In vivo detection of lateral-ventral tier nigral degeneration in Parkinson's disease.

The objective of this study was to measure neuromelanin-sensitive MRI contrast changes in the lateral-ventral tier of substantia nigra pars compacta in Parkinson's disease (PD). Histopathological studies of PD have demonstrated both massive loss of melanized dopamine neurons and iron accumulation in the substantia nigra pars compacta. Neurodegeneration is most profound in the lateral-ventral tier of this structure. We have previously shown in both healthy controls and individuals with PD that neuromelanin-sensitive MRI and iron-sensitive MRI contrast regions in substantia nigra overlap. This overlap region is located in the lateral-ventral tier. Exploiting this area of contrast overlap for region of interest selection, we developed a semi-automated image processing approach to characterize the lateral-ventral tier in MRI data. Here we apply this approach to measure magnetization transfer contrast, which corresponds to local neuromelanin density, in both the lateral-ventral tier and the entire pars compacta in 22 PD patients and 19 controls. Significant contrast reductions were seen in PD in both the entire pars compacta (P = 0.009) and in its lateral-ventral tier (P = 0.0002); in PD contrast was significantly lower in the lateral-ventral tier than in the entire pars compacta (P = 0.0008). These findings are the first in vivo evidence of the selective vulnerability of this nigral subregion in PD, and this approach may be developed for high impact biomarker applications. Hum Brain Mapp 38:2627-2634, 2017. © 2017 Wiley Periodicals, Inc.

Parkinson's disease-related increase of T2*-weighted hypointensity in substantia nigra pars compacta.

BACKGROUND: In PD, at the time of diagnosis, approximately 50% of melanized dopaminergic neurons in SNpc have died, yet ongoing neuronal death and neuromelanin release with associated neuroinflammation and microglial activation continue, as does local iron accumulation. Previous studies investigating nigral iron accumulation used T2 / T2*-weighted contrasts to define the regions of interest in the SN. Given that T2 / T2*-weighted contrasts lack sensitivity to neuromelanin and thereby SNpc, neuromelanin-sensitive MRI provides better delineation of SNpc and allows the examination of increased iron deposition in SNpc more specifically and accurately. OBJECTIVES: To examine regions of the SNpc, defined by neuromelanin-sensitive MRI, exhibiting iron deposition in PD. METHODS: T1 -weighted and susceptibility weighted imaging data were obtained in a cohort of 82 subjects (54 controls and 28 PD patients). The PD patients were clinically diagnosed with an average UPDRS-III score of 37.9 ± 12.5 in the off medication state. Susceptibility weighted imaging data were analyzed using SNpc regions of interest defined by neuromelanin-sensitive MRI. RESULTS: Compared to control subjects, significantly more hypointense signal was observed in the SNpc defined by neuromelanin-sensitive MRI in the PD patients. In the PD group, the lateral ventral region of SNpc exhibited the greatest increase of hypointensity. This increase in the lateral ventral region of SNpc robustly differentiated PD patients from controls. CONCLUSION: T2*-weighted hypointense signal in the SNpc defined by neuromelanin-sensitive MRI is significantly increased in PD. It is most likely a measure sensitive to PD-related iron deposition and may serve as a robust biomarker of PD. © 2016 International Parkinson and Movement Disorder Society.

STN stimulation in general anaesthesia: evidence beyond 'evidence-based medicine'.

Awake surgery is regarded mandatory for optimal electrode implantation into the subthalamic nucleus (STN) for deep brain stimulation (DBS) in Parkinson's disease (PD). However, this is questionable since general anaesthesia (GA) does not preclude intraoperative microrecordings and clinical evaluation of, for example, current spread to the corticospinal tract. In addition, even in the awake state, clinical testing is not without limitations. We report on intra- and postoperative findings in 11 patients suffering from advanced PD who were operated under GA (propofol/remifentanil). The activity of STN neurons under GA was characterized by excessive burst discharges that differed fundamentally from the irregular tonic patterns observed in the STN of awake patients. In all patients, we obtained improved motor symptoms and reduced levodopa-induced dyskinesias and motor fluctuations, which was associated with a reduction in the levodopa equivalent daily dose. Therapeutic DBS was not limited by current spread to the corticospinal tract in any of the patients. The trajectories chosen for electrode implantation in GA compared well to awake surgery. Our results indicate that STN surgery in GA can be performed in a safe manner. It can be offered to anxious patients, and represents a viable option when awake surgery bears a risk for the patient.

Brain iron deposition fingerprints in Parkinson's disease and progressive supranuclear palsy.

It can be difficult to clinically distinguish between classical Parkinson's disease (PD) and progressive supranuclear palsy. Previously, there have been no biomarkers that reliably allow this distinction to be made. We report that an abnormal brain iron accumulation is a marker for ongoing neurodegeneration in both conditions, but the conditions differ with respect to the anatomical distribution of these accumulations. We analyzed quantitative T2' maps as markers of regional brain iron content from PD and progressive supranuclear palsy patients and compared them to age-matched control subjects. T2-weighted and T2*-weighted images were acquired in 30 PD patients, 12 progressive supranuclear palsy patients, and 24 control subjects at 1.5 Tesla. Mean T2' values were determined in regions-of-interest in the basal ganglia, thalamus, and white matter within each hemisphere. The main findings were shortened T2' values in the caudate nucleus, globus pallidus, and putamen in progressive supranuclear palsy compared to PD patients and controls. A stepwise linear discriminant analysis allowed progressive supranuclear palsy patients to be distinguished from PD patients and the healthy controls. All progressive supranuclear palsy patients were correctly classified. No progressive supranuclear palsy patient was classified as a healthy control, no healthy controls were incorrectly classified as having progressive supranuclear palsy, and only 6.7% of the PD patients were incorrectly classified as progressive supranuclear palsy. Regional decreases of T2' relaxation times in parts of the basal ganglia reflecting increased brain iron load in these areas are characteristic for progressive supranuclear palsy but not PD patients.

Image-based classification of parkinsonian syndromes using T2'-atlases.

Parkinsonian syndromes (PS) are genetically and pathologically heterogeneous neurodegenerative disorders. Clinical distinction between different PS can be difficult, particularly in early disease stages. This paper describes an automatic method for the distinction between classical Parkinson's disease (PD) and progressive supranuclear palsy (PSP) using T2' atlases. This procedure is based on the assumption that regional brain iron content differs between PD and PSP, which can be selectively measured using T2' MR imaging. The proposed method was developed and validated based on 33 PD patients, 10 PSP patients, and 24 healthy controls. The first step of the proposed procedure comprises T2' atlas generation for each group using affine and following non-linear registration. For classification, a T2' dataset is registered to the atlases and compared to each one of them using the mean sum of squared differences metric. The dataset is assigned to the group for which the corresponding atlas yields the lowest value. The evaluation using leave-one-out validation revealed that the proposed method achieves a classification accuracy of 91%. The presented method might serve as the basis for an improved automatic classification of PS in the future.

Utility of Multi-Modal MRI for Differentiating of Parkinson's Disease and Progressive Supranuclear Palsy Using Machine Learning.

Background: Patients with Parkinson's disease (PD) and progressive supranuclear palsy Richardson's syndrome (PSP-RS) often show overlapping clinical features, leading to misdiagnoses. The objective of this study was to investigate the feasibility and utility of using multi-modal MRI datasets for an automatic differentiation of PD patients, PSP-RS patients, and healthy control (HC) subjects. Material and Methods: T1-weighted, T2-weighted, and diffusion-tensor (DTI) MRI datasets from 45 PD patients, 20 PSP-RS patients, and 38 HC subjects were available for this study. Using an atlas-based approach, regional values of brain morphology (T1-weighted), brain iron metabolism (T2-weighted), and microstructural integrity (DTI) were measured and employed for feature selection and subsequent classification using combinations of various established machine learning methods. Results: The optimal machine learning model using regional morphology features only achieved a classification accuracy of 65% (67/103 correct classifications) differentiating PD patients, PSP-RS patients, and HC subjects. The optimal machine learning model using only quantitative T2 values performed slightly better and achieved an accuracy of 75.7% (78/103). The optimal classifier using DTI features alone performed considerably better with 95.1% accuracy (98/103). The optimal multi-modal classifier using all features also achieved an accuracy of 95.1% but required more features and achieved a slightly lower F1-score compared to the optimal model using DTI features alone. Conclusion: Machine learning models using multi-modal MRI perform significantly better than uni-modal machine learning models using morphological parameters based on T1-weighted MRI datasets alone or brain iron metabolism markers based on T2-weighted MRI datasets alone. However, machine learnig models using regional brain microstructural integrity metrics computed from DTI datasets perform similar to the optimal multi-modal machine learning model. Thus, given the results from this study cohort, it appears that morphology and brain iron metabolism markers may not provide additional value for classification compared to using DTI metrics alone.

Involvement of motor pathways in corticobasal syndrome detected by diffusion tensor tractography.

Corticobasal syndrome (CBS) is a progressive parkinsonian disease characterized by cortical and subcortical neuronal loss. Although motor disabilities are a core feature of CBS, the involvement of motor pathways in this condition has not been completely clarified. We used magnetic resonance diffusion tensor imaging (DTI) to study corticospinal and transcallosal motor projections in CBS, and applied fiber tractography to analyze the axonal integrity of white matter projections. Ten patients with CBS were compared with 10 age-matched healthy controls. Fiber tracts were computed using a Monte-Carlo simulation approach. Tract-specific mean values of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were determined. CBS patients showed a reduction of corticospinal tract (CST) fibers on the first affected side with significantly increased ADC and reduced FA values. In the corpus callosum (CC), particularly in the posterior trunk, patients also had significantly reduced fiber projections, with a higher ADC and lower FA than controls. This pattern indicates changes of the white matter integrity in both CST and CC. Thus, magnetic resonance DTI can be used to assess motor pathway involvement in CBS patients.

Improved Automatic Morphology-Based Classification of Parkinson's Disease and Progressive Supranuclear Palsy.

OBJECTIVES: The overlapping symptoms of Parkinson's disease (PD) and progressive supranuclear palsy-Richardson's syndrome (PSP-RS) often make a correct clinical diagnosis difficult. The volume of subcortical brain structures derived from high-resolution T1-weighted magnetic resonance imaging (MRI) datasets is frequently used for individual level classification of PD and PSP-RS patients. The aim of this study was to evaluate the benefit of including additional morphological features beyond the simple regional volume, as well as clinical features, and morphological features of cortical structures for an automatic classification of PD and PSP-RS patients. MATERIAL AND METHODS: A total of 98 high-resolution T1-weighted MRI datasets from 76 PD patients, and 22 PSP-RS patients were available for this study. Using an atlas-based approach, the volume, surface area, and surface-area-to-volume ratio (SA:V) of 21 subcortical and 48 cortical brain regions were calculated and used as features for a support vector machine classification after application of a RELIEF feature selection method. RESULTS: The comparison of the classification results suggests that including all three morphological parameters (volume, surface area and SA:V) can considerably improve classification accuracy compared to using volume or surface area alone. Likewise, including clinical patient features in addition to morphological parameters also considerably increases the classification accuracy. In contrast to this, integrating morphological features of other cortical structures did not lead to improved classification accuracy. Using this optimal set-up, an accuracy of 98% was achieved with only one falsely classified PD and one falsely classified PSP-RS patient. CONCLUSION: The results of this study suggest that clinical features as well as more advanced morphological features should be used for future computer-aided diagnosis systems to differentiate PD and PSP-RS patients based on morphological parameters.

Imitation inhibition in children with Tourette syndrome.

OBJECTIVE: Echopraxia, that is, the open and automatic imitation of other peoples' actions, is common in patients with Gilles de la Tourette syndrome, autism spectrum disorder, and also those with frontal lobe lesions. While systematic reaction time tasks have confirmed increased automatic imitation in the latter two groups, adult patients with Tourette syndrome appear to compensate for automatic imitation tendencies by an overall slowing in response times. However, whether children with Tourette syndrome are already able to inhibit automatic imitation tendencies has not been investigated. METHOD: Fifteen children with Tourette syndrome and 15 healthy children (aged 7-12 years) performed an imitation inhibition paradigm. Participants were asked to respond to an auditory cue by lifting their index finger or their little finger. Participants were simultaneously presented with either compatible or incompatible visual stimuli. RESULTS: Overall responses in children with Tourette syndrome were slower than in healthy children. Although responses were faster in compatible than in incompatible trials in both groups, this 'interference effect' was smaller in children with Tourette syndrome. CONCLUSIONS: Children with Tourette syndrome have a smaller interference effect than healthy children, indicating an enhanced ability to behaviourally control automatic imitation tendencies at the cost of reacting slower. The results suggest that children with Tourette syndrome already employ different or additional inhibition strategies compared to healthy children.

Widespread diffusion changes differentiate Parkinson's disease and progressive supranuclear palsy.

BACKGROUND: Parkinson's disease (PD) and progressive supranuclear palsy - Richardson's syndrome (PSP-RS) are often represented by similar clinical symptoms, which may challenge diagnostic accuracy. The objective of this study was to investigate and compare regional cerebral diffusion properties in PD and PSP-RS subjects and evaluate the use of these metrics for an automatic classification framework. MATERIAL AND METHODS: Diffusion-tensor MRI datasets from 52 PD and 21 PSP-RS subjects were employed for this study. Using an atlas-based approach, regional median values of mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were measured and employed for feature selection using RELIEFF and subsequent classification using a support vector machine. RESULTS: According to RELIEFF, the top 17 diffusion values consisting of deep gray matter structures, the brainstem, and frontal cortex were found to be especially informative for an automatic classification. A MANCOVA analysis performed on these diffusion values as dependent variables revealed that PSP-RS and PD subjects differ significantly (p < .001). Generally, PSP-RS subjects exhibit reduced FA, and increased MD, RD, and AD values in nearly all brain structures analyzed compared to PD subjects. The leave-one-out cross-validation of the support vector machine classifier revealed that the classifier can differentiate PD and PSP-RS subjects with an accuracy of 87.7%. More precisely, six PD subjects were wrongly classified as PSP-RS and three PSP-RS subjects were wrongly classified as PD. CONCLUSION: The results of this study demonstrate that PSP-RS subjects exhibit widespread and more severe diffusion alterations compared to PD patients, which appears valuable for an automatic computer-aided diagnosis approach.

The neural site of attention matches the spatial scale of perception.

What is the neural locus of visual attention? Here we show that the locus is not fixed but instead changes rapidly to match the spatial scale of task-relevant information in the current scene. To accomplish this, we obtained electrical, magnetic, and hemodynamic measures of attention from human subjects while they detected large-scale or small-scale targets within multiscale stimulus patterns. Subjects did not know the scale of the target before stimulus onset, and yet the neural locus of attention-related activity between 250 and 300 ms varied according to the scale of the target. Specifically, maximal attention-related activity spread from a high-level, relatively anterior visual area (the lateral occipital complex) for large-scale targets to include a lower-level, more posterior area (visual area V4) for small-scale targets. This rapid change indicates that the neural locus of attention in visual cortex is not static but is instead determined rapidly and dynamically by means of an interaction between top-down task information and local information about the current visual input.

Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult.

Niemann-Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty.

Adrenocorticotropic hormone in serial cerebrospinal fluid in man - Subject to acute regulation by the hypothalamic-pituitary-adrenocortical system?

Acute regulation of adrenocorticotropic hormone (ACTH) in cerebrospinal fluid (CSF) by the hypothalamic-pituitary-adrenocortical system has not been investigated in man. In a pilot study in healthy male volunteers we measured ACTH every twenty minutes in serial CSF for three hours after an intravenous placebo, hydrocortisone (100mg) or insulin (2mg/kg) injection. No acute inhibitory or stimulatory effects of these interventions were discovered. Our results corroborate previous findings in rhesus monkeys. The regulation of CSF ACTH and its potential relevance for behavioral alterations in health and disease (e.g. major depression or anorexia nervosa) in humans need further study.

Attention to features precedes attention to locations in visual search: evidence from electromagnetic brain responses in humans.

Single-unit recordings in macaque extrastriate cortex have shown that attentional selection of nonspatial features can operate in a location-independent manner. Here, we investigated analogous neural correlates at the neural population level in human observers by using simultaneous event-related potential (ERP) and event-related magnetic field (ERMF) recordings. The goals were to determine (1) whether task-relevant features are selected before attention is allocated to the location of the target, and (2) whether this selection reflects the locations of the relevant features. A visual search task was used in which the spatial distribution of nontarget items with attended feature values was varied independently of the location of the target. The presence of task-relevant features in a given location led to a change in ERP/ERMF activity beginning approximately 140 msec after stimulus onset, with a neural origin in the ventral occipito-temporal cortex. This effect was independent of the location of the actual target. This effect was followed by lateralized activity reflecting the allocation of attention to the location of the target (the well known N2pc component), which began at approximately 170 msec poststimulus. Current source localization indicated that the allocation of attention to the location of the target originated in more anterior regions of occipito-temporal cortex anterior than the feature-related effects. These findings suggest that target detection in visual search begins with the detection of task-relevant features, which then allows spatial attention to be allocated to the location of a likely target, which in turn allows the target to be positively identified.

MicroRNA Profiling of CSF Reveals Potential Biomarkers to Detect Alzheimer`s Disease.

The miRBase-21 database currently lists 1881 microRNA (miRNA) precursors and 2585 unique mature human miRNAs. Since their discovery, miRNAs have proved to present a new level of epigenetic post-transcriptional control of protein synthesis. Initial results point to a possible involvement of miRNA in Alzheimer's disease (AD). We applied OpenArray technology to profile the expression of 1178 unique miRNAs in cerebrospinal fluid (CSF) samples of AD patients (n = 22) and controls (n = 28). Using a Cq of 34 as cut-off, we identified positive signals for 441 miRNAs, while 729 miRNAs could not be detected, indicating that at least 37% of miRNAs are present in the brain. We found 74 miRNAs being down- and 74 miRNAs being up-regulated in AD using a 1.5 fold change threshold. By applying the new explorative "Measure of relevance" method, 6 reliable and 9 informative biomarkers were identified. Confirmatory MANCOVA revealed reliable miR-100, miR-146a and miR-1274a as differentially expressed in AD reaching Bonferroni corrected significance. MANCOVA also confirmed differential expression of informative miR-103, miR-375, miR-505#, miR-708, miR-4467, miR-219, miR-296, miR-766 and miR-3622b-3p. Discrimination analysis using a combination of miR-100, miR-103 and miR-375 was able to detect AD in CSF by positively classifying controls and AD cases with 96.4% and 95.5% accuracy, respectively. Referring to the Ingenuity database we could identify a set of AD associated genes that are targeted by these miRNAs. Highly predicted targets included genes involved in the regulation of tau and amyloid pathways in AD like MAPT, BACE1 and mTOR.

A novel computerized algorithm to detect microstructural brainstem pathology in Parkinson's disease using standard 3 Tesla MR imaging.

Increased deposition of α-synuclein in Parkinson's disease (PD) is known to be prominent in the brainstem and discussed to be clinically relevant for motor and non-motor features. Whether structural magnetic resonance imaging is capable to detect degraded tissue microstructure caused by increased deposition of α-synuclein at this predilection site in PD remains unclear. We hypothesize that microstructural degradation in the brainstem leads to a reduced T1 contrast provoking standard tissue segmentation engines to misclassify tissue as additional grey matter in regions predominantly composed of white matter. High-resolution T1-weighted three-dimensional magnetization prepared rapid gradient echo (MPRAGE) imaging at 3 Tesla in fifty-two PD patients with mild-to-moderate disease severity and in forty age- and gender-matched healthy controls was performed. A dedicated computerized algorithm that comprises standard tissue segmentation in combination with a statistical test was set up that evaluates grey matter composition on voxel level. The algorithm detected a single significant cluster of voxels with enhanced grey matter (cluster volume is 1,368 mm(3), p < 0.05 corrected for false discovery rate) in the pontomedullary junction of the brainstem in PD patients as compared to healthy controls. Furthermore, absolute grey matter volume was significantly higher in the brainstem of the PD group compared to healthy controls. We conclude that this cluster may reflect α-synuclein induced microstructural brainstem pathology in PD.

A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial Alzheimer disease.

Mutations in the presenilin 1 (PS1) gene (PSEN1) are associated with familial Alzheimer disease (FAD). Here, we report on a 50-year-old patient presenting with progressive deterioration of his short-term memory and a family history of early-onset dementia. Diagnostic workup included a neuropsychological examination, structural magnetic resonance (MR) imaging, cerebrospinal fluid (CSF) biomarkers including total tau, phosphorylated tau, and Aß42 levels, as well as sequencing relevant fragments of the genes PSEN1, PSEN2, and APP. Additionally, we were able to obtain archival paraffin-embedded cerebellar tissue from the patient's father for cosegregation analysis. Clinical, neuropsychological and MR imaging data were indicative of early-onset Alzheimer disease. Furthermore, CSF biomarkers showed a typical pattern for Alzheimer disease. DNA sequencing revealed a heterozygous nucleotide transition (c.824C>T) in exon 8 of PSEN1, leading to an amino acid change from alanine to valine at codon 275 (Ala275Val). The same mutation was found in an archival brain specimen of the patient's demented father, but not in a blood sample of the non-demented mother. This mutation alters a conserved residue in the large hydrophilic loop of PS1, suggesting pathogenic relevance. Cosegregegation analysis and the structural as well as the presumed functional role of the mutated and highly conserved residue suggest FAD causing characteristics of the novel PSEN1 mutation Ala275Val.

Hirayama disease is a pure spinal motor neuron disorder--a combined DTI and transcranial magnetic stimulation study.

Hirayama disease (HirD) is a juvenile spinal muscular atrophy predominantly affecting young men with an initially progressive course followed by a stable plateau within several years. It is a matter of debate whether HirD is a widespread motor neuron or more focal cervical cord disease. Whether the supraspinal pathways of the corticospinal tract (CST) are also affected has not been studied systematically. We analyzed CST integrity in seven HirD patients and 11 controls of similar age and gender using diffusion tensor imaging at a 1.5-T scanner and central motor conduction time (CMCT) using transcranial magnetic stimulation. The apparent diffusion coefficient, fractional anisotropy, and axial and radial diffusivity coefficients were determined bilaterally at four representative CST levels and along the whole CST using a probabilistic fiber tracking approach. There were no differences between the initially affected and the contralateral side in HirD patients and no difference between HirD patients and controls for both the ROI-based and the whole CST analyses. Radial diffusivity of the CST was positively correlated with years of disease progression in HirD patients. CMCT was normal in HirD patients. Combined anatomical and functional measurements established normal integrity of the supraspinal CST in HirD patients lending support to the notion that HirD is a pure spinal motor neuron disorder.

No acute suppression of cerebrospinal fluid corticotropin-releasing hormone in man by cortisol administration.

Corticotropin-releasing hormone (CRH) in cerebrospinal fluid (CSF) is regarded as index of brain endocrine and behavioral functioning. We investigated the acute effects of intravenous cortisol (100mg) vs. placebo on serial CSF CRH in ten healthy men. CSF CRH concentrations were not significantly suppressed by cortisol within 3h. The origin and regulation of CSF CRH need further research.