the post hoc comparison, SUBJ did not differ from CTR. aMCI disclosed reduced uptake in the left hippocampus and bilateral temporal cortex (compared with CTR) or in the left hippocampus and bilateral parietal cortex (compared with SUBJ). In the naMCI group, reduced VROI values were found in the bilateral temporal cortex and right frontal cortex. In the comparison between aMCI and naMCI, the former had lower values in the left parietal cortex and precuneus. Discriminant analysis between SUBJ/CTR versus all MCI patients allowed correct allocations in 73 % of cases. Mean VROI values were highly correlated (p < 0.0001) with the learning measure of a verbal memory test, especially in the bilateral precunei and parietal cortex and in the left hippocampus. In a subset of 70 patients, mean VROI values showed a significant correlation (p < 0.05) with the white matter hyperintensities score on MRI. In conclusion, MCI subtypes have different perfusion patterns. The aMCI group exhibited a pattern that is typical of early Alzheimer’s disease, while the naMCI group showed a more anterior pattern of hypoperfusion. Instead, a homogeneous group effect was lacking in SUBJ.

Local aspects of sleep: observations from intracerebral recordings in humans.

Human sleep is considered a global phenomenon, orchestrated by central specialized neuronal networks modulating the whole-brain activity. However, recent studies point to a local regulation of sleep. Sleep disorders, such as sleepwalking, suggest that electroencephalographic (EEG) features of sleep and wakefulness might be simultaneously present in different cerebral regions. Recently, intracranial EEG recording techniques, mainly applied for the presurgical evaluation of drug-resistant epileptic patients, have provided new and interesting information on the activity of different cortical and subcortical structures during sleep in humans. In particular, it has been observed that the thalamus, during the transition between wake and sleep undergoes a deactivation process that precedes the one occurring within the cortex, with extensive cortical territories maintaining an activated pattern for several minutes after the thalamic deactivation. Very recent intracerebral EEG studies have also shown that human NREM sleep can be characterized by the coexistence of wake-like and sleep-like EEG patterns in different cortical areas. Moreover, unit-firing recordings in multiple brain regions of neurosurgical patients evidenced that most sleep slow waves and the underlying active and inactive neuronal states do occur locally. These findings add a new dimension to the concept of local sleep regulation and opens new perspectives in the interpretation of the substrates underlying behavioral states of vigilance. The implications for sleep medicine are also discussed.

Cognitive-Nigrostriatal Relationships in De Novo, Drug-Naïve Parkinson's Disease Patients: A [I-123]FP-CIT SPECT Study

To unveil cognitive‐nigrostriatal correlations in Parkinsons disease (PD), 30 de novo, drug‐naïve PD patients and 15 patients with essential tremor (Controls, CTR) underwent a neuropsychological (NPS) battery and brain SPECT with [I‐123]Ioflupane, as a biomarker of nigrostriatal function. Automatic extraction of uptake at caudate and putamen level was conducted through the BasGan software, also allowing partial volume effect correction. Because of the multicollinearity among neuropsychological tests and among SPECT variables, factor analysis was applied to 16 neuropsychological scores; moreover, the four SPECT variables were merged into a mean SPECT value (mSPECT). Factor analysis identified four NPS factors: a dys‐executive (NPS‐EX), a visuospatial (NPS‐VS), a verbal memory (NPS‐VM), and a “mixed” (NPD‐MIX) factor. In PD group, there were inverse correlations between UPDRS‐III score and both NPS‐VS (P < 0.01) and mSPECT (P < 0.05), and a direct correlation between mSPECT and NPS‐EX (P < 0.05). Post hoc analysis showed a direct correlation between NPS‐EX and caudate uptake in both hemispheres (P < 0.05). Moreover, inverse correlations were found between UPDRS‐III and, respectively, putamen uptake in the less affected hemisphere (P < 0.01), and putamen and caudate uptake in the more affected hemisphere (P < 0.05). In CTR, no correlation was found between mSPECT and either NPS or GDS values. Nigro‐caudate function affects executive capabilities in PD but not in CTR, which appears to be unrelated to the disease motor severity at its onset. Instead, PD motor severity is related to nigro‐putaminal impairment and visuospatial dysfunction. The role of these data as predictive features of cognitive decline and eventually dementia remains to be established in longitudinal studies.

Sleep in the human hippocampus: a stereo-EEG study.

Background There is compelling evidence indicating that sleep plays a crucial role in the consolidation of new declarative, hippocampus-dependent memories. Given the increasing interest in the spatiotemporal relationships between cortical and hippocampal activity during sleep, this study aimed to shed more light on the basic features of human sleep in the hippocampus. Methodology/Principal Findings We recorded intracerebral stereo-EEG directly from the hippocampus and neocortical sites in five epileptic patients undergoing presurgical evaluations. The time course of classical EEG frequency bands during the first three NREM-REM sleep cycles of the night was evaluated. We found that delta power shows, also in the hippocampus, the progressive decrease across sleep cycles, indicating that a form of homeostatic regulation of delta activity is present also in this subcortical structure. Hippocampal sleep was also characterized by: i) a lower relative power in the slow oscillation range during NREM sleep compared to the scalp EEG; ii) a flattening of the time course of the very low frequencies (up to 1 Hz) across sleep cycles, with relatively high levels of power even during REM sleep; iii) a decrease of power in the beta band during REM sleep, at odds with the typical increase of power in the cortical recordings. Conclusions/Significance Our data imply that cortical slow oscillation is attenuated in the hippocampal structures during NREM sleep. The most peculiar feature of hippocampal sleep is the increased synchronization of the EEG rhythms during REM periods. This state of resonance may have a supportive role for the processing/consolidation of memory.