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Aging Cell Jul 2023Age is a major risk factor for neurodegenerative diseases. Shortening of leucocyte telomeres with advancing age, arguably a measure of "biological" age, is a known...
Age is a major risk factor for neurodegenerative diseases. Shortening of leucocyte telomeres with advancing age, arguably a measure of "biological" age, is a known phenomenon and epidemiologically correlated with age-related disease. The main mechanism of telomere shortening is cell division, rendering telomere length in post-mitotic cells presumably stable. Longitudinal measurement of human brain telomere length is not feasible, and cross-sectional cortical brain samples so far indicated no attrition with age. Hence, age-related changes in telomere length in the brain and the association between telomere length and neurodegenerative diseases remain unknown. Here, we demonstrate that mean telomere length in the putamen, a part of the basal ganglia, physiologically shortens with age, like leukocyte telomeres. This was achieved by using matched brain and leukocyte-rich spleen samples from 98 post-mortem healthy human donors. Using spleen telomeres as a reference, we further found that mean telomere length was brain region-specific, as telomeres in the putamen were significantly shorter than in the cerebellum. Expression analyses of genes involved in telomere length regulation and oxidative phosphorylation revealed that both region- and age-dependent expression pattern corresponded with region-dependent telomere length dynamics. Collectively, our results indicate that mean telomere length in the human putamen physiologically shortens with advancing age and that both local and temporal gene expression dynamics correlate with this, pointing at a potential mechanism for the selective, age-related vulnerability of the nigro-striatal network.
Topics: Humans; Putamen; Cross-Sectional Studies; Telomere Shortening; Risk Factors; Telomere
PubMed: 37129365
DOI: 10.1111/acel.13861 -
The European Journal of Neuroscience Jan 2022Repetitive transcranial magnetic stimulation (rTMS) holds the ability to modulate the connectivity within the stimulated network. However, whether and how the rTMS... (Randomized Controlled Trial)
Randomized Controlled Trial
Repetitive transcranial magnetic stimulation (rTMS) holds the ability to modulate the connectivity within the stimulated network. However, whether and how the rTMS targeted over the primary motor cortex (M1) could affect the connectivity within the sensorimotor network (SMN) is not fully elucidated. Hence, in this study, we investigated the after-effects of rTMS over left M1 at different frequencies on connectivity within SMN. Forty-five healthy participants were recruited and randomly divided into three groups according to rTMS frequencies (high-frequency [HF], 3 Hz; low-frequency [LF], 1 Hz; and SHAM). Participants received 1-Hz, 3-Hz or sham stimulation and underwent two functional magnetic resonance imaging (fMRI) scanning sessions before and after rTMS intervention. Using resting-state functional connectivity (FC) approach, we found that high- and low-frequency rTMS had opposing effects on FC within the SMN, especially for connectivity with subcortical regions (i.e., putamen, thalamus and cerebellum). Specifically, the reductions in connectivity between cortical and subcortical regions within cortico-basal ganglia thalamo-cortical circuits and the cognitive loop of cerebellum, and increased connectivity between cortical and subdivisions within the sensorimotor loop of cerebellum were observed after high-frequency rTMS intervention, whereas the thalamus and cognitive cerebellum subdivisions exhibited increased connectivity, and sensorimotor cerebellum subdivisions showed decreased connectivity with stimulated target after low-frequency stimulation. Collectively, these findings demonstrated the alterations of connectivity within SMN after rTMS intervention at different frequencies and may help to understand the mechanisms of rTMS treatment for movement disorders associated with deficits in subcortical regions such as Parkinson's disease, Huntington's disease and Tourette's syndrome.
Topics: Cerebellum; Humans; Magnetic Resonance Imaging; Parkinson Disease; Putamen; Transcranial Magnetic Stimulation
PubMed: 34905661
DOI: 10.1111/ejn.15571 -
Frontiers in Neuroscience 2021Neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) are biomarkers for neuroaxonal damage. We assessed whether NfL and other biomarker...
Neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH) are biomarkers for neuroaxonal damage. We assessed whether NfL and other biomarker levels in the CSF are correlated to the loss of presynaptic dopamine transporters in neurons as detected with dopamine transporter SPECT (DaTscan). We retrospectively identified 47 patients (17 Alzheimer's dementia, 10 idiopathic Parkinson's disease, 7 Lewy body dementia, 13 progressive supranuclear palsy or corticobasal degeneration) who received a DaTscan and a lumbar puncture. DaTscan imaging was performed according to current guidelines, and z-scores indicating the decrease in uptake were software based calculated for the nucleus caudatus and putamen. The CSF biomarkers progranulin, total-tau, alpha-synuclein, NfL, and pNfH were correlated with the z-scores. DaTscan results in AD patients did not correlate with any biomarker. Subsuming every movement disorder with nigrostriatal neurodegeneration resulted in a strong correlation between putamen/nucleus caudatus and NfL (nucleus caudatus right < 0.01, putamen right < 0.05, left < 0.05) and between pNfH and putamen (right < 0.05; left < 0.042). Subdividing in disease cohorts did not reveal significant correlations. Progranulin, alpha-synuclein, and total-tau did not correlate with DaTscan results. We show a strong correlation of NfL and pNfH with pathological changes in presynaptic dopamine transporter density in the putamen concomitant to nigrostriatal degeneration. This correlation might explain the reported correlation of impaired motor functions in PD and NfL as seen before, despite the pathological heterogeneity of these diseases.
PubMed: 34924923
DOI: 10.3389/fnins.2021.690013 -
Cerebral Cortex (New York, N.Y. : 1991) Nov 2022The morphological development of the fetal striatum during the second trimester has remained poorly described. We manually segmented the striatum using 7.0-T MR images...
The morphological development of the fetal striatum during the second trimester has remained poorly described. We manually segmented the striatum using 7.0-T MR images of the fetal specimens ranging from 14 to 22 gestational weeks. The global development of the striatum was evaluated by volume measurement. The absolute volume (Vabs) of the caudate nucleus (CN) increased linearly with gestational age, while the relative volume (Vrel) showed a quadratic growth. Both Vabs and Vrel of putamen increased linearly. Through shape analysis, the changes of local structure in developing striatum were specifically demonstrated. Except for the CN tail, the lateral and medial parts of the CN grew faster than the middle regions, with a clear rostral-caudal growth gradient as well as a distinct "outside-in" growth gradient. For putamen, the dorsal and ventral regions grew obviously faster than the other regions, with a dorsal-ventral bidirectional developmental pattern. The right CN was larger than the left, whereas there was no significant hemispheric asymmetry in the putamen. By establishing the developmental trajectories, spatial heterochrony, and hemispheric dimorphism of human fetal striatum, these data bring new insight into the fetal striatum development and provide detailed anatomical references for future striatal studies.
Topics: Pregnancy; Female; Humans; Pregnancy Trimester, Second; Corpus Striatum; Caudate Nucleus; Putamen; Sex Characteristics
PubMed: 35078212
DOI: 10.1093/cercor/bhab532 -
Frontiers in Psychiatry 2021Insomnia disorder (ID) is a common illness associated with mood and cognitive impairments. Subtyping ID is an ongoing debate in sleep medicine, but the underlying...
Insomnia disorder (ID) is a common illness associated with mood and cognitive impairments. Subtyping ID is an ongoing debate in sleep medicine, but the underlying mechanisms of each subtype is poorly understood. Growing evidence suggests that subcortical brain structures play the key roles in pathophysiology of ID and its subtypes. Here, we aimed to investigate structural alteration of subcortical regions in patients with two common ID subtypes i.e., paradoxical and psychophysiological insomnia. Fifty-five patients and 49 healthy controls were recruited for this study and T1-weighted images and subjective and objective sleep parameters (i.e., Pittsburgh Sleep Quality Index and polysomnography) were collected from participants. Subcortical structures including the hippocampus, amygdala, caudate, putamen, globus pallidus, nucleus accumbens, and thalamus were automatically segmented in FSL. Volume and shape (using surface vertices) of each structure were compared between the groups, controlled for covariates, and corrected for multiple comparisons. In addition, correlations of sleep parameters and surface vertices or volumes were calculated. The caudate's volume was smaller in patients than controls. Compared with controls, we found regional shrinkage in the caudate, nucleus accumbens, posterior putamen, hippocampus, thalamus, and amygdala in paradoxical insomnia and shrinkage in the amygdala, caudate, hippocampus, and putamen in psychophysiological insomnia. Interestingly, comparing two patients groups, shape alteration in the caudate, putamen, and nucleus accumbens in paradoxical insomnia and shrinkage in the thalamus, amygdala, and hippocampus in psychophysiological insomnia were observed. Both subjective and objective sleep parameters were associated with these regional shape alterations in patients. Our results support the differential role of subcortical brain structures in pathophysiology of paradoxical and psychophysiological insomnia.
PubMed: 34025484
DOI: 10.3389/fpsyt.2021.661286 -
The American Journal of Psychiatry Jan 2023Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Cortical-subcortical hyperconnectivity related to affective-behavioral integration and cortical network hypoconnectivity related to cognitive control have been demonstrated in obsessive-compulsive disorder (OCD); the study objective was to examine whether these connectivity patterns predict treatment response.
METHODS
Adolescents (ages 12-17) and adults (ages 24-45) were randomly assigned to 12 sessions of exposure and response prevention (ERP) or stress management therapy (SMT), an active control. Before treatment, resting-state connectivity of ventromedial prefrontal cortical (vmPFC), cingulo-opercular, frontoparietal, and subcortical regions was assessed with functional MRI. OCD severity was assessed with the Yale-Brown Obsessive Compulsive Scale before, during, and after treatment. Usable fMRI and longitudinal symptom data were obtained from 116 patients (68 female; 54 adolescents; 60 medicated).
RESULTS
ERP produced greater decreases in symptom scores than SMT. ERP was selectively associated with less vmPFC-subcortical (caudate and thalamus) connectivity in both age groups and primarily in unmedicated participants. Greater symptom improvement with both ERP and SMT was associated with greater cognitive-control (cingulo-opercular and frontoparietal) and subcortical (putamen) connectivity across age groups. Developmental specificity was observed across ERP and SMT treatments, such that greater improvements with ERP than SMT were associated with greater frontoparietal-subcortical (nucleus accumbens) connectivity in adolescents but greater connectivity between frontoparietal regions in adults. Comparison of response-predictive connections revealed no significant differences compared with a matched healthy control group.
CONCLUSIONS
The results suggest that less vmPFC-subcortical connectivity related to affect-influenced behavior may be important for ERP engagement, whereas greater cognitive-control and motor circuit connectivity may generally facilitate response to psychotherapy. Finally, neural predictors of treatment response may differ by age.
Topics: Humans; Adult; Female; Adolescent; Child; Young Adult; Middle Aged; Prefrontal Cortex; Psychotherapy; Nucleus Accumbens; Putamen; Obsessive-Compulsive Disorder; Magnetic Resonance Imaging; Brain Mapping
PubMed: 36475374
DOI: 10.1176/appi.ajp.21111173 -
Neurology Jan 2021To evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adults with phenylketonuria.
OBJECTIVE
To evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adults with phenylketonuria.
METHODS
In this prospective cross-sectional study, early-treated patients with phenylketonuria older than 30 years and age- and sex-matched controls were included. Extensive neurologic evaluation, neuropsychological and behavioral testing, sensory and motor evoked potentials, and MRI were performed. CSF concentrations of neurodegenerative markers were evaluated in addition in a subset of 10 patients.
RESULTS
Nineteen patients with phenylketonuria (median age 41 years) with different phenylalanine levels (median 873 μmol/L) entered the study. They showed higher prevalence of neurologic symptoms, cognitive and behavioral abnormalities, autonomic dysfunction, alterations in neurophysiologic measures, and atrophy in putamen and right thalamus compared to controls. In CSF, patients with phenylketonuria exhibited higher β-amyloid 1-42 ( = 0.003), total tau ( < 0.001), and phosphorylated tau ( = 0.032) levels compared to controls. Plasma phenylalanine levels highly correlated with the number of failed neuropsychological tests ( = 0.64, = 0.003), neuropsychiatric symptoms ( = 0.73, < 001), motor evoked potential latency ( = 0.48, = 0.030), and parietal lobe atrophy.
CONCLUSIONS
Our study provides strong evidence for a correlation between phenylalanine levels and clinical, neuropsychological, neurophysiologic, biochemical, and imaging alterations in adult patients with phenylketonuria.
Topics: Adult; Atrophy; Cognition; Cross-Sectional Studies; Evoked Potentials, Motor; Female; Humans; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Phenylalanine; Phenylketonurias; Prospective Studies; Putamen; Thalamus
PubMed: 33093221
DOI: 10.1212/WNL.0000000000011088 -
Human Brain Mapping Jan 2022To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are... (Meta-Analysis)
Meta-Analysis
To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega-analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case- and control-only sites led to the inadvertent learning of site-effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary-based feature selection leveraging leave-one-site-out cross-validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test-set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi-site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD.
Topics: Alcoholism; Cerebral Cortex; Humans; Machine Learning; Magnetic Resonance Imaging; Multicenter Studies as Topic; Neuroimaging; Putamen; Reproducibility of Results
PubMed: 33064342
DOI: 10.1002/hbm.25248 -
Journal of Neurosurgery Aug 2022Subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease is effective; however, its mechanism is unclear. To investigate the degree of neuronal...
OBJECTIVE
Subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease is effective; however, its mechanism is unclear. To investigate the degree of neuronal terminal survival after STN-DBS, the authors examined the striatal dopamine transporter levels before and after treatment in association with clinical improvement using PET with [11C]2β-carbomethoxy-3β-(4-fluorophenyl)tropane ([11C]CFT).
METHODS
Ten patients with Parkinson's disease who had undergone bilateral STN-DBS were scanned twice with [11C]CFT PET just before and 1 year after surgery. Correlation analysis was conducted between [11C]CFT binding and off-period Unified Parkinson's Disease Rating Scale (UPDRS) scores assessed preoperatively and postoperatively.
RESULTS
[11C]CFT uptake reduced significantly in the posterodorsal putamen contralateral to the parkinsonism-dominant side after 1 year; however, an increase was noted in the contralateral anteroventral putamen and ipsilateral ventral caudate postoperatively (p < 0.05). The percentage increase in [11C]CFT binding was inversely correlated with the preoperative binding level in the bilateral anteroventral putamen, ipsilateral ventral caudate, contralateral anterodorsal putamen, contralateral posteroventral putamen, and contralateral nucleus accumbens. The percentage reduction in UPDRS-II score was significantly correlated with the percentage increase in [11C]CFT binding in the ipsilateral anteroventral putamen (p < 0.05). The percentage reduction in UPDRS-III score was significantly correlated with the percentage increase in [11C]CFT binding in the ipsilateral anteroventral putamen, ventral caudate, and nucleus accumbens (p < 0.05).
CONCLUSIONS
STN-DBS increases dopamine transporter levels in the anteroventral striatum, which is correlated with the motor recovery and possibly suggests the neuromodulatory effect of STN-DBS on dopaminergic terminals in Parkinson's disease patients. A preoperative level of anterior striatal dopamine transporter may predict reserve capacity of STN-DBS on motor recovery.
PubMed: 34972089
DOI: 10.3171/2021.10.JNS211364 -
Journal of Neurology, Neurosurgery, and... Jun 2020Traumatic brain injury (TBI) and rapid eye movement sleep behavioural disorder (RBD) are risk factors for Parkinson's disease (PD). Dopaminergic abnormalities are often...
OBJECTIVE
Traumatic brain injury (TBI) and rapid eye movement sleep behavioural disorder (RBD) are risk factors for Parkinson's disease (PD). Dopaminergic abnormalities are often seen after TBI, but patients usually lack parkinsonian features. We test whether TBI, PD and RBD have distinct striatal dopamine abnormalities using dopamine transporter (DaT) imaging.
METHODS
I-ioflupane single-photon emission CT scans were used in a cross-sectional study to measure DaT levels in moderate/severe TBI, healthy controls, patients with early PD and RBD. Caudate and putamen DaT, putamen to caudate ratios and left-right symmetry of DaT were compared.
RESULTS
108 participants (43 TBI, 26 PD, 8 RBD, 31 controls) were assessed. Patients with early PD scored significantly higher on the Unified Parkinson's Disease Rating Scale motor subscale than other groups. Patients with TBI and PD had reduced DaT levels in the caudate (12.2% and 18.7%, respectively) and putamen (9.0% and 42.6%, respectively) compared with controls. Patients with RBD had reduced DaT levels in the putamen (12.8%) but not in the caudate compared with controls. Patients with PD and TBI showed distinct patterns of DaT reduction, with patients with PD showing a lower putamen to caudate ratio. DaT asymmetry was greater in the PD group than other groups.
CONCLUSIONS
The results show that patients with early PD and TBI have distinct patterns of striatal dopamine abnormalities. Patients with early PD and moderate/severe TBI showed similar reductions in caudate DaT binding, but patients with PD showed a greater reduction in putamen DaT and a lower putamen to caudate ratio. The results suggest that parkinsonian motor signs are absent in these patients with TBI because of relatively intact putaminal dopamine levels.
Topics: Adult; Aged; Brain Injuries, Traumatic; Corpus Striatum; Cross-Sectional Studies; Dopamine Plasma Membrane Transport Proteins; Dopaminergic Neurons; Female; Humans; Male; Middle Aged; Parkinson Disease; REM Sleep Behavior Disorder; Risk Factors; Tomography, Emission-Computed, Single-Photon
PubMed: 32381639
DOI: 10.1136/jnnp-2019-321759