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Neurology Nov 2023There are limited validated biomarkers in Parkinson disease (PD) which substantially hinders the ability to monitor disease progression and consequently measure the...
BACKGROUND AND OBJECTIVES
There are limited validated biomarkers in Parkinson disease (PD) which substantially hinders the ability to monitor disease progression and consequently measure the efficacy of disease-modifying treatments. Imaging biomarkers, such as vesicular monoamine transporter type 2 (VMAT2) PET, enable enhanced diagnostic accuracy and detect early neurodegenerative changes associated with prodromal PD. This study sought to assess whether F-AV-133 VMAT2 PET is sensitive enough to monitor and quantify disease progression over a 2-year window.
METHODS
F-AV-133 PET scans were performed on participants with PD and REM sleep behavior disorder (RBD) and neurologic controls (NC). All participants were scanned twice ∼26 months apart. Regional tracer retention was calculated with a primary visual cortex reference region and expressed as the standard uptake volume ratio. Regions of interest included caudate, anterior, and posterior putamen. At the time of scanning, participants underwent clinical evaluation including UPDRS test, Sniffin' Sticks, and Hospital Anxiety and Depression Score.
RESULTS
Over the 26-month interval, a significant decline in PET signal was observed in all 3 regions in participants with PD (N = 26) compared with NC (N = 12), consistent with a decrease in VMAT2 level and ongoing neurodegeneration. Imaging trajectory calculations suggest that the neurodegeneration in PD occurs over ∼33 years [CI: 27.2-39.5], with ∼10.5 years [CI: 9.1-11.3] of degeneration in the posterior putamen before it becomes detectable on a VMAT2 PET scan, a further ∼6.5 years [CI: 1.6-12.7] until symptom onset, and a further ∼3 years [CI: 0.3-8.7] until clinical diagnosis.
DISCUSSION
Over a 2-year period, F-AV-133 VMAT2 PET was able to detect progression of nigrostriatal degeneration in participants with PD, and it represents a sensitive tool to identify individuals at risk of progression to PD, which are currently lacking using clinical readouts. Trajectory models propose that there is nigrostriatal degeneration occurring for 20 years before clinical diagnosis. These data demonstrate that VMAT2 PET provides a sensitive measure to monitor neurodegenerative progression of PD which has implications for PD diagnostics and subsequently clinical trial patient stratification and monitoring.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that VMAT2 PET can detect patients with Parkinson disease and quantify progression over a 2-year window.
Topics: Humans; Parkinson Disease; Positron-Emission Tomography; Vesicular Monoamine Transport Proteins; Biomarkers; Disease Progression
PubMed: 37816639
DOI: 10.1212/WNL.0000000000207748 -
Academic Radiology Dec 2023Overlapping parkinsonism, cerebellar ataxia, and pyramidal signs render challenges in the clinical diagnosis of multiple system atrophy (MSA). The neuroimaging pattern...
RATIONALE AND OBJECTIVES
Overlapping parkinsonism, cerebellar ataxia, and pyramidal signs render challenges in the clinical diagnosis of multiple system atrophy (MSA). The neuroimaging pattern is valuable to understand its pathophysiology and improve its diagnostic effect.
MATERIALS AND METHODS
We retrospectively obtained magnetic resonance imaging and susceptibility-weighted imaging in patients with MSA (including parkinsonian type [MSA-P] and cerebellar type [MSA-C]), Parkinson's disease, and normal controls. We quantified neuroimaging features to identify the optimal threshold for diagnosis. Furthermore, we explore neuroimaging patterns of MSA by mapping the subcortical morphological alterations and constructing a diagnostic model.
RESULTS
Compared to controls, normalized putaminal volume significantly decreased in patients with MSA-P (P < .001) and normalized pontine volume significantly decreased in patients with MSA-C (P < .001). The Youden index of the threshold-based clinical prediction model was 0.871-0.928 in patients with MSA. The neuroimaging pattern in patients with MSA was jointly located in the lateral putamen, and the neuroimaging pattern prediction model achieved a classification accuracy of 83.9%-100%.
CONCLUSION
The quantitative neuroimaging features and surface-based morphologic anomalies represent the markers of MSA and open new avenues for personalized clinical diagnosis.
Topics: Humans; Multiple System Atrophy; Models, Statistical; Retrospective Studies; Prognosis; Magnetic Resonance Imaging; Neuroimaging; Diagnosis, Differential
PubMed: 37495425
DOI: 10.1016/j.acra.2023.04.014 -
Neuroscience and Biobehavioral Reviews Sep 2023Whether remitted major depressive disorder (rMDD) and MDD present common or distinct neuropathological mechanisms remains unclear. We performed a meta-analysis of... (Meta-Analysis)
Meta-Analysis Review
Common and distinct patterns of task-related neural activation abnormalities in patients with remitted and current major depressive disorder: A systematic review and coordinate-based meta-analysis.
Whether remitted major depressive disorder (rMDD) and MDD present common or distinct neuropathological mechanisms remains unclear. We performed a meta-analysis of task-related whole-brain functional magnetic resonance imaging (fMRI) using anisotropic effect-size signed differential mapping software to compare brain activation between rMDD/MDD patients and healthy controls (HCs). We included 18 rMDD studies (458 patients and 476 HCs) and 120 MDD studies (3746 patients and 3863 HCs). The results showed that MDD and rMDD patients shared increased neural activation in the right temporal pole and right superior temporal gyrus. Several brain regions, including the right middle temporal gyrus, left inferior parietal, prefrontal cortex, left superior frontal gyrus and striatum, differed significantly between MDD and rMDD. Meta-regression analyses revealed that the percentage of females with MDD was positively associated with brain activity in the right lenticular nucleus/putamen. Our results provide valuable insights into the underlying neuropathology of brain dysfunction in MDD, developing more targeted and efficacious treatment and intervention strategies, and more importantly, providing potential neuroimaging targets for the early screening of MDD.
Topics: Female; Humans; Depressive Disorder, Major; Brain; Brain Mapping; Prefrontal Cortex; Temporal Lobe; Magnetic Resonance Imaging
PubMed: 37315658
DOI: 10.1016/j.neubiorev.2023.105284 -
Frontiers in Human Neuroscience 2023A growing body of research has investigated how performing arts training, and more specifically, music training, impacts the brain. Recent meta-analytic work has...
INTRODUCTION
A growing body of research has investigated how performing arts training, and more specifically, music training, impacts the brain. Recent meta-analytic work has identified multiple brain areas where activity varies as a function of levels of musical expertise gained through music training. However, research has also shown that musical sophistication may be high even without music training. Thus, we aim to extend previous work by investigating whether the functional connectivity of these areas relates to interindividual differences in musical sophistication, and to characterize differences in connectivity attributed to performing arts training.
METHODS
We analyzed resting-state functional magnetic resonance imaging from = 74 participants, of whom 37 received performing arts training, that is, including a musical instrument, singing, and/or acting, at university level. We used a validated, continuous measure of musical sophistication to further characterize our sample. Following standard pre-processing, fifteen brain areas were identified based on meta-analytic work and used as seeds in separate seed-to-voxel analyses to examine the effect of musical sophistication across the sample, and between-group analyses to examine the effects of performing arts training.
RESULTS
Connectivity of bilateral superior temporal gyrus, bilateral precentral gyrus and cerebellum, and bilateral putamen, left insula, and left thalamus varied with different aspects of musical sophistication. By including these measures of these aspects as covariates in analyses, we found that connectivity of the right superior temporal gyrus and left precentral gyrus relate to effects of performing arts training beyond effects of individual musical sophistication.
DISCUSSION
Our results highlight the potential role of sensory areas in active engagement with music, the potential role of motor areas in emotion processing, and the potential role of connectivity between putamen and lingual gyrus in general musical sophistication.
PubMed: 37841073
DOI: 10.3389/fnhum.2023.1195996 -
Neuroimaging biomarkers in Huntington's disease: Preparing for a new era of therapeutic development.Parkinsonism & Related Disorders Sep 2023A critical challenge for Huntington's disease (HD) clinical trials in disease modification is the definition of endpoints that can capture change when clinical signs are... (Review)
Review
BACKGROUND
A critical challenge for Huntington's disease (HD) clinical trials in disease modification is the definition of endpoints that can capture change when clinical signs are subtle/non-existent. Reliable biomarkers are therefore urgently needed to facilitate drug development by allowing the enrichment of clinical trial populations and providing measures of benefit that can support the establishment of efficacy.
METHODS
By systematically examining the published literature on HD neuroimaging biomarker studies, we sought to advance knowledge to guide the validation of neuroimaging biomarkers. We started by reviewing both cross-sectional and longitudinal studies and then conducted an in-depth review to make quantitative comparisons between biomarkers using data only from longitudinal studies with samples sizes larger than ten participants in PET studies or 30 participants in MRI studies.
RESULTS
From a total of 2202 publications initially identified, we included 32 studies, 19 of which underwent in-depth comparative review. The majority of included studies used various MRI-based methods (manual to automatic) to longitudinally assess either the volume of the putamen or the caudate, which have been shown to undergo significant structural change during HD natural history.
CONCLUSION
Despite the impressively large number of neuroimaging biomarker studies, only a small number of adequately designed studies met our criteria. Among these various biomarkers, MRI-based volumetric analyses of the caudate and putamen are currently the best validated for use in the disease phase before clinical motor diagnosis. A biomarker that can be used to demonstrate a disease-modifying effect is still missing.
Topics: Humans; Huntington Disease; Cross-Sectional Studies; Neuroimaging; Magnetic Resonance Imaging; Biomarkers; Disease Progression
PubMed: 37407343
DOI: 10.1016/j.parkreldis.2023.105488 -
Behavioural Brain Research Jun 2024Parkinson's is the most common neurodegenerative disease after Alzheimer's. Motor findings in Parkinson's occur as a result of the degeneration of dopaminergic neurons... (Review)
Review
Parkinson's is the most common neurodegenerative disease after Alzheimer's. Motor findings in Parkinson's occur as a result of the degeneration of dopaminergic neurons starting in the substantia nigra pars compacta and ending in the putamen and caudate nucleus. Loss of neurons and the formation of inclusions called Lewy bodies in existing neurons are characteristic histopathological findings of Parkinson's. The disease primarily impairs the functional capacity of the person with cardinal findings such as tremor, bradykinesia, etc., as a result of the loss of dopaminergic neurons in the substantia nigra. Experimental animal models of Parkinson's have been used extensively in recent years to investigate the pathology of this disease. These models are generally based on systemic or local(intracerebral) administration of neurotoxins, which can replicate many features of Parkinson's mammals. The development of transgenic models in recent years has allowed us to learn more about the modeling of Parkinson's. Applying animal modeling, which shows the most human-like effects in studies, is extremely important. It has been demonstrated that oxidative stress increases in many neurodegenerative diseases such as Parkinson's and various age-related degenerative diseases in humans and that neurons are sensitive to it. In cases where oxidative stress increases and antioxidant systems are inadequate, natural molecules such as flavonoids and polyphenols can be used as a new antioxidant treatment to reduce neuronal reactive oxygen species and improve the neurodegenerative process. Therefore, in this article, we examined experimental animal modeling in Parkinson's disease and the effect of green chemistry approaches on Parkinson's disease.
PubMed: 38844056
DOI: 10.1016/j.bbr.2024.115092 -
Movement Disorders : Official Journal... Jan 2024To determine the rates of brain atrophy progression in vivo in patients with multiple system atrophy (MSA).
OBJECTIVE
To determine the rates of brain atrophy progression in vivo in patients with multiple system atrophy (MSA).
BACKGROUND
Surrogate biomarkers of disease progression are a major unmet need in MSA. Small-scale longitudinal studies in patients with MSA using magnetic resonance imaging (MRI) to assess progression of brain atrophy have produced inconsistent results. In recent years, novel MRI post-processing methods have been developed enabling reliable quantification of brain atrophy in an automated fashion.
METHODS
Serial 3D-T1-weighted MRI assessments (baseline and after 1 year of follow-up) of 43 patients with MSA were analyzed and compared to a cohort of early-stage Parkinson's disease (PD) patients and healthy controls (HC). FreeSurfer's longitudinal analysis stream was used to determine the brain atrophy rates in an observer-independent fashion.
RESULTS
Mean ages at baseline were 64.4 ± 8.3, 60.0 ± 7.5, and 59.8 ± 9.2 years in MSA, PD patients and HC, respectively. A mean disease duration at baseline of 4.1 ± 2.5 years in MSA patients and 2.3 ± 1.4 years in PD patients was observed. Brain regions chiefly affected by MSA pathology showed progressive atrophy with annual rates of atrophy for the cerebellar cortex, cerebellar white matter, pons, and putamen of -4.24 ± 6.8%, -8.22 ± 8.8%, -4.67 ± 4.9%, and - 4.25 ± 4.9%, respectively. Similar to HC, atrophy rates in PD patients were minimal with values of -0.41% ± 1.8%, -1.47% ± 4.1%, -0.04% ± 1.8%, and -1.54% ± 2.2% for cerebellar cortex, cerebellar white matter, pons, and putamen, respectively.
CONCLUSIONS
Patients with MSA show significant brain volume loss over 12 months, and cerebellar, pontine, and putaminal volumes were the most sensitive to change in mid-stage disease. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Multiple System Atrophy; Parkinson Disease; Magnetic Resonance Imaging; Brain; Atrophy; Diagnosis, Differential
PubMed: 37933745
DOI: 10.1002/mds.29633 -
Journal of Neurology, Neurosurgery, and... Dec 2023The choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain, as a part of the glymphatic system. This study aimed to investigate the...
BACKGROUND
The choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain, as a part of the glymphatic system. This study aimed to investigate the association between CP volume (CPV), nigrostriatal dopaminergic degeneration and motor outcomes in Parkinson's disease (PD).
METHODS
We retrospectively searched drug-naïve patients with early-stage PD who underwent dopamine transporter (DAT) scanning and MRI. Automatic CP segmentation was performed, and the CPV was calculated. The relationship between CPV, DAT availability and Unified PD Rating Scale Part III (UPDRS-III) scores was assessed using multivariate linear regression. We performed longitudinal analyses to assess motor outcomes according to CPV.
RESULTS
CPV was negatively associated with DAT availability in each striatal subregion (anterior caudate, β=-0.134, p=0.012; posterior caudate, β=-0.162, p=0.002; anterior putamen, β=-0.133, p=0.024; posterior putamen, β=-0.125, p=0.039; ventral putamen, β=-0.125, p=0.035), except for the ventral striatum. CPV was positively associated with the UPDRS-III score even after adjusting for DAT availability in the posterior putamen (β=0.121; p=0.035). A larger CPV was associated with the future development of freezing of gait in the Cox regression model (HR 1.539, p=0.027) and a more rapid increase in dopaminergic medication in the linear mixed model (CPV×time, p=0.037), but was not associated with the risk of developing levodopa-induced dyskinesia or wearing off.
CONCLUSION
These findings suggest that CPV has the potential to serve as a biomarker for baseline and longitudinal motor disabilities in PD.
Topics: Humans; Parkinson Disease; Retrospective Studies; Choroid Plexus; Gait Disorders, Neurologic; Dopamine; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins
PubMed: 37399288
DOI: 10.1136/jnnp-2023-331170 -
Cells Nov 2023Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DANs), and Non-human primates (NHPs) injected with...
Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DANs), and Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinson's disease (PD) patients. Here, we obtained well-characterized DANs from hESCs and transplanted them into two parkinsonian monkeys to assess their behavioral and imaging changes. DANs from hESCs expressed dopaminergic markers, generated action potentials, and released dopamine (DA) in vitro. These neurons were transplanted bilaterally into the putamen of parkinsonian NHPs, and using magnetic resonance imaging techniques, we calculated the fractional anisotropy (FA) and mean diffusivity (MD), both employed for the first time for these purposes, to detect in vivo axonal and cellular density changes in the brain. Likewise, positron-emission tomography scans were performed to evaluate grafted DANs. Histological analyses identified grafted DANs, which were quantified stereologically. After grafting, animals showed signs of partially improved motor behavior in some of the HALLWAY motor tasks. Improvement in motor evaluations was inversely correlated with increases in bilateral FA. MD did not correlate with behavior but presented a negative correlation with FA. We also found higher 11C-DTBZ binding in positron-emission tomography scans associated with grafts. Higher DA levels measured by microdialysis after stimulation with a high-potassium solution or amphetamine were present in grafted animals after ten months, which has not been previously reported. Postmortem analysis of NHP brains showed that transplanted DANs survived in the putamen long-term, without developing tumors, in immunosuppressed animals. Although these results need to be confirmed with larger groups of NHPs, our molecular, behavioral, biochemical, and imaging findings support the integration and survival of human DANs in this pre-clinical PD model.
Topics: Animals; Humans; Dopaminergic Neurons; Human Embryonic Stem Cells; Haplorhini; Mesencephalon; Dopamine; Parkinson Disease
PubMed: 38067166
DOI: 10.3390/cells12232738 -
Med (New York, N.Y.) Mar 2024Addiction is a chronic and relapsing brain disorder. Despite numerous neuroimaging and neurophysiological studies on individuals with substance use disorder (SUD) or... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Addiction is a chronic and relapsing brain disorder. Despite numerous neuroimaging and neurophysiological studies on individuals with substance use disorder (SUD) or behavioral addiction (BEA), currently a clear neural activity signature for the addicted brain is lacking.
METHODS
We first performed systemic coordinate-based meta-analysis and partial least-squares regression to identify shared or distinct brain regions across multiple addictive disorders, with abnormal resting-state activity in SUD and BEA based on 46 studies (55 contrasts), including regional homogeneity (ReHo) and low-frequency fluctuation amplitude (ALFF) or fractional ALFF. We then combined Neurosynth, postmortem gene expression, and receptor/transporter distribution data to uncover the potential molecular mechanisms underlying these neural activity signatures.
FINDINGS
The overall comparison between addiction cohorts and healthy subjects indicated significantly increased ReHo and ALFF in the right striatum (putamen) and bilateral supplementary motor area, as well as decreased ReHo and ALFF in the bilateral anterior cingulate cortex and ventral medial prefrontal cortex, in the addiction group. On the other hand, neural activity in cingulate cortex, ventral medial prefrontal cortex, and orbitofrontal cortex differed between SUD and BEA subjects. Using molecular analyses, the altered resting activity recapitulated the spatial distribution of dopaminergic, GABAergic, and acetylcholine system in SUD, while this also includes the serotonergic system in BEA.
CONCLUSIONS
These results indicate both common and distinctive neural substrates underlying SUD and BEA, which validates and supports targeted neuromodulation against addiction.
FUNDING
This work was supported by the National Natural Science Foundation of China and Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health.
Topics: United States; Humans; Magnetic Resonance Imaging; Brain; Brain Mapping; Behavior, Addictive; Prefrontal Cortex; Substance-Related Disorders
PubMed: 38359839
DOI: 10.1016/j.medj.2024.01.008