-
European Radiology Mar 2022To evaluate clinico-radiologic markers that predict poor overall survival (OS) in sporadic Creutzfeldt-Jakob disease (sCJD) and to develop a prognostic model.
OBJECTIVES
To evaluate clinico-radiologic markers that predict poor overall survival (OS) in sporadic Creutzfeldt-Jakob disease (sCJD) and to develop a prognostic model.
MATERIALS AND METHODS
Patients with newly diagnosed sCJD were included who underwent diffusion-weighted imaging (DWI) from February 2000 to July 2020. The impact of 9 clinico-radiologic features on OS was analyzed using univariable and multivariable Cox proportional hazards regression model. The DWI prognostic score model was generated. The weighted kappa was calculated for interobserver agreement.
RESULTS
Sixty patients (mean age ± SD, 61.0 ± 9.7 years, 32 women) were included. Univariable analysis showed positive associations between poor OS and patient age (p = 0.003), extent of involved cortical lobes (p = 0.11), involvement of caudate nucleus (p = 0.07), and putamen (p = 0.04). Multivariable analysis demonstrated two independent prognostic factors: age ≥ 60 (HR 2.65, 95% CI, 1.41-4.98), and diffusion restriction in caudate nucleus and putamen (HR 2.24, 95% CI, 1.15-4.37). Based on these features, the DWI prognostic score model was generated: low-risk (0-1 point), intermediate-risk (2-3 points), and high-risk (4-5 points) groups. Median OS in high-risk group was 1.7 months, which was significantly shorter than those in the intermediate-risk (14.2 months) and low-risk (26.5 months) groups (p < 0.001). Interobserver agreements were excellent (κ = 0.91-0.92).
CONCLUSIONS
Our study demonstrated that age and diffusion restriction in caudate nucleus and putamen were the independent prognostic factors of poor overall survival in sporadic Creutzfeldt-Jakob disease. Our DWI prognostic score model may be useful in clinical settings for disease stratification.
KEY POINTS
• Age ≥ 60, and diffusion restriction in caudate nucleus and putamen were the independent prognostic factors of poor overall survival in sCJD. • Based on our DWI prognostic score model, median overall survival in high-risk group was 1.7 months, which was significantly shorter than those in the intermediate-risk group (14.2 months) and low-risk group (26.5 months) (p < 0.001). • The proposed DWI prognostic score model may be useful in clinical settings for disease stratification.
Topics: Caudate Nucleus; Creutzfeldt-Jakob Syndrome; Diffusion Magnetic Resonance Imaging; Female; Humans; Prognosis; Putamen
PubMed: 34842958
DOI: 10.1007/s00330-021-08363-1 -
NPJ Parkinson's Disease Oct 2022The extent to which the degeneration of the substantia nigra (SN) and putamen each contribute to motor impairment in Parkinson's disease (PD) is unclear, as they are...
The extent to which the degeneration of the substantia nigra (SN) and putamen each contribute to motor impairment in Parkinson's disease (PD) is unclear, as they are usually investigated using different imaging modalities. To examine the pathophysiological significance of the SN and putamen in both motor impairment and the levodopa response in PD using diffusion microstructure imaging (DMI). In this monocentric retrospective cross-sectional study, DMI parameters from 108 patients with PD and 35 healthy controls (HC) were analyzed using a voxel- and region-based approach. Linear models were applied to investigate the association between individual DMI parameters and Movement Disorder Society Unified Parkinson's Disease Rating Scale-Part 3 performance in ON- and OFF-states, as well as the levodopa response, controlling for age and sex. Voxel- and region-based group comparisons of DMI parameters between PD and HC revealed significant differences in the SN and putamen. In PD, a poorer MDS-UPDRS-III performance in the ON-state was associated with increased free fluid in the SN (b-weight = 65.79, p = 0.004) and putamen (b-weight = 86.00, p = 0.006), and contrariwise with the demise of cells in both structures. The levodopa response was inversely associated with free fluid both in the SN (b-weight = -83.61, p = 0.009) and putamen (b-weight = -176.56, p < 0.001). Interestingly, when the two structures were assessed together, the integrity of the putamen, but not the SN, served as a predictor for the levodopa response (b-weight = -158.03, p < 0.001). Structural alterations in the SN and putamen can be measured by diffusion microstructure imaging in PD. They are associated with poorer motor performance in the ON-state, as well as a reduced response to levodopa. While both nigral and putaminal integrity are required for good performance in the ON-state, it is putaminal integrity alone that determines the levodopa response. Therefore, the structural integrity of the putamen is crucial for the improvement of motor symptoms to dopaminergic medication, and might therefore serve as a promising biomarker for motor staging.
PubMed: 36241644
DOI: 10.1038/s41531-022-00401-z -
Brain Pathology (Zurich, Switzerland) Sep 2021Prion-like spreading of abnormal proteins is proposed to occur in neurodegenerative diseases, and the progression of α-synuclein (α-syn) deposits has been reported in...
Prion-like spreading of abnormal proteins is proposed to occur in neurodegenerative diseases, and the progression of α-synuclein (α-syn) deposits has been reported in the brains of animal models injected with synthetic α-syn fibrils or pathological α-syn prepared from patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, α-syn transmission in nonhuman primates, which are more similar to humans, has not been fully clarified. Here, we injected synthetic human α-syn fibrils into the left striatum of a macaque monkey (Macaca fuscata). At 3 months after the injection, we examined neurodegeneration and α-syn pathology in the brain using α-syn epitope-specific antibodies, antiphosphorylated α-syn antibodies (pSyn#64 and pSer129), anti-ubiquitin antibodies, and anti-p62 antibodies. Immunohistochemical examination with pSyn#64, pSer129, and α-syn epitope-specific antibodies revealed Lewy bodies, massive α-syn-positive neuronal intracytoplasmic inclusions (NCIs), and neurites in the left putamen. These inclusions were also positive for ubiquitin and p62. LB509, a human-specific α-syn antibody targeting amino acid residues 115-122, showed limited immunoreactivity around the injection site. The left substantia nigra (SN) and the bilateral frontal cortex also contained some NCIs and neurites. The left hemisphere, including parietal/temporal cortex presented sparse α-syn pathology, and no immunoreactivity was seen in olfactory nerves, amygdala, hippocampus, or right parietal/temporal cortex. Neuronal loss and gliosis in regions with α-syn pathology were mild, except for the left striatum and SN. Our results indicate that abnormal α-syn fibrils propagate throughout the brain of M. fuscata via projection, association, and commissural fibers, though the progression of α-syn pathology is limited.
Topics: Animals; Brain; Inclusion Bodies; Lewy Bodies; Macaca fuscata; Male; Parkinson Disease; Putamen; Substantia Nigra; Synucleinopathies; alpha-Synuclein
PubMed: 33754430
DOI: 10.1111/bpa.12952 -
Frontiers in Aging Neuroscience 2022The cerebellum is associated with the emergence of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), yet the neural mechanism remains obscure. Our aim was...
The cerebellum is associated with the emergence of levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), yet the neural mechanism remains obscure. Our aim was to ascertain the role of functional connectivity (FC) patterns of the cerebellar dentate nucleus (DN) in the pathogenesis of peak-dose dyskinesia in PD. Twenty-three peak-dose dyskinetic PD patients, 27 non-dyskinetic PD patients, and 36 healthy controls (HCs) were enrolled and underwent T1-weighted and resting-state functional magnetic resonance imaging (rs-fMRI) scans after dopaminergic medication intake. We selected left and right DN as the regions of interest and then employed voxel-wise FC analysis and voxel-based morphometry analysis (VBM). The correlations between the altered FC pattern and clinical scores were also examined. Finally, receiver operating characteristic (ROC) curve analysis was performed to assess the potential of DN FC measures as a feature of peak-dose dyskinesia in PD. Dyskinetic PD patients showed excessively increased FC between the left DN and right putamen compared with the non-dyskinetic. When compared with controls, dyskinetic PD patients mainly exhibited increased FC between left DN and bilateral putamen, left paracentral lobule, right postcentral gyrus, and supplementary motor area. Additionally, non-dyskinetic PD patients displayed increased FC between left DN and left precentral gyrus and right paracentral lobule compared with controls. Meanwhile, increased FC between DN (left/right) and ipsilateral cerebellum lobule VIII was observed in both PD subgroups. However, no corresponding alteration in gray matter volume (GMV) was found. Further, a positive correlation between the -FC values of left DN-right putamen and the Unified Dyskinesia Rating Scale (UDysRS) was confirmed in dyskinetic PD patients. Notably, ROC curve analyses revealed that the -FC values of left DN-right putamen could be a potential neuroimaging feature identifying dyskinetic PD patients. Our findings demonstrated that the excessively strengthened connectivity of DN-putamen might contribute to the pathophysiological mechanisms of peak-dose dyskinesia in PD.
PubMed: 36034152
DOI: 10.3389/fnagi.2022.943179 -
Annals of Nuclear Medicine Jan 2021Aging decreases dopamine transporter (DAT) availability of striatum both in humans and rodents. We aimed to investigate the relationship of DAT availabilities from...
OBJECTIVE
Aging decreases dopamine transporter (DAT) availability of striatum both in humans and rodents. We aimed to investigate the relationship of DAT availabilities from ventral striatum, caudate nucleus, and putamen with aging in healthy subjects.
METHODS
I-FP-CIT single photon emission computed tomography (SPECT) was performed in all subjects. Specific binding of I-FP-CIT regarding DAT was calculated using a volume-of-interest-based analysis of ventral striatum, caudate nucleus, putamen. The cerebellum was chosen as a reference region. Specific binding ratios (SBRs) were calculated as follows: SBR = (target- cerebellum)/cerebellum.
RESULTS
A total of 166 healthy subjects (109 males and 57 females) were included in this study. SBRs of ventral striatum, caudate nucleus, and putamen were negatively correlated with age. In young males, SBRs of ventral striatum and putamen were not correlated with aging. However, SBRs of caudate nucleus showed the trend toward negative correlation with age in the young group. In old males, SBR of caudate nucleus was negatively correlated with age and SBR of ventral striatum showed a trend toward negative correlation with age. Slopes of regression lines were not significantly different according to age groups in ventral striatum, caudate nucleus, or putamen. SBRs of ventral striatum, caudate nucleus, and putamen were negatively correlated with age in young females, but not in old females. Interestingly, slopes of regression line were significantly different between young and old females in ventral striatum, caudate nucleus, and putamen.
CONCLUSIONS
We have shown that slopes of regression lines of DAT availabilities and age were significantly different between young and old subjects in females, not in males. Therefore, sex has an impact on aging-related decline of striatal DAT availability.
Topics: Adult; Aged; Aging; Dopamine Plasma Membrane Transport Proteins; Female; Healthy Volunteers; Humans; Male; Middle Aged; Sex Characteristics; Tomography, Emission-Computed, Single-Photon
PubMed: 33052524
DOI: 10.1007/s12149-020-01538-8 -
Biological Psychiatry. Cognitive... Jul 2023Previous neuroimaging studies have investigated reward-processing dysfunction in major depressive disorder and have led to the common finding that major depressive...
BACKGROUND
Previous neuroimaging studies have investigated reward-processing dysfunction in major depressive disorder and have led to the common finding that major depressive disorder is associated with reduced reward responses within the reward circuit. Yet it is unclear whether such reward-processing dysfunction is specifically associated with the severity of depressive symptoms in major depressive disorder or is associated with common comorbidities.
METHODS
We investigated reward-processing differences using a classic juice-delivery functional magnetic resonance imaging experiment to compare psychiatric patients with severe depressive symptoms (DEPs) to both psychiatric control subjects (PCs) and healthy control subjects. In this study, the DEPs (n = 108) were matched to healthy control subjects (n = 62) for demographic characteristics and to the PCs (n = 108) for demographics and comorbid psychiatric diagnoses. An a priori region of interest, the left putamen, was selected using previous studies. An exploratory whole-brain analysis was performed to explore for nonhypothesized regions.
RESULTS
Relative to the PCs and healthy control subjects, the DEP group showed smaller responses to reward stimulus in the left putamen. Whole-brain exploratory analysis revealed that DEPs had significantly lower responses to reward stimulus in the bilateral dorsal striatum (putamen and caudate), middle frontal gyrus, left precentral gyrus, and middle cingulate cortex than PCs.
CONCLUSIONS
Our findings suggest that DEPs may have a lesser ability to modulate behavior as a function of reward, especially in those individuals who experience the most severe depressive symptoms. In both DEPs and PCs, the severity of depressive symptoms was related to reduced reward responses in the left putamen.
Topics: Humans; Depressive Disorder, Major; Depression; Inpatients; Brain; Reward
PubMed: 34174484
DOI: 10.1016/j.bpsc.2021.05.010 -
Parkinsonism & Related Disorders Sep 2021This study aimed to evaluate whether novel individual voxel-based morphometry adjusting covariates (iVAC), such as age, sex, and total intracranial volume, could...
INTRODUCTION
This study aimed to evaluate whether novel individual voxel-based morphometry adjusting covariates (iVAC), such as age, sex, and total intracranial volume, could increase the accuracy of a diagnosis of multiple system atrophy (MSA) and enable the differentiation of MSA from Parkinson's disease (PD).
METHODS
We included 53 MSA patients (MSA-C: 33, MSA-P: 20), 53 PD patients, and 189 healthy controls in this study. All participants underwent high-resolution T1-weighted imaging (WI) and T2-WI with a 3.0-T MRI scanner. We evaluated the occurrence of significant atrophic findings in the pons/middle cerebellar peduncle (MCP) and putamen on iVAC and compared these findings with characteristic changes on T2-WI.
RESULTS
On iVAC, abnormal findings were observed in the pons/MCP of 96.2% of MSA patients and in the putamen of 80% of MSA patients; however, on T2-WI, they were both observed at a frequency of 60.4% in MSA patients. On iVAC, all but one MSA-P patient (98.1%) showed significant atrophic changes in the pons/MCP or putamen. By contrast, 69.8% of patients with MSA showed abnormal signal changes in the pons/MCP or putamen on T2-WI. iVAC yielded 95.0% sensitivity and 96.2% specificity for differentiating MSA-P from PD.
CONCLUSION
iVAC enabled us to recognize the morphological characteristics of MSA visually and with high accuracy compared to T2-WI, indicating that iVAC is a potential diagnostic screening tool for MSA.
Topics: Adult; Aged; Case-Control Studies; Diagnosis, Differential; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Middle Cerebellar Peduncle; Multiple System Atrophy; Parkinson Disease; Pons; Putamen; Reproducibility of Results; Sensitivity and Specificity
PubMed: 34481140
DOI: 10.1016/j.parkreldis.2021.07.025 -
Brain : a Journal of Neurology Mar 2024Dopaminergic dysfunction in the basal ganglia, particularly in the posterior putamen, is often viewed as the primary pathological mechanism behind motor slowing (i.e....
Dopaminergic dysfunction in the basal ganglia, particularly in the posterior putamen, is often viewed as the primary pathological mechanism behind motor slowing (i.e. bradykinesia) in Parkinson's disease. However, striatal dopamine loss fails to account for interindividual differences in motor phenotype and rate of decline, implying that the expression of motor symptoms depends on additional mechanisms, some of which may be compensatory in nature. Building on observations of increased motor-related activity in the parieto-premotor cortex of Parkinson patients, we tested the hypothesis that interindividual differences in clinical severity are determined by compensatory cortical mechanisms and not just by basal ganglia dysfunction. Using functional MRI, we measured variability in motor- and selection-related brain activity during a visuomotor task in 353 patients with Parkinson's disease (≤5 years disease duration) and 60 healthy controls. In this task, we manipulated action selection demand by varying the number of possible actions that individuals could choose from. Clinical variability was characterized in two ways. First, patients were categorized into three previously validated, discrete clinical subtypes that are hypothesized to reflect distinct routes of α-synuclein propagation: diffuse-malignant (n = 42), intermediate (n = 128) or mild motor-predominant (n = 150). Second, we used the scores of bradykinesia severity and cognitive performance across the entire sample as continuous measures. Patients showed motor slowing (longer response times) and reduced motor-related activity in the basal ganglia compared with controls. However, basal ganglia activity did not differ between clinical subtypes and was not associated with clinical scores. This indicates a limited role for striatal dysfunction in shaping interindividual differences in clinical severity. Consistent with our hypothesis, we observed enhanced action selection-related activity in the parieto-premotor cortex of patients with a mild-motor predominant subtype, both compared to patients with a diffuse-malignant subtype and controls. Furthermore, increased parieto-premotor activity was related to lower bradykinesia severity and better cognitive performance, which points to a compensatory role. We conclude that parieto-premotor compensation, rather than basal ganglia dysfunction, shapes interindividual variability in symptom severity in Parkinson's disease. Future interventions may focus on maintaining and enhancing compensatory cortical mechanisms, rather than only attempting to normalize basal ganglia dysfunction.
Topics: Humans; Parkinson Disease; Hypokinesia; Basal Ganglia; Corpus Striatum; Dopamine; Putamen
PubMed: 37757883
DOI: 10.1093/brain/awad325 -
Movement Disorders : Official Journal... Sep 2023Neurturin is a member of the glial cell line-derived neurotrophic factor family of neurotrophic factors and has the potential to protectdegenerating dopaminergic neurons.
BACKGROUND
Neurturin is a member of the glial cell line-derived neurotrophic factor family of neurotrophic factors and has the potential to protectdegenerating dopaminergic neurons.
OBJECTIVE
Here, we performed post-mortem studies on two patients with advanced Parkinson's disease that survived 10 years following AAV-neurturin gene (Cere120) delivery to verify long-term effects of trophic factor neurturin.
METHODS
Cere120 was delivered to the putamen bilaterally in one case and to the putamen plus substantia nigra bilaterally in the second. Immunohistochemistry was used to examine neurturin, Rearranged during transfection(RET), phosphor-S6, and tyrosine hydroxylase expressions, inflammatory reactions, and α-synuclein accumulation.
RESULTS
In both patients there was persistent, albeit limited, neurturin expression in the putamen covering 1.31% to 5.92% of the putamen. Dense staining of tyrosine hydroxylase-positive fibers was observed in areas that contained detectable neurturin expression. In substantia nigra, neurturin expression was detected in 11% of remaining melanin-containing neurons in the patient with combined putamenal and nigral gene delivery, but not in the patient with putamenal gene delivery alone. Tyrosine hydroxylase positive neurons were 66% to 84% of remaining neuromelanin neurons in substantia nigra with Cere120 delivery and 23% to 24% in substantia nigra without gene delivery. More RET and phosphor-S6 positive neurons were observed in substantia nigra following nigral Cere120. Inflammatory and Lewy pathologies were similar in substantia nigra with or without Cere120 delivery.
CONCLUSIONS
This study provides evidence of long-term persistent transgene expression and bioactivity following gene delivery to the nigrostriatal system. Therefore, future efforts using gene therapy for neurodegenerative diseases should consider means to enhance remaining dopamine neuron function and stop pathological propagation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; Neurturin; Tyrosine 3-Monooxygenase; Neurons; Genetic Therapy; Substantia Nigra
PubMed: 37544016
DOI: 10.1002/mds.29518 -
NeuroImage. Clinical 2022Perinatal stroke affects millions of children and results in lifelong disability. Two forms prevail: arterial ischemic stroke (AIS), and periventricular venous...
INTRODUCTION
Perinatal stroke affects millions of children and results in lifelong disability. Two forms prevail: arterial ischemic stroke (AIS), and periventricular venous infarction (PVI). With such focal damage early in life, neural structures may reorganize during development to determine clinical function, particularly in the contralesional hemisphere. Such processes are increasingly understood in the motor system, however, the role of the basal ganglia, a group of subcortical nuclei that are critical to movement, behaviour, and learning, remain relatively unexplored. Perinatal strokes that directly damage the basal ganglia have been associated with worse motor outcomes, but how developmental plasticity affects bilateral basal ganglia structure is unknown. We hypothesized that children with perinatal stroke have alterations in bilateral basal ganglia volumes, the degree of which correlates with clinical motor function.
METHODS
Children with AIS or PVI, and controls, aged 6-19 years, were recruited from a population-based cohort. MRIs were acquired on a 3 T GE MR750w scanner. High-resolution T1-weighted images (166 slices, 1 mm isotropic voxels) underwent manual segmentations of bilateral caudate and putamen. Extracted volumes were corrected for total intracranial volume. A structure volume ratio quantified hemispheric asymmetry of caudate and putamen (non-dominant/dominant hemisphere structure volume) with ratios closer to 1 reflecting a greater degree of symmetry between structures. Participants were additionally dichotomized by volume ratios into two groups, those with values above the group mean (0.8) and those below. Motor function was assessed using the Assisting Hand Assessment (AHA) and the Box and Blocks test in affected (BBTA) and unaffected (BBTU) hands. Group differences in volumes were explored using Kruskal-Wallis tests, and interhemispheric differences using Wilcoxon. Partial Spearman correlations explored associations between volumes and motor function (factoring out age, and whole-brain white matter volume, a proxy for lesion extent).
RESULTS
In the dominant (non-lesioned) hemisphere, volumes were larger in AIS compared to PVI for both the caudate (p < 0.05) and putamen (p < 0.01) but comparable between stroke groups and controls. Non-dominant (lesioned) hemisphere volumes were larger for controls than AIS for the putamen (p < 0.05), and for the caudate in PVI (p = 0.001). Interhemispheric differences showed greater dominant hemisphere volumes for the putamen in controls (p < 0.01), for both the caudate (p < 0.01) and putamen (p < 0.001) in AIS, and for the caudate (p = 0.01) in PVI. Motor scores did not differ between AIS and PVI thus groups were combined to increase statistical power. Better motor scores were associated with larger non-dominant putamen volumes (BBTA: r = 0.40, p = 0.011), and larger putamen volume ratios (BBTA: r = 0.52, p < 0.001, AHA: r = 0.43, p < 0.01). For those with relatively symmetrical putamen volume ratios (ratio > group mean of 0.8), age was positively correlated with BBTA (r = 0.54, p < 0.01) and BBTU (r = 0.69, p < 0.001). For those with more asymmetrical putamen volume ratios, associations with motor function and age were not seen (BBTA: r = 0.21, p = 0.40, BBTU: r = 0.37, p = 0.13).
CONCLUSION
Specific perinatal stroke lesions affect different elements of basal ganglia development. PVI primarily affected the caudate, while AIS primarily affected the putamen. Putamen volumes in the lesioned hemisphere are associated with clinical motor function. The basal ganglia should be included in evolving models of developmental plasticity after perinatal stroke.
Topics: Basal Ganglia; Child; Female; Hand; Humans; Magnetic Resonance Imaging; Pregnancy; Putamen; Stroke
PubMed: 36002972
DOI: 10.1016/j.nicl.2022.103143