Title. Caring for a relative with dementia: family caregiver burden
Aim. This paper is a report of part of a study to investigate the burden experienced by families giving care to a relative with ...dementia, the consequences of care for the mental health of the primary caregiver and the strategies families use to cope with the care giving stressors.
Background. The cost of caring for people with dementia is enormous, both monetary and psychological. Partners, relatives and friends who take care of patients experience emotional, physical and financial stress, and care giving demands are central to decisions on patient institutionalization.
Method. A volunteer sample of 172 caregiver/care recipient dyads participated in the study in Cyprus in 2004–2005. All patients were suffering from probable Alzheimer's type dementia and were recruited from neurology clinics. Data were collected using the Memory and Behaviour Problem Checklist, Burden Interview, Center for Epidemiological Studies‐Depression scale and Ways of Coping Questionnaire.
Findings. The results showed that 68·02% of caregivers were highly burdened and 65% exhibited depressive symptoms. Burden was related to patient psychopathology and caregiver sex, income and level of education. There was no statistically significant difference in level of burden or depression when patients lived in the community or in institutions. High scores in the burden scale were associated with use of emotional‐focused coping strategies, while less burdened relatives used more problem‐solving approaches to care‐giving demands.
Conclusion. Caregivers, especially women, need individualized, specific training in how to understand and manage the behaviour of relatives with dementia and how to cope with their own feelings.
Epileptic seizure detection and prediction by using noninvasive measurements such as scalp EEG signals or invasive, intracranial recordings, has been at the heart of epilepsy studies for at least ...three decades. To this end, the most common approach has been to consider short‐length recordings (several seconds to a few minutes) around a seizure, aiming to identify significant changes that occur before or during seizures. An inherent assumption in this approach is the presence of a relatively constant EEG activity in the interictal period, which is interrupted by seizure occurrence. Here, we examine this assumption by using long‐duration scalp EEG data (21–94 hr) in nine patients with epilepsy, based on which we construct functional brain networks. Our results reveal that these networks vary over time in a periodic fashion, exhibiting multiple peaks at periods ranging between 1 and 24 hr. The effects of seizure onset on the functional brain network properties were found to be considerably smaller in magnitude compared to the changes due to these inherent periodic cycles. Importantly, the properties of the identified network periodic components (instantaneous phase) were found to be strongly correlated to seizure onset, especially for the periodicities around 3 and 5 hr. These correlations were found to be largely absent between EEG signal periodicities and seizure onset, suggesting that higher specificity may be achieved by using network‐based metrics. In turn, this implies that more robust seizure detection and prediction can be achieved if longer term underlying functional brain network periodic variations are taken into account.
Glial gap junction proteins, called connexins (Cxs), form gap junctions in the central nervous system (CNS) to allow the bidirectional cytosolic exchange of molecules between adjacent cells. Their ...involvement in inheritable diseases and the use of experimental animal models that closely mimic such diseases revealed the critical role of glial GJs in myelination and homeostasis. Cxs are also implicated in acquired demyelinating disorders, such as Multiple Sclerosis (MS) and Alzheimer's disease (AD). Animal and human studies have revealed a role of the astrocytic Cx43 in the progression of AD but the role of Cx47, which is the main partner of Cx43 in the astrocyte-oligodendrocyte GJs is still unknown. The aim of this study was to investigate the astrocytic connexins, Cx43 and Cx30 in relation to oligodendrocytic Cx47 in the cortex and thalamus of the 5XFAD mouse model of AD. The model was characterized by increased Aβ deposition, gliosis, neuronal loss, and memory impairment. Compared to wild-type mice, Cx43 and Cx30 showed increased immunoreactivity in older 5XFAD mice, reflecting astrogliosis, while Cx47 immunoreactivity was reduced. Moreover, Cx47 GJ plaques showed reduced colocalization with Cx43 plaques. Oligodendrocyte precursor cells (OPCs) and mature oligodendrocyte populations were also depleted, and myelin deficits were observed. Our findings indicate reduced astrocyte-oligodendrocyte gap junction connectivity and possibly a shift in Cx43 expression toward astrocyte-astrocyte gap junctions and/or hemichannels, that could impair oligodendrocyte homeostasis and myelination. However, other factors, such as Aβ toxicity, could directly affect oligodendrocyte survival in AD. Our study provides evidence that Cxs might have implications in the progression of AD, although the role of oligodendrocyte Cxs in AD requires further investigation.
Objective:
The effects of normal cognitive aging on executive functions (EF), Verbal Episodic Memory (VEM) and the contribution of age, sex, education, and APOΕ ε4 in a group of old Greek Cypriots ...across a five-year period were investigated.
Design:
NEUROAGE, the first project on cognitive aging in Cyprus, is a prospective longitudinal study with a rolling admission process. Participants are assessed at baseline and retested every 24–30 months.
Subjects:
170 participants completed all three testing cycles; 86 men and 84 women with ages ranging between 60 and 88 years (mean = 73.21,
SD
= 5.84); education, 2–20 years (mean = 9.07,
SD
= 4.27).
Results:
Α Repeated Measures Multivariate Analysis of Covariance was conducted with one between-subject factor: sex; two covariates: age and education, while Time (time 1, time 2, time 3) served as a within – subject factor. Time did not have an effect on mini mental status examination in Greek (MMSE), EF or VEM. Also, sex had no effect on MMSE, EF and VEM. There was no time by sex interaction. Age and Education significantly predicted the EF performance,
F
(1, 168) = 11.23,
p
< 0.05;
F
(1, 158) = 90.03,
p
< 0.001 and VEM performance,
F
(1, 171) = 17.22,
p
< 0.001;
F
(1, 171) = 61.25,
p
< 0.001. Furthermore, there was a significant interaction effect between time and education, for EF,
F
(2, 167) = 7.02,
p
< 0.001. Performance of the
APOE
ε4 carriers did not differ on any of the above measures as compared to performance of non-carriers in this older adult group.
Conclusion:
Cognitively healthy adults maintained overall cognitive performance across the five-year period. Male and female participants performed similarly and the pattern of change over time was similar across the two sexes. Education was predictive of VEM and EF performance across time. Furthermore, those with higher education maintained higher levels of EF performance.
APOE
results did not differentiate performance at baseline. Implications of findings are discussed.
Gap junctions (GJs) are specialized transmembrane channels assembled by two hemi-channels of six connexin (Cx) proteins that facilitate neuroglial crosstalk in the central nervous system (CNS). ...Previous studies confirmed the crucial role of glial GJs in neurodegenerative disorders with dementia or motor dysfunction including Alzheimer's disease (AD). The aim of this study was to examine the alterations in astrocyte and related oligodendrocyte GJs in association with Aβ plaques in the spinal cord of the 5xFAD mouse model of AD. Our analysis revealed abundant Aβ plaque deposition, activated microglia, and astrogliosis in 12-month-old (12M) 5xFAD mice, with significant impairment of motor performance starting from 3-months (3M) of age. Additionally, 12M 5xFAD mice displayed increased immunoreactivity of astroglial Cx43 and Cx30 surrounding Aβ plaques and higher protein levels, indicating upregulated astrocyte-to-astrocyte GJ connectivity. In addition, they demonstrated increased numbers of mature CC1-positive and precursor oligodendrocytes (OPCs) with higher immunoreactivity of Cx47-positive GJs in individual cells. Moreover, total Cx47 protein levels were significantly elevated in 12M 5xFAD, reflecting increased oligodendrocyte-to-oligodendrocyte Cx47-Cx47 GJ connectivity. In contrast, we observed a marked reduction in Cx32 protein levels in 12M 5xFAD spinal cords compared with controls, while qRT-PCR analysis revealed a significant upregulation in
mRNA levels. Finally, myelin deficits were found focally in the areas occupied by Aβ plaques, whereas axons themselves remained preserved. Overall, our data provide novel insights into the altered glial GJ expression in the spinal cord of the 5xFAD model of AD and the implicated role of GJ pathology in neurodegeneration. Further investigation to understand the functional consequences of these extensive alterations in oligodendrocyte-astrocyte (O/A) GJ connectivity is warranted.
According to the amyloid hypothesis of Alzheimer's disease (AD) the deposition of prefibrillar and fibrillar Aβ peptide sets off the pathogenic cascades of neuroinflammation and neurodegeneration ...that lead to synaptic and neuronal loss resulting in cognitive decline. Various approaches to reduce amyloid load by reducing production of the Aβ peptide or enhancing amyloid clearance by primary or secondary immunization have not proven successful in clinical trials. Interfering with the normal function of secretases and suboptimal timing of Aβ peptide removal have been put forward as possible explanations. Complement, an innate component of the immune system, has been found to modulate disease pathology and in particular neuronal loss in the AD mouse model but its mechanism of action is complex. C1Q has been shown to facilitate phagocytosis of Aβ peptide but its Ablation attenuates neuroinflammation. Experiments in AD mouse models show that inhibition of complement component C5a reduces amyloid deposition and alleviates neuroinflammation. Phagocytes including microglia, monocytes and neutrophils carry C5a receptors. Here, a widely used mouse model of AD, 5XFAD, was intermittently treated with the oral C5a receptor agonist EP67 and several neuronal and neuroinflammatory markers as well as memory function were assessed. EP67 treatment enhanced phagocytosis, resulting in a significant reduction of both fibrillar and non-fibrillar Aβ, reduced astrocytosis and preserved synaptic and neuronal markers as well as memory function. Timely and phasic recruitment of the innate immune system offers a new therapeutic avenue of treating pre-symptomatic Alzheimer disease.
It is well-established that both volume conduction and the choice of recording reference (montage) affect the correlation measures obtained from scalp EEG, both in the time and frequency domains. As ...a result, a number of correlation measures have been proposed aiming to reduce these effects. In our previous work, we have showed that scalp-EEG based functional brain networks in patients with epilepsy exhibit clear periodic patterns at different time scales and that these patterns are strongly correlated to seizure onset, particularly at shorter time scales (around 3 and 5 h), which has important clinical implications. In the present work, we use the same long-duration clinical scalp EEG data (multiple days) to investigate the extent to which the aforementioned results are affected by the choice of reference choice and correlation measure, by considering several widely used montages as well as correlation metrics that are differentially sensitive to the effects of volume conduction. Specifically, we compare two standard and commonly used linear correlation measures, cross-correlation in the time domain, and coherence in the frequency domain, with measures that account for zero-lag correlations: corrected cross-correlation, imaginary coherence, phase lag index, and weighted phase lag index. We show that the graphs constructed with corrected cross-correlation and WPLI are more stable across different choices of reference. Also, we demonstrate that all the examined correlation measures revealed similar periodic patterns in the obtained graph measures when the bipolar and common reference (Cz) montage were used. This includes circadian-related periodicities (e.g., a clear increase in connectivity during sleep periods as compared to awake periods), as well as periodicities at shorter time scales (around 3 and 5 h). On the other hand, these results were affected to a large degree when the average reference montage was used in combination with standard cross-correlation, coherence, imaginary coherence, and PLI, which is likely due to the low number of electrodes and inadequate electrode coverage of the scalp. Finally, we demonstrate that the correlation between seizure onset and the brain network periodicities is preserved when corrected cross-correlation and WPLI were used for all the examined montages. This suggests that, even in the standard clinical setting of EEG recording in epilepsy where only a limited number of scalp EEG measurements are available, graph-theoretic quantification of periodic patterns using appropriate montage, and correlation measures corrected for volume conduction provides useful insights into seizure onset.
The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive lysosomal storage disorders that are characterized by neurodegeneration, progressive ...cognitive decline, motor impairment, ataxia, loss of vision, seizures, and premature death. To date, pathogenic variants in more than 13 genes have been associated with NCLs.
CLN6
encodes an endoplasmic reticulum non-glycosylated transmembrane protein, which is involved in lysosomal acidification. Mutations in
CLN6
cause late-infantile juvenile NCL (JNCL) adult-onset NCL, and Kufs disease. Members from two available families with JNCL were clinically evaluated, and samples were collected from consenting individuals. The molecular investigation was performed by whole-exome sequencing, Sanger sequencing, and family segregation analysis. Furthermore,
in silico
prediction analysis and structural modeling of the identified
CLN6
variants were performed. We report clinical and genetic findings of three patients from two Greek-Cypriot families (families 915 and 926) with JNCL. All patients were males, and the first symptoms appeared at the age of 6 years. The proband of family 926 presented with loss of motor abilities, ataxia, spasticity, seizure, and epilepsy. The proband of family 915 had ataxia, spasticity, dysarthria, dystonia, and intellectual disability. Both probands did not show initial signs of vision and/or hearing loss. Molecular analysis of family 926 revealed two
CLN6
biallelic variants: the novel,
de novo
p.Tyr295Cys and the known p.Arg136His variants. In family 915, both patients were homozygous for the p.Arg136His
CLN6
variant. Prediction analysis of the two
CLN6
variants characterized them as probably damaging and disease-causing. Structural modeling of the variants predicted that they probably cause protein structural differentiation. In conclusion, we describe two unrelated Cypriot families with JNCL. Both families had variants in the
CLN6
gene; however, they presented with slightly different symptoms, and notably none of the patients has loss of vision.
In silico
prediction and structural analyses indicate that both variants are most likely pathogenic.
•We present automatic unsupervised & supervised muscle artifact detection and rejection algorithms.•Results from 10 patients with epilepsy show excellent performance, outperforming CCA and ICA.•Our ...approach removes the need for expert marking, reference signal recording and visual inspection.
This paper proposes supervised and unsupervised algorithms for automatic muscle artifact detection and removal from long-term EEG recordings, which combine canonical correlation analysis (CCA) and wavelets with random forests (RF).
The proposed algorithms first perform CCA and continuous wavelet transform of the canonical components to generate a number of features which include component autocorrelation values and wavelet coefficient magnitude values. A subset of the most important features is subsequently selected using RF and labelled observations (supervised case) or synthetic data constructed from the original observations (unsupervised case). The proposed algorithms are evaluated using realistic simulation data as well as 30min epochs of non-invasive EEG recordings obtained from ten patients with epilepsy.
We assessed the performance of the proposed algorithms using classification performance and goodness-of-fit values for noisy and noise-free signal windows. In the simulation study, where the ground truth was known, the proposed algorithms yielded almost perfect performance. In the case of experimental data, where expert marking was performed, the results suggest that both the supervised and unsupervised algorithm versions were able to remove artifacts without affecting noise-free channels considerably, outperforming standard CCA, independent component analysis (ICA) and Lagged Auto-Mutual Information Clustering (LAMIC).
The proposed algorithms achieved excellent performance for both simulation and experimental data. Importantly, for the first time to our knowledge, we were able to perform entirely unsupervised artifact removal, i.e. without using already marked noisy data segments, achieving performance that is comparable to the supervised case.
Overall, the results suggest that the proposed algorithms yield significant future potential for improving EEG signal quality in research or clinical settings without the need for marking by expert neurophysiologists, EMG signal recording and user visual inspection.
encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action ...potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.
Individuals with
variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in
oocytes.
We identified novel
variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms.
These findings implicate
as a novel causative gene for epilepsy and emphasize the critical role of K
3.2 in the regulation of brain excitability.