Elissaios Karageorgiou

Synchronous neural interactions assessed by magnetoencephalography: a functional biomarker for brain disorders

We report on a test to assess the dynamic brain function at high temporal resolution using magnetoencephalography (MEG). The essence of the test is the measurement of the dynamic synchronous neural interactions, an essential aspect of the brain function. MEG signals were recorded from 248 axial gradiometers while 142 human subjects fixated a spot of light for 45-60 s. After fitting an autoregressive integrative moving average (ARIMA) model and taking the stationary residuals, all pairwise, zero-lag, partial cross-correlations (PCC(ij)(0)) and their z-transforms (z(ij)(0)) between i and j sensors were calculated, providing estimates of the strength and sign (positive, negative) of direct synchronous coupling at 1 ms temporal resolution. We found that subsets of z(ij)(0) successfully classified individual subjects to their respective groups (multiple sclerosis, Alzheimers disease, schizophrenia, Sjögrens syndrome, chronic alcoholism, facial pain, healthy controls) and gave excellent external cross-validation results.

Frontotemporal Lobar Degeneration: A Clinical Approach

In this review, the authors outline a clinical approach to frontotemporal lobar degeneration (FTLD), a term coined to describe a pathology associated with atrophy of the frontal and temporal lobes commonly seen with abnormal protein aggregates. It accounts for ∼10% of pathologically confirmed dementias. The three clinical syndromes associated with FTLD are jointly classified as frontotemporal dementia (FTD) and include behavioral variant frontotemporal dementia (bvFTD), nonfluent-agrammatic primary progressive aphasia (nfvPPA), and semantic variant PPA (svPPA; left: l-svPPA and right: r-svPPA). All syndromes have differential impairment in behavioral (bvFTD; r-svPPA), executive (bvFTD; nfvPPA), and language (nfvPPA; svPPA) functions early in the disease course. With all three there is relative sparing of short-term memory and visuospatial abilities early on, and with the two language syndromes, nfvPPA and svPPA, behavior is also intact. Symptoms are associated with specific atrophy patterns, lending unique imaging signatures to each syndrome (frontal: bvFTD and nfvPPA; temporal: svPPA). Common proteinopathies involve accumulation of tau, transactive response DNA binding protein 43, and fusion in sarcoma protein. Parkinsonism presents in all syndromes, especially cases with tau pathology and MAPT or GRN mutations. nfvPPA often has corticobasal degeneration or progressive supranuclear palsy as the underlying neuropathological substrate. bvFTD co-occurs with motor neuron disease in ∼15% of cases, and many such cases are due to C9Orf72 mutations. Other common genetic mutations in FTLD involve GRN and MAPT. Behavioral symptoms are best managed by selective serotonin reuptake inhibitors, while atypical antipsychotics should be used with caution given side effects. Promising etiologic treatments include anti-tau antibodies, antisense oligonucleotides, and progranulin enhancers.

Neuropsychological testing and structural magnetic resonance imaging as diagnostic biomarkers early in the course of schizophrenia and related psychoses

Making an accurate diagnosis of schizophrenia and related psychoses early in the course of the disease is important for initiating treatment and counseling patients and families. In this study, we developed classification models for early disease diagnosis using structural MRI (sMRI) and neuropsychological (NP) testing. We used sMRI measurements and NP test results from 28 patients with recent-onset schizophrenia and 47 healthy subjects, drawn from the larger sample of the Mind Clinical Imaging Consortium. We developed diagnostic models based on Linear Discriminant Analysis (LDA) following two approaches; namely, (a) stepwise (STP) LDA on the original measurements, and (b) LDA on variables created through Principal Component Analysis (PCA) and selected using the Humphrey-Ilgen parallel analysis. Error estimation of the modeling algorithms was evaluated by leave-one-out external cross-validation. These analyses were performed on sMRI and NP variables separately and in combination. The following classification accuracy was obtained for different variables and modeling algorithms. sMRI only: (a) STP-LDA: 64.3% sensitivity and 76.6% specificity, (b) PCA-LDA: 67.9% sensitivity and 72.3% specificity. NP only: (a) STP-LDA: 71.4% sensitivity and 80.9% specificity, (b) PCA-LDA: 78.5% sensitivity and 91.5% specificity. Combined sMRI-NP: (a) STP-LDA: 64.3% sensitivity and 83.0% specificity, (b) PCA-LDA: 89.3% sensitivity and 93.6% specificity. (i) Maximal diagnostic accuracy was achieved by combining sMRI and NP variables. (ii) NP variables were more informative than sMRI, indicating that cognitive deficits can be detected earlier than volumetric structural abnormalities. (iii) PCA-LDA yielded more accurate classification than STP-LDA. As these sMRI and NP tests are widely available, they can increase accuracy of early intervention strategies and possibly be used in evaluating treatment response.

Brain rhythm attractor breakdown in Alzheimer's disease: Functional and pathologic implications

This perspective binds emerging evidence on the bidirectional relationship between Alzheimers disease (AD) and sleep disorders through a model of brain rhythm attractor breakdown. This approach explains behavioral‐cognitive changes in AD across the sleep‐wake cycle and supports a causal association between early brainstem tau pathology and subsequent cortical amyloid β accumulation. Specifically, early tau dysregulation within brainstem‐hypothalamic nuclei leads to breakdown of sleep‐wake attractor networks, with patients displaying an attenuated range of behavioral and electrophysiological activity patterns, a “twilight zone” of constant activity between deep rest and full alertness. This constant cortical activity promotes activity‐dependent amyloid β accumulation in brain areas that modulate their activity across sleep‐wake states, especially the medial prefrontal cortex. In addition, the accompanying breakdown of hippocampal–medial prefrontal cortex interplay across sleep stages could explain deficient memory consolidation through dysregulation of synaptic plasticity. Clinical implications include the potential therapeutic benefit of attractor consolidation (e.g., slow‐wave sleep enhancers) in delaying AD progression.

Canonical correlation analysis of synchronous neural interactions and cognitive deficits in Alzheimer's dementia

In previous work (Georgopoulos et al 2007 J. Neural Eng. 4 349-55) we reported on the use of magnetoencephalographic (MEG) synchronous neural interactions (SNI) as a functional biomarker in Alzheimers dementia (AD) diagnosis. Here we report on the application of canonical correlation analysis to investigate the relations between SNI and cognitive neuropsychological (NP) domains in AD patients. First, we performed individual correlations between each SNI and each NP, which provided an initial link between SNI and specific cognitive tests. Next, we performed factor analysis on each set, followed by a canonical correlation analysis between the derived SNI and NP factors. This last analysis optimally associated the entire MEG signal with cognitive function. The results revealed that SNI as a whole were mostly associated with memory and language, and, slightly less, executive function, processing speed and visuospatial abilities, thus differentiating functions subserved by the frontoparietal and the temporal cortices. These findings provide a direct interpretation of the information carried by the SNI and set the basis for identifying specific neural disease phenotypes according to cognitive deficits.

Relative Incidence of Seizures and Myoclonus in Alzheimer’s Disease, Dementia with Lewy Bodies, and Frontotemporal Dementia

BACKGROUND Patients with Alzheimers disease (AD) are more prone to seizures and myoclonus, but relative risk of these symptoms among other dementia types is unknown. OBJECTIVE To determine incidence of seizures and myoclonus in the three most common neurodegenerative dementias: AD, dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). METHODS Our institutions medical records were reviewed for new-onset unprovoked seizures and myoclonus in patients meeting criteria for AD (n = 1,320), DLB (n = 178), and FTD (n = 348). Cumulative probabilities of developing seizures and myoclonus were compared between diagnostic groups, whereas age-stratified incidence rates were determined relative to control populations. RESULTS The cumulative probability of developing seizures after disease onset was 11.5% overall, highest in AD (13.4%) and DLB (14.7%) and lowest in FTD (3.0%). The cumulative probability of developing myoclonus was 42.1% overall, highest in DLB (58.1%). The seizure incidence rates, relative to control populations, were nearly 10-fold in AD and DLB, and 6-fold in FTD. Relative seizure rates increased with earlier age-at-onset in AD (age <50, 127-fold; 50-69, 21-fold; 70+, 2-fold) and FTD (age <50, 53-fold; 50-69, 9-fold), and relative myoclonus rates increased with earlier age-at-onset in all groups. Seizures began an average of 3.9 years after the onset of cognitive or motor decline, and myoclonus began 5.4 years after onset. CONCLUSIONS Seizures and myoclonus occur with greater incidence in patients with AD, DLB, and FTD than in the general population, but rates vary with diagnosis, suggesting varied pathomechanisms of network hyperexcitability. Patients often experience these symptoms early in disease, suggesting hyperexcitability could be an important target for interventions.

Sleepless Night and Day, the Plight of Progressive Supranuclear Palsy

Objectives To elucidate the unique sleep and waking characteristics in progressive supranuclear palsy (PSP), a neurodegenerative disease associated with motor deficits and dementia that largely affects the brainstem and thalamic regions. Methods A total of 20 PSP and 16 healthy older adult controls participated in this study. The participants underwent an overnight polysomnography and multiple sleep latency test (MSLT) the following day. Prior to the MSLT last trial, they were asked to complete the Stanford Sleepiness Scale. Data were assessed for measures of latency to sleep onset, sleep duration, waking, and sleep staging during the night. Mean sleep latency, a measure of daytime sleepiness, sleep onset rapid eye movement (REM) periods, and microsleeps were studied with the MSLT. Spectral analysis of wake electroencephalogram (EEG) was performed for 30-second periods at the start of each MSLT trial. Results PSP took significantly longer time to fall asleep (p < .001), slept less during the night (p ≤ .001), and had more wake after sleep onset than controls (p ≤ .001). PSP had less N2 sleep (p < .05) and N3 sleep (p < .05), and REM sleep (p < .001) than controls. During the MSLT, PSP took significantly longer to fall asleep (p < .001), did not have microsleeps when they remained awake throughout the assessment periods, but were subjectively sleepier than controls (p < .05). Gamma power was increased during wake EEG in PSP (p < .01). Conclusions Sleep/waking regulation and REM sleep regulation are disrupted in PSP, leading to profound sleep deprivation without recuperation. Our findings suggest a diminished homeostatic sleep drive in PSP. This hyperaroused state is unique and is a severely disabling feature of PSP.

FLAIR with contrast linked to better correlation with stroke symptoms than diffision-weighted imaging in a patient: detecting hyperintense acute reperfusion injury marker and cortical enhancement.

Discussion HARM is a little-known imaging marker for the evaluation of acute stroke which has been identified in 33% of ischemic stroke patients [2] , 85% of intracerebral hemorrhage patients [4] , and 57% of carotid artery stenting patients [5] . HARM can help in ischemic stroke prognosis since it has been observed in 73% of patients with subsequent hemorrhagic transformation versus only 25% of patients without hemorrhagic transformation [2] . HARM may be distant from the intraparenchymal lesion [3, 4] and is more frequently noted after thrombolysis [6] . Theories on HARM pathophysiology focus on matrix metalloproteinase involvement in microvasculature damage, where endogenous tissue plasminogen activator release during vascular injury increases matrix metalloproteinases 2 and 9 [1, 7] . Thus, inclusion of FWC in MRI stroke protocols can help identify an additional pathophysiological component in the setting of reperfusion injury. Finally, the literature to date has not correlated HARM with clinical symptoms independent of the underlying intraparenchymal pathology. The current case report demonstrates that HARM in FWC is associated with clinical deficits not explained by other MRI sequences. This raises the possibility that transient ischemic attacks and imaging-negative strokes might be HARM positive, and linked to focal BBBD and BCSFD.

Focal cerebral β-amyloid angiopathy: A distinct clinicopathologic presentation

We report on a 70-year-old right-handed woman who presented with an 11-year history of a gradually progressive motor and cognitive-behavioral syndrome caused by focal cerebral β-amyloid angiopathy manifesting as discrete mass lesions. At age 59, she developed left leg clumsiness and cramping, evolving within a year into leg stiffness. Similar symptoms gradually affected her left arm. At age 65, she noted progressive word-finding difficulties, anxiety, mental rigidity, and compulsive traits. By age 68, she had difficulties with processing speed, planning, and navigation. Her history was notable for mild hypertension, hyperlipidemia, hypothyroidism, sleep apnea, bilateral carpal tunnel syndrome, and uterine fibroids; her mother had late-onset parkinsonism. She never smoked or used illicit drugs.

Neglect and extinction in kinesthesia and thesesthesia: understanding proprioceptive inattention

Abstract This paper describes a new observation of neglect and extinction of kinesthesia and thesesthesia (movement and position imperception), jointly reflecting proprioceptive inattention, in a series of patients with parietal lesions. A prototypical case is discussed in detail and unaddressed aspects of proprioceptive inattention are discussed through findings from four additional cases. Thesesthetic and kinesthetic extinction were tested through simultaneous antidromic vertical displacement of index fingers, while having patients report on finger proprioceptive perception with eyes closed. Patients had variable degrees of proprioceptive inattention affecting a specific limb, but without pallesthetic inattention or somatoagnosia, whereas symptoms often resolved with visual feedback or active limb movements. Findings support that kinesthesia and thesesthesia (a) are subserved by near-identical brain networks, (b) relate more to tactile perception than pallesthesia in higher order cortical areas, and (c) have a somatotopic cortical organization even in association brain areas. Furthermore, proprioceptive extinction and neglect involve (i) “attention network” structures, (ii) either hemisphere, (iii) gray or subcortical white matter damage, (iv) defective vigilance mechanisms possibly through premature habituation of spatiotemporally saturated neural capacitor circuits, and (v) are not the result of somatoagnosia, while (vi) their resolution is observed through reafferent motor-sensory or visual feedback.