Chemoarchitectural signatures of subcortical shape alterations in generalized epilepsy.

Genetic generalized epilepsies (GGE) exhibit widespread morphometric alterations in the subcortical structures. Subcortical structures are essential for understanding GGE pathophysiology, but their fine-grained morphological diversity has yet to be comprehensively investigated. Furthermore, the relationships between macroscale morphological disturbances and microscale molecular chemoarchitectures are unclear. High-resolution structural images were acquired from patients with GGE (n = 97) and sex- and age-matched healthy controls (HCs, n = 184). Individual measurements of surface shape features (thickness and surface area) of seven bilateral subcortical structures were quantified. The patients and HCs were then compared vertex-wise, and shape anomalies were co-located with brain neurotransmitter profiles. We found widespread morphological alterations in GGE and prominent disruptions in the thalamus, putamen, and hippocampus. Shape area dilations were observed in the bilateral ventral, medial, and right dorsal thalamus, as well as the bilateral lateral putamen. We found that the shape area deviation pattern was spatially correlated with the norepinephrine transporter and nicotinic acetylcholine (Ach) receptor (α4ß2) profiles, but a distinct association was seen in the muscarinic Ach receptor (M1). The findings provided a comprehensive picture of subcortical morphological disruptions in GGE, and further characterized the associated molecular mechanisms. This information may increase our understanding of the pathophysiology of GGE.

Is the Caudate, Putamen, and Globus Pallidus the Delusional Disorder's Trio? A Texture Analysis Study.

BACKGROUND: The neurobiological basis of delusional disorder is less explored through neuroimaging techniques than in other psychotic disorders. This study aims to provide information about the neural origins of delusional disorder (DD) by examining the neuroanatomical features of some basal nuclei with magnetic resonance imaging (MRI) texture analysis. MATERIALS AND METHODS: Twenty DD patients and 20 healthy individuals were included in the study. Globus pallidus, putamen, and caudate nuclei were selected individually with a region of interest (ROI) on the axial MRI images. The entire texture analysis algorithm applied to all selected ROIs was done with an in-house software. Nuclei on both sides were taken as separate samples. RESULTS: There were no significant differences between groups in terms of age and gender. The average "mean, median and maximum" values of all three nuclei were decreased in DD patients. The small putamen area and the differences detected in different tissue parameters for all three nuclei in delusional disorder patients indicate that they differ in delusional disorder from normal controls (p < 0.05). CONCLUSION: The differences detected in the texture parameters for all three nuclei indicate that there is something different in the DD from in the normal controls. Neuroimaging studies with larger samples and different techniques in the future may shed light on the etiology of delusional disorder.

Persistent fatigue in post-acute COVID syndrome is associated with altered T1 MRI texture in subcortical structures: a preliminary investigation.

Post-acute COVID syndrome (PACS) is a global health concern and is often associated with debilitating symptoms. Post-COVID fatigue is a particularly frequent and troubling issue, and its underlying mechanisms remain incompletely understood. One potential contributor is micropathological injury of subcortical and brainstem structures, as has been identified in other patient populations. Texture-based analysis (TA) may be used to measure such changes in anatomical MRI data. The present study develops a methodology of voxel-wise TA mapping in subcortical and brainstem regions, which is then applied to T1-weighted MRI data from a cohort of 48 individuals who had PACS (32 with and 16 without ongoing fatigue symptoms) and 15 controls who had cold and flu-like symptoms but tested negative for COVID-19. Both groups were assessed an average of 4-5 months post-infection. There were no significant differences between PACS and control groups, but significant differences were observed within the PACS groups, between those with and without fatigue symptoms. This included reduced texture energy and increased entropy, along with reduced texture correlation, cluster shade and profile in the putamen, pallidum, thalamus and brainstem. These findings provide new insights into the neurophysiological mechanisms that underlie PACS, with altered tissue texture as a potential biomarker of this debilitating condition.

The neurostructural consequences of glaucoma and their overlap with disorders exhibiting emotional dysregulations: A voxel-based meta-analysis and tripartite system model.

BACKGROUND: Glaucoma, a progressive neurodegenerative disorder leading to irreversible blindness, is associated with heightened rates of generalized anxiety and depression. This study aims to comprehensively investigate brain morphological changes in glaucoma patients, extending beyond visual processing areas, and explores overlaps with morphological alterations observed in anxiety and depression. METHODS: A comparative meta-analysis was conducted, using case-control studies of brain structural integrity in glaucoma patients. We aimed to identify regions with gray matter volume (GMV) changes, examine their role within distinct large-scale networks, and assess overlap with alterations in generalized anxiety disorder (GAD) and major depressive disorder (MDD). RESULTS: Glaucoma patients exhibited significant GMV reductions in visual processing regions (lingual gyrus, thalamus). Notably, volumetric reductions extended beyond visual systems, encompassing the left putamen and insula. Behavioral and functional network decoding revealed distinct large-scale networks, implicating visual, motivational, and affective domains. The insular region, linked to pain and affective processes, displayed reductions overlapping with alterations observed in GAD. LIMITATIONS: While the study identified significant morphological alterations, the number of studies from both the glaucoma and GAD cohorts remains limited due to the lack of independent studies meeting our inclusion criteria. CONCLUSION: The study proposes a tripartite brain model for glaucoma, with visual processing changes related to the lingual gyrus and additional alterations in the putamen and insular regions tied to emotional or motivational functions. These neuroanatomical changes extend beyond the visual system, implying broader implications for brain structure and potential pathological developments, providing insights into the overall neurological consequences of glaucoma.

White Matter Microstructural Underpinnings of Mild Behavioral Impairment in Parkinson's Disease.

BACKGROUND: Patients with Parkinson's disease (PD) experience changes in behavior, personality, and cognition that can manifest even in the initial stages of the disease. Previous studies have suggested that mild behavioral impairment (MBI) should be considered an early marker of cognitive decline. However, the precise neurostructural underpinnings of MBI in early- to mid-stage PD remain poorly understood. OBJECTIVE: The aim was to explore the changes in white matter microstructure linked to MBI and mild cognitive impairment (MCI) in early- to mid-stage PD using diffusion magnetic resonance imaging (dMRI). METHODS: A total of 91 PD patients and 36 healthy participants were recruited and underwent anatomical MRI and dMRI, a comprehensive neuropsychological battery, and the completion of the Mild Behavioral Impairment-Checklist. Metrics of white matter integrity included tissue fractional anisotropy (FAt) and radial diffusivity (RDt), free water (FW), and fixel-based apparent fiber density (AFD). RESULTS: The connection between the left amygdala and the putamen was disrupted when comparing PD patients with MBI (PD-MBI) to PD-non-MBI, as evidenced by increased RDt (η2 = 0.09, P = 0.004) and both decreased AFD (η2 = 0.05, P = 0.048) and FAt (η2 = 0.12, P = 0.014). Compared to controls, PD patients with both MBI and MCI demonstrated increased FW for the connection between the left orbitofrontal gyrus (OrG) and the hippocampus (η2 = 0.22, P = 0.008), augmented RDt between the right OrG and the amygdala (η2 = 0.14, P = 0.008), and increased RDt (η2 = 0.25, P = 0.028) with decreased AFD (η2 = 0.10, P = 0.046) between the right OrG and the caudate nucleus. CONCLUSION: MBI is associated with abnormal microstructure of connections involving the orbitofrontal cortex, putamen, and amygdala. To our knowledge, this is the first assessment of the white matter microstructure in PD-MBI using dMRI. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The longitudinal volumetric and shape changes of subcortical nuclei in Parkinson's disease.

Brain structural changes in Parkinson's disease (PD) are progressive throughout the disease course. Changes in surface morphology with disease progression remain unclear. This study aimed to assess the volumetric and shape changes of the subcortical nuclei during disease progression and explore their association with clinical symptoms. Thirty-four patients and 32 healthy controls were enrolled. The global volume and shape of the subcortical nuclei were compared between patients and controls at baseline. The volume and shape changes of the subcortical nuclei were also explored between baseline and 2 years of follow-up. Association analysis was performed between the volume of subcortical structures and clinical symptoms. In patients with PD, there were significantly atrophied areas in the left pallidum and left putamen, while in healthy controls, the right putamen was dilated compared to baseline. The local morphology of the left pallidum was correlated with Mini Mental State Examination scores. The left putamen shape variation was negatively correlated with changes in Unified Parkinson's Disease Rating Scale PART III scores. Local morphological atrophy of the putamen and pallidum is an important pathophysiological change in the development of PD, and is associated with motor symptoms and cognitive status in patients with PD.

18F-FP-DTBZ PET/CT detectable associations between monoaminergic depletion in the putamen with rigidity and the pallidus with tremor in Parkinson's disease.

INTRODUCTION: The motor subtypes of Parkinson's disease (PD) are widely accepted and implemented. However, the motor subtypes have been thought to represent different stages of PD recently because some patients experience tremor-dominant (TD) conversion to the non-tremor-dominant subtype, such as postural instability-gait difficulty (PIGD). In this study, we explore the monoaminergic denervation features of the striatal and extra-striatal areas in patients with different subtypes of PD with 18F-9-fluoropropyl-(+)-dihydrotetrabenazine (18F-FP-DTBZ) PET/CT. METHODS: Sixty-five patients diagnosed with PD were included and classified as TD (n = 25) and PIGD (n = 40). We evaluated the difference of monoaminergic features of each subregion of brain between motor subtypes of PD, as well as associations between these features and Parkinsonian motor symptoms. RESULTS: The striatal standardized uptake value ratios (SUVR) showed that dopaminergic disruption of patients with PIGD was more symmetrical in the posterior ventral putamen (p < 0.001) and more severe in the ipsilateral posterior dorsal putamen (p < 0.001 corrected) compared with that of patients with TD. The severity of PIGD scores was associated with striatal dopaminergic depletion, while tremor was associated with monoaminergic changes in extra-striatal areas, including pallidus, thalamus, and raphe nuclie. CONCLUSION: These results indicate that patients with different motor subtypes may have different underlying mechanisms of PD pathogenesis. Therefore, accurate diagnosis of PD subtypes can aid prognosis evaluation and treatment decision-making.

Evaluation of putamen area and cerebral peduncle with surrounding cistern in patients with Parkinson's disease: is there a difference from controls in cranial MRI?

OBJECTIVES: Nigrostriatal dopaminergic neuron loss is essential in pathogenesis of Parkinson's disease (PD). The purpose of this study was to evaluate nigrostriatal structures including the putamen, cerebral peduncle, widths of interpeduncular cistern, and ambient cistern around the midbrain with conventional cranial magnetic resonance images (MRI) in patients with PD. METHODS: The MRI of 56 subjects was included, which was selected from the radiological data system for this retrospective study. The 29 patients with idiopathic PD were included and their disease duration, Hoehn&Yahr stage, and Levodopa equivalent dose (LED) were recorded. The 27 controls had a normal neurologic examination and cranial MRI. All subjects in the patient and control groups had right-hand dominance. Putamen and cerebral peduncle areas and widths of interpeduncular and ambient cisterns were measured in T2 sequences of MRI. Further statistical analysis was applied to exclude gender and age effect on areas. RESULTS: The areas of putamen and cerebral peduncles were significantly reduced in patients with PD compared to the control bilaterally (p < 0.001). Enlargement of interpeduncular and ambient cisterns in patients was higher than in controls, and it was significant (p < 0.001). A correlation was not observed between measurement results and clinical characteristics of patients with PD. Only the cerebral peduncle area/ambient cistern width ratio was significantly correlated with disease duration positively (right r = 0.46 p = 0.012, left r = 0.389 p = 0.037). CONCLUSION: Clinicians should be careful with conventional MRIs of patients with idiopathic PD in practice. It may be different from controls without any neurological disorder, particularly putamen, cerebral peduncles, interpeduncular, and ambient cisterns.

The areas of putamen and cerebral peduncles were significantly reduced in patients with PDEnlargement of interpeduncular and right ambient cisterns were detected in patients with PDCerebral peduncle area/ambient cistern width ratio was significantly correlated with disease duration positivelyMRIs of patients with idiopathic PD may be different from controls without any neurological disorder, particularly putamen, cerebral peduncles, interpeduncular, and ambient cisterns.

Putative neurochemical and cell type contributions to hemodynamic activity in the rodent caudate putamen.

Functional magnetic resonance imaging (fMRI) is widely used by researchers to noninvasively monitor brain-wide activity. The traditional assumption of a uniform relationship between neuronal and hemodynamic activity throughout the brain has been increasingly challenged. This relationship is now believed to be impacted by heterogeneously distributed cell types and neurochemical signaling. To date, most cell-type- and neurotransmitter-specific influences on hemodynamics have been examined within the cortex and hippocampus of rodent models, where glutamatergic signaling is prominent. However, neurochemical influences on hemodynamics are relatively unknown in largely GABAergic brain regions such as the rodent caudate putamen (CPu). Given the extensive contribution of CPu function and dysfunction to behavior, and the increasing focus on this region in fMRI studies, improved understanding of CPu hemodynamics could have broad impacts. Here we discuss existing findings on neurochemical contributions to hemodynamics as they may relate to the CPu with special consideration for how these contributions could originate from various cell types and circuits. We hope this review can help inform the direction of future studies as well as interpretation of fMRI findings in the CPu.

Magnetic Resonance T1w/T2w Ratio in the Putamen and Cerebellum as a Marker of Cognitive Impairment in MSA: a Longitudinal Study.

The exact pathophysiology of cognitive impairment in multiple system atrophy (MSA) is unclear. In our longitudinal study, we aimed to analyze (I) the relationships between cognitive functions and some subcortical structures, such as putamen and cerebellum assessed by voxel-based morphometry (VBM) and T1-weighted/T2-weighted (T1w/T2w) ratio, and (II) the neuroimaging predictors of the progression of cognitive deficits. Twenty-six patients with MSA underwent a comprehensive neuropsychological battery, motor examination, and brain MRI at baseline (T0) and 1-year follow-up (T1). Patients were then divided according to cognitive status into MSA with normal cognition (MSA-NC) and MSA with mild cognitive impairment (MCI). At T1, we divided the sample according to worsening/non worsening of cognitive status compared to baseline evaluation. Logistic regression analysis showed that age (ß = - 9.45, p = .02) and T1w/T2w value in the left putamen (ß = 230.64, p = .01) were significant predictors of global cognitive status at T0, explaining 65% of the variance. Logistic regression analysis showed that ∆-values of WM density in the cerebellum/brainstem (ß = 2188.70, p = .02) significantly predicted cognitive worsening at T1, explaining 64% of the variance. Our results suggest a role for the putamen and cerebellum in the cognitive changes of MSA, probably due to their connections with the cortex. The putaminal T1w/T2w ratio may deserve further studies as a marker of cognitive impairment in MSA.

Importance of Susceptibility-weighted-imaging in Methanol Toxicity.

Methanol poisoning is a rare but potentially lethal condition. Haemorrhagic necrosis of bilateral basal ganglia, particularly of the putamen, is one of the distinctive features of this entity. One of the proposed responsible mechanisms for putaminal haemorrhagic necrosis due to methanol toxicity is inadequate venous drainage of this region. Advanced imaging modalities are used to guide diagnosis and patient management. Here, we report a 61-year man who had a fulminant acute methanol toxicity due to accidental ingestion. Susceptibility-weighted-imaging (SWI) showed marked bilateral basal ganglia and brainstem haemorrhage. Also, congested and dilated venous structures were detected in SWI, which may be an indirect sign of inadequate venous drainage of this region. We intend to present the cerebral SWI features of a patient with fulminant methanol toxicity in order to clarify the underlying physiopathology of the brain damage, which has not yet been presented in the literature to the best of our knowledge. Key Words: Methanol, Toxic encephalopathy, Magnetic resonance imaging, Cerebral haemorrhage.

Putamen Structure and Function in Familial Risk for Depression: A Multimodal Imaging Study.

BACKGROUND: The putamen has been implicated in depressive disorders, but how its structure and function increase depression risk is not clearly understood. Here, we examined how putamen volume, neuronal density, and mood-modulated functional activity relate to family history and prospective course of depression. METHODS: The study includes 115 second- and third-generation offspring at high or low risk for depression based on the presence or absence of major depressive disorder in the first generation. Offspring were followed longitudinally using semistructured clinical interviews blinded to their familial risk; putamen structure, neuronal integrity, and functional activation were indexed by structural magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy (N-acetylaspartate/creatine ratio), and functional MRI activity modulated by valence and arousal components of a mood induction task, respectively. RESULTS: After adjusting for covariates, the high-risk individuals had lower putamen volume (standardized betas, ß-left = -0.17, ß-right = -0.15, ps = .002), N-acetylaspartate/creatine ratio (ß-left= -0.40, ß-right= -0.37, ps < .0001), and activation modulated by valence (ß-left = -0.22, ß-right = -0.27, ps < .05) than low-risk individuals. Volume differences were greater at younger ages, and N-acetylaspartate/creatine ratio differences were greater at older ages. Lower putamen volume also predicted major depressive disorder episodes up to 8 years after the scan (ß-left = -0.72, p = .013; ß-right = -0.83, p = .037). Magnetic resonance spectroscopy and task functional MRI measures were modestly correlated (0.27 ≤ r ≤ 0.33). CONCLUSIONS: Findings demonstrate abnormalities in putamen structure and function in individuals at high risk for major depressive disorder. Future studies should focus on this region as a potential biomarker for depressive illness, noting meanwhile that differences attributable to family history may peak at different ages based on which MRI modality is being used to assay them.

Bihemispheric developmental alterations in basal ganglia volumes following unilateral perinatal stroke.

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.

Reduced brain subcortical volumes in patients with glaucoma: a pilot neuroimaging study using the region-of-interest-based approach.

BACKGROUND: While numerous neuroimaging studies have demonstrated that glaucoma is associated with smaller volumes of the visual cortices in the brain, only a few studies have linked glaucoma with brain structures beyond the visual cortices. Therefore, the objective of this study was to compare brain imaging markers and neuropsychological performance between individuals with and without glaucoma. METHODS: We identified 64 individuals with glaucoma and randomly selected 128 age-, sex-, and education level-matched individuals without glaucoma from a community-based cohort. The study participants underwent 3 T brain magnetic resonance imaging and neuropsychological assessment battery. Regional cortical thickness and subcortical volume were estimated from the brain images of the participants. We used a linear mixed model after adjusting for potential confounding variables. RESULTS: Cortical thickness in the occipital lobe was significantly smaller in individuals with glaucoma than in the matched individuals (ß = - 0.04 mm, P = 0.014). This did not remain significant after adjusting for cardiovascular risk factors (ß = - 0.02 mm, P = 0.67). Individuals with glaucoma had smaller volumes of the thalamus (ß = - 212.8 mm3, P = 0.028), caudate (ß = - 170.0 mm3, P = 0.029), putamen (ß = - 151.4 mm3, P = 0.051), pallidum (ß = - 103.6 mm3, P = 0.007), hippocampus (ß = - 141.4 mm3, P = 0.026), and amygdala (ß = - 87.9 mm3, P = 0.018) compared with those without glaucoma. Among neuropsychological battery tests, only the Stroop color reading test  score was significantly lower in individuals with glaucoma compared with those without glaucoma (ß = - 0.44, P = 0.038). CONCLUSIONS: We found that glaucoma was associated with smaller volumes of the thalamus, caudate, putamen, pallidum, amygdala, and hippocampus.

Phospholipid Profiles Are Selectively Altered in the Putamen and White Frontal Cortex of Huntington's Disease.

Huntington's disease (HD) is a genetic, neurodegenerative illness that onsets in late adulthood as a series of progressive and terminal cognitive, motor, and psychiatric deficits. The disease is caused by a polyQ mutation in the Huntingtin gene (HTT), producing a polyglutamine expansion in the Huntingtin protein (HTT). HTT interacts with phospholipids in vitro; however, its interactions are changed when the protein is mutated in HD. Emerging evidence suggests that the susceptibility of brain regions to pathological stimuli is influenced by lipid composition. This study aimed to identify where and how phospholipids are changed in human HD brain tissue. Phospholipids were extracted using a modified MTBE method from the post-mortem brain of 13 advanced-stage HD patients and 13 age- and sex-matched controls. Targeted precursor ion scanning mass spectrometry was used to detect phospholipid species. In the white cortex of HD patients, there was a significantly lower abundance of phosphatidylcholine (PC) and phosphatidylserine (PS), but no difference in phosphatidylethanolamine (PE). In HD putamen, ester-linked 22:6 was lower in all phospholipid classes promoting a decrease in the relative abundance of ester polyunsaturated fatty acids in PE. No differences in phospholipid composition were identified in the caudate, grey cortex or cerebellum. Ether-linked PE fatty acids appear protected in the HD brain, as no changes were identified. The nature of phospholipid alterations in the HD brain is dependent on the lipid (subclass, species, and bond type) and the location.

Modulation effect of substantia nigra iron deposition and functional connectivity on putamen glucose metabolism in Parkinson's disease.

Neurodegeneration of the substantia nigra affects putamen activity in Parkinson's disease (PD), yet in vivo evidence of how the substantia nigra modulates putamen glucose metabolism in humans is missing. We aimed to investigate how substantia nigra modulates the putamen glucose metabolism using a cross-sectional design. Resting-state fMRI, susceptibility-weighted imaging, and [18 F]-fluorodeoxyglucose-PET (FDG-PET) data were acquired. Forty-two PD patients and 25 healthy controls (HCs) were recruited for simultaneous PET/MRI scanning. The main measurements of the current study were R2* images representing iron deposition (28 PD and 25 HCs), standardized uptake value ratio (SUVr) images representing FDG-uptake (33 PD and 25 HCs), and resting state functional connectivity maps from resting state fMRI (34 PD and 25 HCs). An interaction term based on the general linear model was used to investigate the joint modulation effect of nigral iron deposition and nigral-putamen functional connectivity on putamen FDG-uptake. Compared with HCs, we found increased iron deposition in the substantia nigra (p = .007), increased FDG-uptake in the putamen (left: PFWE < 0.001; right: PFWE < 0.001), and decreased functional connectivity between the substantia nigra and the anterior putamen (left PFWE < 0.001, right: PFWE  = 0.007). We then identified significant interaction effect of nigral iron deposition and nigral-putamen connectivity on FDG-uptake in the putamen (p = .004). The current study demonstrated joint modulation effect of the substantia nigra iron deposition and nigral-putamen functional connectivity on putamen glucose metabolic distribution, thereby revealing in vivo pathological mechanism of nigrostriatal neurodegeneration of PD.

Predicting alcohol dependence from multi-site brain structural measures.

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.

Therapeutic potential of iron modulating drugs in a mouse model of multiple system atrophy.

Multiple System Atrophy (MSA) is a rare neurodegenerative synucleinopathy which leads to severe disability followed by death within 6-9 years of symptom onset. There is compelling evidence suggesting that biological trace metals like iron and copper play an important role in synucleinopathies like Parkinson's disease and removing excess brain iron using chelators could slow down the disease progression. In human MSA, there is evidence of increased iron in affected brain regions, but role of iron and therapeutic efficacy of iron-lowering drugs in pre-clinical models of MSA have not been studied. We studied age-related changes in iron metabolism in different brain regions of the PLP-αsyn mice and tested whether iron-lowering drugs could alleviate disease phenotype in aged PLP-αsyn mice. Iron content, iron-ferritin association, ferritin protein levels and copper-ceruloplasmin association were measured in prefrontal cortex, putamen, substantia nigra and cerebellum of 3, 8, and 20-month-old PLP-αsyn and age-matched non-transgenic mice. Moreover, 12-month-old PLP-αsyn mice were administered deferiprone or ceruloplasmin or vehicle for 2 months. At the end of treatment period, motor testing and stereological analyses were performed. We found iron accumulation and perturbed iron-ferritin interaction in substantia nigra, putamen and cerebellum of aged PLP-αsyn mice. Furthermore, we found significant reduction in ceruloplasmin-bound copper in substantia nigra and cerebellum of the PLP-αsyn mice. Both deferiprone and ceruloplasmin prevented decline in motor performance in aged PLP-αsyn mice and were associated with higher neuronal survival and reduced density of α-synuclein aggregates in substantia nigra. This is the first study to report brain iron accumulation in a mouse model of MSA. Our results indicate that elevated iron in MSA mice may result from ceruloplasmin dysfunction and provide evidence that targeting iron in MSA could be a viable therapeutic option.