Alzheimer's disease research progress in the Mediterranean region: The Alzheimer's Association International Conference Satellite Symposium.

As research and services in the Mediterranean region continue to increase, so do opportunities for global collaboration. To support such collaborations, the Alzheimer's Association was due to hold its seventh Alzheimer's Association International Conference Satellite Symposium in Athens, Greece in 2021. Due to the COVID-19 pandemic, the meeting was held virtually, which enabled attendees from around the world to hear about research efforts in Greece and the surrounding Mediterranean countries. Research updates spanned understanding the biology of, treatments for, and care of people with Alzheimer's disease (AD_ and other dementias. Researchers in the Mediterranean region have outlined the local epidemiology of AD and dementia, and have identified regional populations that may expedite genetic studies. Development of biomarkers is expected to aid early and accurate diagnosis. Numerous efforts have been made to develop culturally specific interventions to both reduce risk of dementia, and to improve quality of life for people living with dementia.

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

This perspective binds emerging evidence on the bidirectional relationship between Alzheimer's 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 ß 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 ß 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.

Neglect and extinction in kinesthesia and thesesthesia: understanding proprioceptive inattention.

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.

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.

Connections Between Insomnia and Cognitive Aging.

Insomnia is a common sleep disorder among older adults, and a risk factor for poor physical and mental health. However, the relationship between insomnia and cognitive health is not well understood. Here, we review observational studies that have investigated whether insomnia is associated with deficits in objective cognitive performance and an increased risk of dementia, magnetic resonance imaging studies that have assessed grey matter volumes and white matter microstructure, and interventional studies that have explored whether the treatment of insomnia can improve cognitive outcomes. There are inconsistent findings regarding impaired performance in objective cognitive tests and reduced grey matter volumes, and limited, emerging, evidence that suggests that insomnia is associated with an increased risk of dementia and reduced white matter integrity. Although the interventional literature is still in its infancy, there is some indication that treatment may have an impact on vigilance. Well-powered studies examining sources of heterogeneity are warranted.

Long-Term Trazodone Use and Cognition: A Potential Therapeutic Role for Slow-Wave Sleep Enhancers.

BACKGROUND: Recent studies reveal an association between slow-wave sleep (SWS), amyloid-ß aggregation, and cognition. OBJECTIVE: This retrospective study examines whether long-term use of trazodone, an SWS enhancer, is associated with delayed cognitive decline. METHODS: We identified 25 regular trazodone users (mean age 75.4±7.5; 9 women, 16 men) who carried a diagnosis of Alzheimer's dementia, mild cognitive impairment, or normal cognition, and 25 propensity-matched trazodone non-users (mean age 74.5±8.0; 13 women, 12 men), accounting for age, sex, education, type of sleep deficit (hypersomnia, insomnia, parasomnia), diagnosis, and baseline Mini-Mental State Examination (MMSE). Longitudinal group differences in cognitive testing were evaluated through repeated measures tests over an average inter-evaluation interval of four years. RESULTS: Trazodone non-users had 2.6-fold faster decline MMSE (primary outcome) compared to trazodone users, 0.27 (95% confidence interval [CI]: 0.07-0.48) versus 0.70 (95% CI: 0.50-0.90) points per year (p = 0.023). The observed effects were especially associated with subjective improvement of sleep complaints in post-hoc analyses (p = 0.0006). Secondary outcomes of other cognitive and functional scores had variable worsening in non-users and varied in significance when accounting for co-administered medications and multiple comparisons. Trazodone effects on MMSE remained significant within participants with AD-predicted pathology, with 2.4-fold faster decline in non-users (p = 0.038). CONCLUSIONS: These results suggest an association between trazodone use and delayed cognitive decline, adding support for a potentially attractive and cost-effective intervention in dementia. Whether the observed relationship of trazodone to cognitive function is causal or an indirect marker of other effects, such as treated sleep disruption, and if such effects are mediated through SWS enhancement requires confirmation through prospective studies.

Cortical processing of tactile stimuli applied in quick succession across the fingertips: temporal evolution of dipole sources revealed by magnetoencephalography.

We used magnetoencephalography (MEG) in 10 healthy human subjects to study cortical responses to tactile stimuli applied to the fingertips of digits 2-5 of the right hand. Each stimulus lasted 50 ms and was produced by air-driven elastic membranes. Four-hundred stimuli were delivered on each finger in three temporal patterns (conditions). In the "Discrete" condition, stimuli were applied to each finger repetitively with an interstimulus interval (ISI) of 1-2 s. In the "Continuous" condition, stimuli were applied to the fingers sequentially as four-stimulus trains with zero ISI and 1-2 s intervening between trains. Finally, in the "Gap" condition, stimuli were applied as in the Continuous condition but with an ISI of 50 ms. A sensation of tactile motion across fingers (digit 2 --> digit 5) was reported by all subjects in the Continuous and Gap conditions. Cortical responses were extracted as single equivalent current dipoles over a period of 1 s following stimulus onset. In all three conditions, initial responses in left primary somatosensory cortex (SI) were observed ~20 to 50 ms after stimulus onset and were followed by additional left SI responses and bilateral responses in the secondary somatosensory cortex (SII). In addition, in the Continuous and Gap conditions, there was an activation of the precentral gyrus, the temporal aspects of which depended on the temporal relation of the administered stimuli, as follows. An ISI of 0 ms led to activation of the precentral gyrus shortly after the second stimulation, whereas an ISI of 50 ms led to activation of the precentral gyrus after the third stimulation. The current findings support results from previous studies on temporal activity patterns in SI and SII, verify the participation of the precentral gyrus during tactile motion perception and, in addition, reveal aspects of integration of sequential sensory stimulations over nonadjacent areas as well as temporal activity patterns in the postcentral and precentral gyri.

On the calculation of transcallosal conduction time using transcranial magnetic stimulation.

Transcallosal conduction time (TCT), based on the results of transcranial magnetic stimulation studies, is currently calculated as a function of the ipsilateral silent period (iSP) and of the motor evoked potential (MEP) obtained from a target muscle (TCTcurrent = iSP latency - MEP latency). We argue that this measure overestimates TCT and may lead to a bias in statistical group comparisons. We propose an alternative measure, TCTproposed, which we defined as TCTproposed = iSP latency - cSP latency, where cSP is the contralateral silent period. We report our results on the comparison of the two measures in twenty healthy individuals and provide a theoretical basis for TCTproposed.

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, Alzheimer's disease, schizophrenia, Sjögren's syndrome, chronic alcoholism, facial pain, healthy controls) and gave excellent external cross-validation results.

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

BACKGROUND: Patients with Alzheimer's 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 institution's 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.

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 Alzheimer's 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.

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.

Neurostatistics: applications, challenges and expectations.

Brain function and its relations to cognition and behavior can be elucidated only by the use of various complementary methods. Over the past 20 years, we have been studying the brain mechanisms underlying spatial processes using different methods, including the recording of single cell activity in behaving monkeys, functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) in human subjects, all performing the same tasks. These methods provide partially overlapping perspectives, resulting in a gain in knowledge beyond the province of the individual method. A common aspect in this endeavor is the statistical analysis of the data acquired by different methods, especially regarding the encoding of information in unitary elements (single cell activity in neurophysiology, blood oxygenation level-dependent (BOLD) activation of voxels in fMRI, magnetic field strength in MEG) and the decoding of information from ensembles. In this paper we illustrate the various approaches, their data analysis and possible applications to medicine in the context of operations in space.