Changes In Substantia Nigra Research Articles

Dopaminergic and noradrenergic integrity are differentially associated with late‐life memory performance

AbstractBackgroundAge‐related deficits in dopaminergic neuromodulation play a key role in determining memory decline. Facilitated by technical advancements, recent research has also implicated noradrenergic neuromodulation in shaping late‐life memory development. However, investigations disentangling the contribution of the two neuromodulators to the neurobiological basis of human cognitive aging are scarce.MethodWe collected high‐resolution magnetic resonance imaging (MRI) data of the dopaminergic substantia nigra–ventral tegmental area and the noradrenergic locus coeruleus of 320 younger and older adults at two time points (T1, T2; ∼1.9 years delay). The imaging protocol included three scans sensitive for the substantia nigra–ventral tegmental area and locus coeruleus—a Fast‐Spin‐Echo [FSE] sequence, and a Magnetization‐Transfer sequence, acquired once with a dedicated magnetic saturation pulse [MT+] and once without, resulting in a proton‐density like image [MT–]. We aggregated the information shared across imaging modalities by estimating multimodal latent factors expressing dopaminergic and noradrenergic integrity.Participants also completed a comprehensive cognitive battery at three time points (T1, T2, T3), including tests of fluid intelligence, episodic and working memory. We used structural equation modeling to evaluate cross‐sectional associations of substantia nigra–ventral tegmental area and locus coeruleus integrity with late‐life cognition. In a second set of models, we probed longitudinal changes in substantia nigra–ventral tegmental area and locus coeruleus integrity (T1–T2) and used them to predict participants’ future cognitive performance (at T3).ResultCross‐sectionally, we found differential associations of dopaminergic and noradrenergic nuclei with late‐life cognition. While locus coeruleus integrity was related to better episodic memory across several memory tasks, substantia nigra–ventral tegmental area integrity was related to working memory performance. Moreover, consistent with a largely shared biosynthesis of the neuromodulators, dopaminergic and noradrenergic nuclei were positively related. Longitudinally, we found that older age was associated with more‐negative change in substantia nigra–ventral tegmental area and locus coeruleus integrity (T1–T2). Importantly, changes in locus coeruleus integrity reliably predicted future episodic memory performance (at T3).ConclusionThese findings support the utility of in‐vivo indices for catecholaminergic integrity and highlight differential roles of dopaminergic and noradrenergic neuromodulation in late‐life cognitive decline.

MiR-494-3p Promotes Erastin-Induced Ferroptosis by Targeting REST to Activate the Interplay between SP1 and ACSL4 in Parkinson's Disease.

Background Ferroptosis is a type of iron-dependent programmed cell death. Ferroptosis has been shown to be a significant factor for the pathogenesis of Parkinson's disease (PD). However, the mechanism involved in ferroptosis has not been fully elucidated in PD. Methods Repressor element-1 silencing transcription factor (REST) and specificity protein 1 (SP1) expressions were monitored by qRT-PCR. Cell viability, reactive oxygen species (ROS), and mitochondrial injury were validated by CCK-8, flow cytometry, and transmission electron microscope. The levels of neurons-related proteins and ferroptosis-associated proteins were identified by western blot and immunofluorescence assays. The interaction between miR-494-3p and REST or SP1 and ACSL4 was analyzed by luciferase, chromatin immunoprecipitation, or EMSA assay. Results Erastin could dose-dependently induce neuron injury and ferroptosis of LUHMES cells. miR-494-3p overexpression induced ROS production, mitochondrial damage, ferroptosis, and neuron injury in erastin-induced LUHMES cells. Likewise, miR-494-3p inhibition had the opposite effects. We also showed that REST was a target gene of miR-494-3p and could repress erastin-induced ferroptosis, neuron injury, ROS, and mitochondrial injury via SP1 in LUHMES cells. Moreover, we demonstrated that SP1 could interact with ACSL4. We also confirmed that miR-494-3p could aggravate the pathological changes of substantia nigra and corpus striatum in the MPTP-induced PD mouse model. Conclusion miR-494-3p significantly promotes ferroptosis by regulating the REST/SP1/ACSL4 axis in PD. Thus, our results open potential therapeutic targets for PD.

A distinct neuromelanin magnetic resonance imaging pattern in parkinsonian multiple system atrophy

BackgroundParkinsonian variant of multiple system atrophy is a neurodegenerative disorder frequently misdiagnosed as Parkinson’s disease. No early imaging biomarkers currently differentiate these disorders.MethodsSimple visual imaging analysis of the substantia nigra and locus coeruleus in neuromelanin-sensitive magnetic resonance imaging and nigrosome 1 in susceptibility-weighted sequences was performed in thirty patients with parkinsonian variant of multiple system atrophy fulfilling possible/probable second consensus diagnostic criteria. The neuromelanin visual pattern was compared to patients with Parkinson’s disease with the same disease duration (n = 10) and healthy controls (n = 10). Substantia nigra semi-automated neuromelanin area/signal intensity was compared to the visual data.ResultsGroups were similar in age, sex, disease duration, and levodopa equivalent dose. Hoehn & Yahr stage was higher in parkinsonian multiple system atrophy patients, 69% of whom had normal neuromelanin size/signal, significantly different from Parkinson’s disease patients, and similar to controls. Nigrosome 1 signal was lost in 74% of parkinsonian multiple system atrophy patients. Semi-automated neuromelanin substantia nigra signal, but not area, measurements were able to differentiate groups.ConclusionsIn patients with parkinsonism, simple visual magnetic resonance imaging analysis showing normal neuromelanin substantia nigra and locus coeruleus, combined with nigrosome 1 loss, allowed the distinction of the parkinsonian variant of multiple system atrophy from Parkinson’s disease and healthy controls. This easy and widely available method was superior to semi-automated measurements in identifying specific imaging changes in substantia nigra and locus coeruleus.

Transcriptomic profiles in Parkinson's disease.

Transcriptomics in Parkinson's disease offers insights into the pathogenesis of Parkinson's disease but obtaining brain tissue has limitations. In order to bypass this issue, we profile and compare differentially expressed genes and enriched pathways (KEGG) in two peripheral tissues (blood and skin) of 12 Parkinson's disease patients and 12 healthy controls using RNA-sequencing technique and validation with RT-qPCR. Furthermore, we compare our results to previous Parkinson's disease post mortem brain tissue and blood results using the robust rank aggregation method. The results show no overlapping differentially expressed genes or enriched pathways in blood vs. skin in our sample sets (25 vs. 1068 differentially expressed genes with an FDR ≤ 0.05; 1 vs. 9 pathways in blood and skin, respectively). A meta-analysis from previous transcriptomic sample sets using either microarrays or RNA-Seq yields a robust rank aggregation list of cortical gene expression changes with 43 differentially expressed genes; a list of substantia nigra changes with 2 differentially expressed genes and a list of blood changes with 1 differentially expressed gene being statistically significant at FDR ≤ 0.05. In cortex 1, KEGG pathway was enriched, four in substantia nigra and two in blood. None of the differentially expressed genes or pathways overlap between these tissues. When comparing our previously published skin transcription analysis, two differentially expressed genes between the cortex robust rank aggregation and skin overlap. In this study, for the first time a meta-analysis is applied on transcriptomic sample sets in Parkinson's disease. Simultaneously, it explores the notion that Parkinson's disease is not just a neuronal tissue disease by exploring peripheral tissues. The comparison of different Parkinson's disease tissues yields surprisingly few significant differentially expressed genes and pathways, suggesting that divergent gene expression profiles in distinct cell lineages, metabolic and possibly iatrogenic effects create too much transcriptomic noise for detecting significant signal. On the other hand, there are signs that point towards Parkinson's disease-specific changes in non-neuronal peripheral tissues in Parkinson's disease, indicating that Parkinson's disease might be a multisystem disorder.

Tau Tangles in Parkinson's Disease: A 2-Year Follow-Up Flortaucipir PET Study.

Flortaucipir PET, a marker of tau tangles, has shown lower than expected cortical uptake in Parkinson's disease (PD), than would be predicted from neuropathologic estimates of Alzheimer's disease co-pathology. Instead, the most characteristic finding of flortaucipir imaging in PD is decreased uptake in the substantia nigra, reflecting reduction in its "off-target" binding to neuromelanin. We have previously reported these observations in cross-sectional studies. Here, we present two-year follow-up data of cortical and nigral flortaucipir uptake in PD patients. Seventeen PD patients received repeat flortaucipir PET two years after baseline. We interrogated vertex-based group-wise cortical tracer binding (SUVRs) with a cerebellar reference using the general linear model while mean substantia nigra SUVRs were compared with volumes of interest group comparisons and voxel-wise group analyses using ANOVA. Finally, we performed linear regressions of tau load with changes in MoCA and UPDRS motor scores. We found no significant changes in substantia nigra or cortex flortaucipir uptake in Parkinson's disease patients over two years and no association with changes in cognitive symptoms. Signal reduction in the medial substantia nigra trended towards an association with worsening of motor symptoms. No significant increase in tau tangles occurred after a two-year follow-up of Parkinson's disease patients using flortaucipir PET.

Quantitative transcranial sonography of the substantia nigra as a predictor of therapeutic response to intravenous iron therapy in restless legs syndrome

ObjectiveTo analyze changes in substantia nigra (SN) iron deposits, assessed by quantitative transcranial sonography (TCS), to obtain and compare substantia nigra echogenicity indices (SNEI) at baseline and after intravenous (IV) iron therapy in patients with restless legs syndrome (RLS)/Willis−Ekbom disease (WED). MethodsA total of 30 consecutive subjects diagnosed with RLS/WED were recruited and underwent IV iron treatment. The SNEI, total daily dose of dopamine equivalents, and International Restless Legs Syndrome Rating Scale (IRLS) scores were obtained at baseline and following IV iron administration. Comparative statistics were performed by means of nonparametric testing. ResultsThe sample was stratified into two groups according to the median baseline SNEI and the grade of SN hypoechogenicity: severely hypoechogenic (HE) (n = 13) and moderately HE (n = 17). Following IV iron, the increase in SNEI among severely HE subjects was 19% (0.038 ± 0.046 cm2; P < 0.01), whereas in moderately HE subjects it was 10% (0.021 ± 0.069 cm2; P = 0.28). Among severely HE subjects, the average reduction in IRLS following IV iron was 10 ± 7.12 points (P < 0.01), in contrast to 1.85 ± 9.85 (not significant) among moderately HE subjects. Finally, we quantified the percentage of patients in each group who were able to reduce by ≥30% their total daily dopaminergic requirements (TDR) after IV iron, with a 57.14% reduction in the severely HE group vs 25% in the moderately HE group (P = 0.1). Three of 30 subjects (17%) were able to completely cease all dopaminergic treatment. ConclusionIntravenous iron caused changes in SNEI in both groups of patients, reflecting an increase in brain iron stores. However, the increase in SNEI was greater in patients previously defined as severely HE. Furthermore, RLS/WED symptoms also improved more in severely HE subjects, and there was a greater reduction in TDR. This study highlights the role of TCS in quantifying brain iron deposits and in predicting which patients will likely benefit from IV iron.

MRI biomarkers of motor and non-motor symptoms in Parkinson's disease

Parkinson's disease is a heterogeneous disorder with both motor and non-motor symptoms that contribute to functional impairment. To develop effective, disease modifying treatments for these symptoms, biomarkers are necessary to detect neuropathological changes early in the disease course and monitor changes over time. Advances in MRI scan sequences and analytical techniques present numerous promising metrics to detect changes within the nigrostriatal system, implicated in the cardinal motor symptoms of the disease, and detect broader dysfunction involved in the non-motor symptoms, such as cognitive impairment. There is emerging evidence that iron sensitive, neuromelanin sensitive, diffusion sensitive, and resting state functional magnetic imaging measures can capture changes within the nigrostriatal system. Iron, neuromelanin, and diffusion sensitive measures demonstrate high specificity and sensitivity in distinguishing Parkinson's disease relative to controls, with inconsistent results differentiating Parkinson's disease relative to atypical parkinsonian disorders. They may also serve as useful monitoring biomarkers, with each possibly detecting different aspects of the disease course (early nigrosome changes versus broader substantia nigra changes). Investigations of non-motor symptoms, such as cognitive impairment, require careful consideration of the nature of cognitive deficits to characterize regional and network specific impairment. While the early, executive dysfunction observed is consistent with nigrostriatal degeneration, the memory and visuospatial impairments, the harbingers of a dementia process reflect dopaminergic independent dysfunction involving broader regions of the brain.

Early white matter injuries associated with dopamine transporter dysfunction in patients with acute CO intoxication: A diffusion kurtosis imaging and Tc-99m TRODAT-1 SPECT study.

Patients with CO intoxication were demonstrated to exhibit white matter (WM) injuries, changes in substantia nigra, dopamine transporter dysfunctions of striatum and Parkinsonism symptoms. We aimed to investigate the relationship between WM injuries of dopaminergic pathways and dopamine transporter dysfunctions of the striatum in patients with acute CO intoxication using both diffusion kurtosis imaging (DKI) and single photon-emission computed tomography (SPECT). Seventeen patients with acute CO intoxication and 19 age- and gender-matched healthy subjects were enrolled. DKI data were acquired from all participants and Tc-99m-TRODAT-1 SPECT scan was performed on each patient. DKI datasets were fitted to obtain axial, radial and mean diffusivity, fractional anisotropy, axial, radial and mean kurtosis for voxel-based comparison. In addition, the TRODAT-1 binding ratio of the striatum was calculated using the occipital cortices as a reference. In significant regions, correlational analysis was performed to understand the relationship between DKI indices and TRODAT-1 binding ratio. The results showed that DKI indices were significantly altered in multiple WM regions broadly involving the basal ganglia-thalamocortical circuit and nigrostriatal pathway. The correlation analysis further revealed significant correlations between DKI indices and the TRODAT-1 binding ratio in the nigrostriatal pathway (absolute correlation coefficients ranged from 0.5992 to 0.6950, p<0.05), suggesting that CO-induced early WM injuries were associated with dopamine transporter dysfunctions of striatum. We concluded that DKI and Tc-99m-TRODAT-1 SPECT scans were helpful in early detection of global WM injuries associated with dysfunctions of dopamine transporter in patients with acute CO intoxication. • Voxel-based diffusion kurtosis imaging analysis was helpful in globally detecting early white matter injuries in patients with acute CO intoxication. • CO-induced early white matter injuries were broadly located in basal ganglia-thalamocortical circuit and nigrostriatal pathway. • Early white matter injuries in dopaminergic pathways were significantly correlated with dopamine transporter dysfunctions of the striatum.

Structural changes of substantia nigra in patients with unilateral Parkinson′s disease

Magnetic resonance imaging (MRI) findings were studied in 19 patients with non-dementia Parkinson′s disease (PD) Hoehn-Yahr Stage 1 and 1.5 and 38 healthy subjects. The width and area of pars compacta of substantia nigra (SNc), substantia nigra (SN) and midbrain were measured. The width and area ratios of SNc to SN were calculated. Compared with controls, the widths of right SNc was narrower, bilateral ratios of SNc to SN width were decreased in PD group. As to the area of substantia nigra, there was no significant difference between PD and controls. The width of left SN and the ratio of right SNc to SN width was negatively correlation with age of patients. The ratio of left SNc to SN width, the area of bilateral SNc and left SN, as well as the ratio of right SNc to SN area had negative correlation with the disease duration; however, there was no correlation with gender, Hoehn-Yahr Stage, the Unified Parkinson disease rating scale score, mini mental state scale, education years, levodopa equivalent daily dose, Hamilton Depression Scale or Hamilton Anxiety Scale in PD group. The results indicate that there are bilateral structural changes of SN in unilateral PD patients, which may be more significant with increasing disease duration. The measurement of SNc width and SN area can be used as an objective indicator for diagnosis and disease progression monitoring of PD. Key words: Parkinson disease; Magnetic resonance imaging; Pars compacta of substantia nigra

Alpha-synuclein as a pathological link between chronic traumatic brain injury and Parkinson's disease.

The long-term consequences of traumatic brain injury (TBI) are closely associated with the development of histopathological deficits. Notably, TBI may predispose long-term survivors to age-related neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by a gradual degeneration of the nigrostriatal dopaminergic neurons. However, preclinical studies on the pathophysiological changes in substantia nigra (SN) after chronic TBI are lacking. In the present in vivo study, we examined the pathological link between PD-associated dopaminergic neuronal loss and chronic TBI. Sixty days post-TBI, rats were euthanized and brain tissues harvested. Immunostaining was performed using tyrosine hydroxylase (TH), an enzyme required for the synthesis of dopamine in neurons, α-synuclein, a presynaptic protein that plays a role in synaptic vesicle recycling, and major histocompatibility complex II (MHCII), a protein found in antigen presenting cells such as inflammatory microglia cells, all key players in PD pathology. Unbiased stereology analyses revealed significant decrease of TH-positive expression in the surviving dopaminergic neurons of the SN pars compacta (SNpc) relative to sham control. In parallel, increased α-synuclein accumulation was detected in the ipsilateral SN compared to the contralateral SN in TBI animals or sham control. In addition, exacerbation of MHCII+ cells was recognized in the SN and cerebral peduncle ipsilateral to injury relative to contralateral side and sham control. These results suggest α-synuclein as a pathological link between chronic effects of TBI and PD symptoms as evidenced by significant overexpression and abnormal accumulation of α-synuclein in inflammation-infiltrated SN of rats exposed to chronic TBI. J. Cell. Physiol. 230: 1024–1032, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

Secondary parenchymal and vascular changes after middle cerebral artery stroke in children

Ischemic brain lesions might present with unexpected increased signal intensity at MR angiography within the ischemic lesion and secondary parenchymal changes in regions distal to the ischemia itself. We retrospectively investigated the rate and time course of vascular and parenchymal changes in children with isolated middle cerebral artery (MCA) stroke. Twelve children (mean age at stroke onset 4.8years, range 0.8-15years, six females, seven right MCA strokes) suffering from a first ever acute isolated MCA stroke had repeated MR scans (mean scan number, 3.5; range 2-6; mean follow-up, 11months; range 0.5-24months). Ipsilaterally to MCA stroke, we recorded increased vessel signal at MR angiography during first to fourth day in 4/7 children (all had MCA recanalization), corticospinal tract cytotoxic-like edema during second day to second month in 7/11 (three children with globus pallidum ischemia had concomitant substantia nigra changes during second to third week), corticospinal tract T2 abnormalities from fifth day onwards in 9/12, focal thalamic cytotoxic-like edema during fifth day to first month in 5/8, focal thalamic T2 hyperintensity during sixth day to third week in 2/4, and faint T2 hypointensity from second month in 7/10 children. Vascular and secondary parenchymal changes, likely due to luxury perfusion, Wallerian, retrograde, or trans-synaptic degeneration, are common in pediatric MCA stroke population. They might mimic new ischemic lesions or suggest conditions different from stroke leading to diagnostic pitfalls and inappropriate treatment.

Changes in substantia nigra and locus coeruleus in patients with early-stage Parkinson's disease using neuromelanin-sensitive MR imaging

Neuromelanin-sensitive magnetic resonance imaging is able to visualize changes associated with neuronal loss in the substantia nigra pars compacta (SNc) and locus coeruleus (LC) in patients with Parkinson's disease (PD). However, the diagnostic accuracy of this technique in the early stages of PD remains unknown. Therefore, changes in the SNc and LC observed using neuromelanin imaging were evaluated in patients with early PD. The signal intensities of the lateral, central, and medial parts of the SNc and that of the LC were measured, and the contrast ratios (CRs) were calculated against the adjacent white matter structures. CRs in the lateral part of the SNc and in the LC were significantly reduced in the early PD group when compared with the controls. Sensitivities and specificities in discriminating early PD patients from healthy controls were 73% and 87% in lateral SNc and 82% and 90% in LC, respectively. Neuromelanin imaging can depict signal alterations in the lateral part of the SNc and in the LC in patients with PD, even in its early stage, and can discriminate between these patients and healthy individuals with high sensitivities and specificities.

Signal alterations of the basal ganglia in the differential diagnosis of Parkinson's disease: a retrospective case-controlled MRI data bank analysis.

BackgroundBased upon the acquainted loss of dopaminergic neurons in the substantia nigra in Parkinson’s disease (PD), we hypothesised changes in magnetic resonance imaging signal intensities of the basal ganglia to be useful as an additional technical tool in the diagnostic work-up.MethodsRegion-of-interest analyses (substantia nigra and globus pallidus internus) of T2-weighted scans were performed in seventy subjects with PD, 170 age- and gender-matched controls and 38 patients with an atypical form of neurodegenerative Parkinsonian syndrome (N = 11 multisystem atrophy, N = 22 progressive supranuclear palsy, N = 5 corticobasal syndrome).ResultsIn patients with PD, significant changes in signal intensities within the substantia nigra were observed compared to controls at p < 0.001. For the globus pallidus internus, signal alterations in PD and progressive supranuclear palsy were found to be significant (p < 0.001) if compared to controls. Furthermore, signal changes of substantia nigra correlated with signal intensities of globus pallidus internus in the ipsilateral hemisphere in both groups. Sensitivity was 86% and specificity was 90% for the combined analysis of substantia nigra and globus pallidus internus in the complete patient sample versus controls.ConclusionsSignal alterations of substantia nigra and globus pallidus internus in routine magnetic resonance imaging were useful to distinguish patients with PD from controls. In addition, signal changes in globus pallidus internus could be used to differentiate progressive supranuclear palsy patients from controls. These analyses have the potential to serve as an additional non-invasive technical tool to support the individual differential diagnosis of PD.

Neurosteroid Biosynthetic Pathway Changes in Substantia Nigra and Caudate Nucleus in Parkinson's Disease

There is emerging evidence from animal studies for a neuroprotective role of sex steroids in neurodegenerative diseases, but studies in human brain are lacking. We have carried out an extensive study of the neurosteroid biosynthetic pathways in substantia nigra (SN), caudate nucleus (CN) and putamen (PU) of 7 Parkinson's disease (PD) patients and 7 matched controls. The mRNA levels of 37 genes including neurosteroid biosynthetic enzymes, hormone receptors and the neurosteroid-modulated gamma-amino-butyric acid -A (GABA-A) receptor subunits were analyzed by quantitative PCR (qPCR). In the SN, we found downregulation of 5alpha-reductase type 1 (5alpha-R1), sulfotransferase 2B1 (SULT2B1) and some GABA-A receptor subunits (alpha4, beta1) while in the CN, upregulation of 3alpha-hydroxysteroid dehydrogenase type 3 (3alpha-HSD3) and alpha4 GABA-A receptor subunit (22-fold) was observed. No significant differences were found in the PU. These data imply an involvement of pregnane steroids and changes in GABAergic neurotransmission in the neurodegenerative process and suggest that neurosteroids may deserve further investigation as potential therapeutic agents in PD.

Expression of somatostatin and somatostatin receptor subtypes in Apolipoprotein D (ApoD) knockout mouse brain: An immunohistochemical analysis

Apolipoprotein D (ApoD) is widely distributed in central and peripheral nervous system. ApoD expression has been shown to increase in several neurodegenerative and neuropsychiatric disorders, as well as during regeneration in the nervous system. Like ApoD, in the central nervous system somatostatin (SST) is widely present and functions as neurotransmitter and neuromodulator. The biological effects of SST are mediated via binding to five high-affinity G-protein coupled receptors termed SSTR1–5. Mice lacking ApoD exhibit reduced SST labeling in cortex and hippocampus and increased expression in striatum and amygdala without any noticeable changes in substantia nigra. Changes in SSTRs expressions have been described in several neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's diseases. In the present study, using SSTR1–5 receptor-specific antibodies, we mapped their distribution in wild type ( w t ) and ApoD knockout (ApoD −/−) mouse brain. SSTR1–5 expression was observed both as membrane and cytoplasmic protein and display regions and receptor specific differences between w t and ApoD −/− mice brains. In cortex and hippocampus, SSTR subtypes like immunoreactivity are decreased in ApoD −/− mice brain. Unlike cortex and hippocampus, in the striatum of ApoD −/− mice, projection neurons showed increased SSTR immunoreactivity, as compared to w t . Higher SSTR subtypes immunoreactivity is seen in substantia nigra pars compacta (SNpc) whereas lower in substantia nigra pars reticulata (SNpr) of ApoD −/− mice brains as compared to w t . Whereas, amygdala displayed SSTR subtypes changes in different nuclei of ApoD −/− mice in comparison to w t mice brain. Taken together, our results describe receptor and region specific changes in SST and SSTR subtypes expression in ApoD −/− mice brain, which may be linked to specific neurological disorders.

Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I

In glutaric aciduria type I, an autosomal recessive disease of mitochondrial lysine, hydroxylysine and tryptophan catabolism, striatal lesions are characteristically induced by acute encephalopathic crises during a finite period of brain development (age 3-36 months). The frequency of striatal injury is significantly less in patients diagnosed as asymptomatic newborns by newborn screening. Most previous studies have focused on the onset and mechanism of striatal injury, whereas little is known about neuroradiological abnormalities in pre-symptomatically diagnosed patients and about dynamic changes of extrastriatal abnormalities. Thus, the major aim of the present retrospective study was to improve our understanding of striatal and extrastriatal abnormalities in affected individuals including those diagnosed by newborn screening. To this end, we systematically analysed magnetic resonance imagings (MRIs) in 38 patients with glutaric aciduria type I diagnosed before or after the manifestation of neurological symptoms. To identify brain regions that are susceptible to cerebral injury during acute encephalopathic crises, we compared the frequency of magnetic resonance abnormalities in patients with and without such crises. Major specific changes after encephalopathic crises were found in the putamen (P < 0.001), nucleus caudatus (P < 0.001), globus pallidus (P = 0.012) and ventricles (P = 0.001). Analysis of empirical cumulative distribution frequencies, however, demonstrated that isolated pallidal abnormalities did not significantly differ over time in both groups (P = 0.544) suggesting that isolated pallidal abnormalities are not induced by acute crises--in contrast to striatal abnormalities. The manifestation of motor disability was associated with signal abnormalities in putamen, caudate, pallidum and ventricles. In addition, we found a large number of extrastriatal abnormalities in patients with and without preceding encephalophatic crises. These abnormalities include widening of anterior temporal and sylvian CSF spaces, pseudocysts, signal changes of substantia nigra, nucleus dentatus, thalamus, tractus tegmentalis centralis and supratentorial white matter as well as signs of delayed maturation (myelination and gyral pattern). In contrast to the striatum, extrastriatal abnormalities were variable and could regress or even normalize with time. This includes widening of sylvian fissures, delayed maturation, pallidal signal changes and pseudocysts. Based on these results, we hypothesize that neuroradiological abnormalities and neurological symptoms in glutaric aciduria type I can be explained by overlaying episodes of cerebral alterations including maturational delay of the brain in utero, acute striatal injury during a vulnerable period in infancy and chronic progressive changes that may continue lifelong. This may have widespread consequences for the pathophysiological understanding of this disease, long-term outcomes and therapeutic considerations.

Magnetic Resonance Imaging-Based Volumetric Analysis of Basal Ganglia Nuclei and Substantia Nigra in Patients with Parkinson’s Disease

Parkinson's disease (PD) is associated with well-documented morphological changes in substantia nigra and basal ganglia nuclei. This study evaluates the ability of magnetic resonance imaging to detect these changes and investigates the relationship between severity of clinical findings and degree of morphological change. This correlation may provide valuable information in early diagnosis of PD. Sixteen patients with early stage PD, eight patients with advanced PD, and eight normal controls were studied by 3T magnetic resonance imaging. The whole brain volume and the volumes of the caudate, putamen, globus pallidus, and substantia nigra were calculated on three-dimensional reconstructed images. Putamen volume was significantly diminished in patients with early PD and advanced PD compared with that in controls (P < 0.05), and the percentage of atrophy was 12.5 and 26.5%, respectively. The putamen volume was negatively correlated with Hoehn and Yahr staging (r = -0.720, P < 0.001). Pallidal volume was reduced only in advanced PD (P = 0.023). There were no significant differences in total brain, caudate, or substantia nigra among these three groups Magnetic resonance imaging-based volumetric measurement is a sensitive method in the assessment of morphological changes of PD in vivo. The putamen atrophy was correlated with the severity of clinical findings. The volumetric measurement of putamen could potentially be a useful indicator of PD in the early stage.

In vivo models of multiple system atrophy

Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disorder of unknown etiology clinically characterized by a combination of parkinsonian, pyramidal, and cerebellar signs. Levodopa-unresponsive parkinsonism is present in 80% of MSA cases, and this dominant clinical presentation (MSA-P) is associated with a combined degeneration of the substantia nigra pars compacta and the striatum in anatomically related areas. The limited knowledge of the pathophysiology of MSA and the lack of therapeutic strategies prompted the development of lesion models reproducing striatonigral degeneration, the substrate of levodopa-unresponsive parkinsonism in MSA-P. This method was carried out first in rats with two different stereotaxic strategies using either two neurotoxins ("double toxin-double lesion") or a single neurotoxin ("single toxin-double lesion"). Double-lesioned rat models showed severe motor impairment compared to those with a single nigral or striatal lesion and helped to mimic different stages of the disease. Systemic models were also developed in mice and primates using the nigral toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and the striatal toxin 3-nitropropionic (3-NP). In mice, although MPTP reduced the subsequent sensitivity to 3-NP in a sequential lesion, simultaneous nigral and striatal insults were shown to exacerbate striatal damage. MPTP-treated monkeys displayed a significant worsening of parkinsonism and a loss of levodopa-responsiveness after the appearance of hindlimb dystonia and striatal lesion formation induced by subsequent 3-NP intoxication. The different species and intoxication paradigms used will be useful to investigate functional changes in substantia nigra and striatum and to define neuroprotective, neurorestorative, or symptomatic therapeutic strategies.

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We have evaluated the ability of the injured nigrostriatal dopaminergic system to produce highly reactive hydroxyl radicals (•OH) by the electrochemical detection of salicylate hydroxylation. Unilateral transection of the medial forebrain bundle transiently increased the formation of •OH in substantia nigra (SN) but not in striatum during the first 48 h postlesion, when most relevant changes in terms of oxidatively modified proteins take place. Short-term adaptive axotomy-induced changes in substantia nigra included downregulation of nigral tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA expression and more intense TH immunoreactivity. Maintained inhibition of monoamine oxidase activity with deprenyl totally prevented the axotomy-induced formation of •OH, thus demonstrating the dopaminergic nature of these radicals. In contrast, deprenyl treatment, which is associated with a diminution in free radical production, failed to delay the onset of dopaminergic degeneration. This observation highlights the importance of being extremely cautious when analyzing parameters of oxidative stress and extrapolating them as a primary cause of cell death in the context of neurodegeneration. Long-term adaptive changes included a dramatic downregulation of DAT mRNA expression along with a moderate decrease in TH mRNA levels in SN. We anticipate a key regulatory role of the DAT to maximally optimize dopaminergic transmission in the synaptic cleft under conditions of degeneration.

Evidence for dopamine-derived hydroxyl radical formation in the nigrostriatal system in response to axotomy.

We have evaluated the ability of the injured nigrostriatal dopaminergic system to produce highly reactive hydroxyl radicals ((*)OH) by the electrochemical detection of salicylate hydroxylation. Unilateral transection of the medial forebrain bundle transiently increased the formation of (*)OH in substantia nigra (SN) but not in striatum during the first 48 h postlesion, when most relevant changes in terms of oxidatively modified proteins take place. Short-term adaptive axotomy-induced changes in substantia nigra included downregulation of nigral tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA expression and more intense TH immunoreactivity. Maintained inhibition of monoamine oxidase activity with deprenyl totally prevented the axotomy-induced formation of (*)OH, thus demonstrating the dopaminergic nature of these radicals. In contrast, deprenyl treatment, which is associated with a diminution in free radical production, failed to delay the onset of dopaminergic degeneration. This observation highlights the importance of being extremely cautious when analyzing parameters of oxidative stress and extrapolating them as a primary cause of cell death in the context of neurodegeneration. Long-term adaptive changes included a dramatic downregulation of DAT mRNA expression along with a moderate decrease in TH mRNA levels in SN. We anticipate a key regulatory role of the DAT to maximally optimize dopaminergic transmission in the synaptic cleft under conditions of degeneration.