Objectives
Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's ...disease AD), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross‐sectionally and longitudinally across various neurodegenerative diagnoses.
Methods
The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2‐years follow‐up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal‐executive circuits.
Results
Cross‐sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal‐executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal‐executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal‐executive circuits, respectively.
Conclusions
The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross‐sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.
Key points
What is the primary question addressed by this study?
The structural neural correlates of neuropsychiatric symptoms (NPS) in multiple neurodegenerative diagnoses.
What is the main finding of this study?
Our study reveals the involvement of both corticolimbic and frontal‐executive circuits in three populations at risk for developing dementia, with these circuits showing significant associations with NPS. The distinct neural correlates were observed within each population, shedding light on the neurobiological mechanisms underlying NPS in these disorders and providing a better understanding of their progression toward dementia.
What is the meaning of the finding?
These results have significant implications for the early detection and management of NPS in patients with neurodegenerative disorders and may inform the development of more effective treatment strategies in the future. Furthermore, the difference between cross‐sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.
Tourette syndrome (TS) is a heritable neuropsychiatric disorder that presents in childhood with a constellation of motor and non-motor symptoms. The defining feature of the disorder is the presence ...of brief, stereotyped, motor or vocal behaviours called tics. Although tics are themselves voluntary, they are typically performed secondary to involuntary sensory symptoms or irresistible urges. TS is therefore said to be a disorder of human volition that likely represents a general failure of inhibition. It shares many features with obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD) and impulse control disorder with which it is also commonly associated. Much of the anatomic substrate for TS probably lies in the circuits that connect multiple areas of cortex with the basal ganglia and thalamus to subserve motivation, inhibition of behaviour, planning of motor acts and detection of threats. To date, pathological studies of TS have been very few and the number of subjects evaluated too small to reliably elucidate the nature and significance of several reported abnormalities. However, evidence derived from both pharmacological trials and selected functional imaging studies suggests that disturbances of the dopaminergic and serotonergic neurotransmitter systems play a key role in the pathogenesis of TS. At the same time, multiple studies have demonstrated reciprocal interactions between the serotonin and dopamine systems of the brain. This information, when placed in the context of the observed functional imaging abnormalities, may generate further insights into the pathophysiology of TS.
The circadian oscillator generates a rhythmic output with a period of about 24 hours. Despite extensive studies in several model systems, the biochemical mode of action has not yet been demonstrated ...for any of its components. Here, the Drosophila CLOCK protein was shown to induce transcription of the circadian rhythm genes period and timeless. dCLOCK functioned as a heterodimer with a Drosophila homolog of BMAL1. These proteins acted through an E-box sequence in the period promoter. The timeless promoter contains an 18-base pair element encompassing an E-box, which was sufficient to confer dCLOCK responsiveness to a reporter gene. PERIOD and TIMELESS proteins blocked dCLOCK's ability to transactivate their promoters via the E-box. Thus, dCLOCK drives expression of period and timeless, which in turn inhibit dCLOCK's activity and close the circadian loop.
This article seeks to provide the practising clinician with guidance on the pharmacological management of tic disorders in children and adults. We performed a systematic review of the literature on ...the treatment of tic disorders. A multi-institutional group of 14 experts in psychiatry, child psychiatry, neurology, pediatrics, and psychology engaged in a consensus meeting. The evidence was presented and discussed, and nominal group techniques were employed to arrive at consensus on recommendations. A strong recommendation is made when the benefits of treatment clearly outweigh the risks and burdens, and can apply to most patients in most circumstances without reservation. With a weak recommendation, the benefits, risks, and burdens are more closely balanced, and the best action may differ depending on the circumstances. Based on these principles, weak recommendations were made for the use of pimozide, haloperidol, fluphenazine, metoclopramide (children only), risperidone, aripiprazole, olanzapine, quetiapine, ziprasidone, topiramate, baclofen (children only), botulinum toxin injections, tetrabenazine, and cannabinoids (adults only). Strong recommendations were made for the use of clonidine and guanfacine (children only). While the evidence supports the efficacy of many of the antipsychotics for the treatment of tics, the high rates of side effects associated with these medications resulted in only weak recommendations for these drugs. In situations where tics are not severe or disabling, the use of a medication with only a weak recommendation is not warranted. However, when tics are more distressing and interfering, the need for tic suppression to improve quality of life is stronger, and patients and clinicians may be more willing to accept the risks of pharmacotherapy.
Background
Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number ...variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied.
Methods
Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519).
Results
In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1–5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7–11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies.
Conclusion
The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.
Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative (n = 519). In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer’s disease participant; (2) a duplication of exons 1–5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6, in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7–11 in SAMHD1 in a mild cognitive impairment participant. The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.
In recent years, Artificial Intelligence has been used to assist healthcare professionals in detecting and diagnosing neurodegenerative diseases. In this study, we propose a methodology to analyze ...functional Magnetic Resonance Imaging signals and perform classification between Parkinson’s disease patients and healthy participants using Machine Learning algorithms. In addition, the proposed approach provides insights into the brain regions affected by the disease. The functional Magnetic Resonance Imaging from the PPMI and 1000-FCP datasets were pre-processed to extract time series from 200 brain regions per participant, resulting in 11,600 features. Causal Forest and Wrapper Feature Subset Selection algorithms were used for dimensionality reduction, resulting in a subset of features based on their heterogeneity and association with the disease. We utilized Logistic Regression and XGBoost algorithms to perform PD detection, achieving 97.6% accuracy, 97.5% F1 score, 97.9% precision, and 97.7%recall by analyzing sets with fewer than 300 features in a population including men and women. Finally, Multiple Correspondence Analysis was employed to visualize the relationships between brain regions and each group (women with Parkinson, female controls, men with Parkinson, male controls). Associations between the Unified Parkinson’s Disease Rating Scale questionnaire results and affected brain regions in different groups were also obtained to show another use case of the methodology. This work proposes a methodology to (1) classify patients and controls with Machine Learning and Causal Forest algorithm and (2) visualize associations between brain regions and groups, providing high-accuracy classification and enhanced interpretability of the correlation between specific brain regions and the disease across different groups.
We used positional cloning to identify the circadian Clock gene in mice. Clock is a large transcription unit with 24 exons spanning approximately 100,000 bp of DNA from which transcript classes of ...7.5 and approximately 10 kb arise. Clock encodes a novel member of the bHLH-PAS family of transcription factors. In the Clock mutant allele, an A-->T nucleotide transversion in a splice donor site causes exon skipping and deletion of 51 amino acids in the CLOCK protein. Clock is a unique gene with known circadian function and with features predicting DNA binding, protein dimerization, and activation domains. CLOCK represents the second example of a PAS domain-containing clock protein (besides Drosophila PERIOD), which suggests that this motif may define an evolutionarily conserved feature of the circadian clock mechanism.
A 56-year-old woman presented with an acute confusional state and moderate global aphasia. Thyroperoxidase antibody level was elevated (3,890 IU/mL) and SREAT was diagnosed. MRI findings were normal. ...Cerebrospinal fluid examination revealed only a mildly increased protein. The initial electroencephalogram EEG showed slowing and markedly decreased amplitude over the left hemisphere and left temporal sharp waves. An EEG performed after treatment with intravenous steroids showed a significant improvement of the background slowing, which correlated with clinical improvement. One week later, the patient had an episode of forced head-turning and fencing posture to the right. The EEG shortly afterward showed slowing and a decreased amplitude over the right hemisphere. Continuous EEG monitoring was performed at the time of steroid treatment. Again, there was a significant improvement of the EEG after this treatment that correlated with the clinical condition. SREAT is characterized by fluctuations in mental status and variable EEG findings. These patients often show an excellent clinical improvement to immunosuppressive therapy, including corticosteroids. This case report documents the dramatic clinical and EEG improvement with steroid therapy.
Genetic heterogeneity underlies many phenotypic variations observed in circadian rhythmicity. Continuous distributions in measures of circadian behavior observed among multiple inbred strains of mice ...suggest that the inherent contributions to variability are polygenic in nature. To identify genetic loci that underlie this complex behavior, we have carried out a genome-wide complex trait analysis in 196 (C57BL/6J X BALB/cJ)F(2) hybrid mice. We have characterized variation in this panel of F(2) mice among five circadian phenotypes: free-running circadian period, phase angle of entrainment, amplitude of the circadian rhythm, circadian activity level, and dissociation of rhythmicity. Our genetic analyses of these phenotypes have led to the identification of 14 loci having significant effects on this behavior, including significant main effect loci that contribute to three of these phenotypic measures: period, phase, and amplitude. We describe an additional locus detection method, genome-wide genetic interaction analysis, developed to identify locus pairs that may interact epistatically to significantly affect phenotype. Using this analysis, we identified two additional pairs of loci that have significant effects on dissociation and activity level; we also detected interaction effects in loci contributing to differences of period, phase, and amplitude. Although single gene mutations can affect circadian rhythms, the analysis of interstrain variants demonstrates that significant genetic complexity underlies this behavior. Importantly, most of the loci that we have detected by these methods map to locations that differ from the nine known clock genes, indicating the presence of additional clock-relevant genes in the mammalian circadian system. These data demonstrate the analytical value of both genome-wide complex trait and epistatic interaction analyses in further understanding complex phenotypes, and point to promising approaches for genetic analysis of such phenotypes in other mammals, including humans.
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