Degeneration of core neural tracts for emotional regulation in a patient with traumatic brain injury: A case report.

RATIONALE: Several brain structures, including the orbital prefrontal cortex, ventrolateral prefrontal cortex, dorsolateral prefrontal cortex, amygdala, and anterior cingulate cortex, are considered key structures in the neural circuitry underlying emotion regulation. We report on a patient showing behavior changes and degeneration of core neural tracts for emotional regulation following traumatic brain injury (TBI). PATIENT CONCERNS: A 51-year-old male patient suffered an in-car accident. The patient lost consciousness for approximately 30 days, and his Glasgow Coma Scale score was 3. He underwent stereotactic drainage for traumatic intraventricular and intracerebral hemorrhages. At approximately 6.5-year after onset, he began to show disinhibition behaviors such as shouting with anger, which worsened over time. At approximately 8-year after onset, he showed severe depression signs and disinhibition, including violence. DIAGNOSES: The patient who showed delayed-onset behavioral changes (disinhibition and depression). INTERVENTIONS: Diffusion tensor imaging data were acquired at 3 months and 8 years after TBI onset. OUTCOMES: The patient showed degeneration of core neural tracts for emotional regulation that was associated with delayed behavioral changes following TBI. On both 3-month and 8-year diffusion tensor tractographies (DTTs), the right dorsolateral prefronto-thalamic tract, ventrolateral prefronto-thalamic tract, orbital prefronto-thalamic tract, uncinate fasciculus, and both cinguli were reconstructed whereas other neural tracts were not reconstructed. Compared with the 3-month DTT, all reconstructed neural tracts on the 8-year DTT were narrow, except for the left cingulum, which showed new transcallosal fibers between both anterior cingula. The fractional anisotropy and tract volume of all reconstructed neural tracts were lower on the 8-year DTT than the 3-month DTT, except for the tract volume of left cingulum. LESSONS: The evaluation of dorsolateral, ventrolateral, and orbital prefronto-thalamic tract, uncinate fasciculus, and cingulum using follow-up DTTs is useful when a patient with TBI shows delayed-onset behavioral problems.

The role of neuroinflammation in the pathogenesis of glaucoma neurodegeneration.

The chapter is a review enclosed in the volume "Glaucoma: A pancitopatia of the retina and beyond." No cure exists for glaucoma. Knowledge on the molecular and cellular alterations underlying glaucoma neurodegeneration (GL-ND) includes innovative and path-breaking research on neuroinflammation and neuroprotection. A series of events involving immune response (IR), oxidative stress and gene expression are occurring during the glaucoma course. Uveitic glaucoma (UG) is a prevalent acute/chronic complication, in the setting of chronic anterior chamber inflammation. Managing the disease requires a team approach to guarantee better results for eyes and vision. Advances in biomedicine/biotechnology are driving a tremendous revolution in ophthalmology and ophthalmic research. New diagnostic and imaging modalities, constantly refined, enable outstanding criteria for delimiting glaucomatous neurodegeneration. Moreover, biotherapies that may modulate or inhibit the IR must be considered among the first-line for glaucoma neuroprotection. This review offers the readers useful and practical information on the latest updates in this regard.

Diffusion tensor and restriction spectrum imaging reflect different aspects of neurodegeneration in Parkinson's disease.

To meet the need for Parkinson's disease biomarkers and evidence for amount and distribution of pathological changes, MRI diffusion tensor imaging (DTI) has been explored in a number of previous studies. However, conflicting results warrant further investigations. As tissue microstructure, particularly of the grey matter, is heterogeneous, a more precise diffusion model may benefit tissue characterization. The purpose of this study was to analyze the diffusion-based imaging technique restriction spectrum imaging (RSI) and DTI, and their ability to detect microstructural changes within brain regions associated with motor function in Parkinson's disease. Diffusion weighted (DW) MR images of a total of 100 individuals, (46 Parkinson's disease patients and 54 healthy controls) were collected using b-values of 0-4000s/mm2. Output diffusion-based maps were estimated based on the RSI-model combining the full set of DW-images (Cellular Index (CI), Neurite Density (ND)) and DTI-model combining b = 0 and b = 1000 s/mm2 (fractional anisotropy (FA), Axial-, Mean- and Radial diffusivity (AD, MD, RD)). All parametric maps were analyzed in a voxel-wise group analysis, with focus on typical brain regions associated with Parkinson's disease pathology. CI, ND and DTI diffusivity metrics (AD, MD, RD) demonstrated the ability to differentiate between groups, with strongest performance within the thalamus, prone to pathology in Parkinson's disease. Our results indicate that RSI may improve the predictive power of diffusion-based MRI, and provide additional information when combined with the standard diffusivity measurements. In the absence of major atrophy, diffusion techniques may reveal microstructural pathology. Our results suggest that protocols for MRI diffusion imaging may be adapted to more sensitive detection of pathology at different sites of the central nervous system.

Delayed-onset central poststroke pain due to degeneration of the spinothalamic tract following thalamic hemorrhage: A case report.

RATIONALE: Recent studies have used diffusion tensor tractography (DTT) to demonstrate that central poststroke pain (CPSP) was related to spinothalamic tract (STT) injury in patients with stroke. However, few studies have been reported about delayed-onset CPSP due to degeneration of the STT following a stroke. PATIENT'S CONCERNS: A 57-year-old female patient presented with right hemiparesis after stroke. Two weeks after onset, she did not report any pain. At approximately 6 months after onset, she reported pain in the right arm and leg, and the pain slowly intensified with the passage of time. At 14 months after onset, the characteristics and severity of her pain were assessed to be continuous pain without allodynia or hyperalgesia; tingling and cold-sensational pain in her right whole arm and leg (visual analog scale score: 5). DIAGNOSES: The patient was diagnosed as the right hemiparesis due to spontaneous thalamic hemorrhage. INTERVENTIONS: Clinical assessment and diffusion tensor imaging (DTI) were performed 2 weeks and 14 months after onset. OUTCOMES: She suffered continuous pain in her right whole arm and leg (visual analog scale score: 5). On DTT of the 2-week postonset DTI scans, the configuration of the STT was well-preserved in both hemispheres. However, in contrast to those 2-week postonset results, the 14-month postonset DTT results showed partial tearing and thinning in the left STT. Regardless, both the 2-week and 14-month postonset DTT showed that the left STT passed through the vicinity of the thalamic lesion. LESSONS: Diagnostic importance of performing a DTT-based evaluation of the STT in patients exhibiting delayed-onset CPSP following intracerebral hemorrhage.

Thalamic atrophy in multiple sclerosis: A magnetic resonance imaging marker of neurodegeneration throughout disease.

OBJECTIVE: Thalamic volume is a candidate magnetic resonance imaging (MRI)-based marker associated with neurodegeneration to hasten development of neuroprotective treatments. Our objective is to describe the longitudinal evolution of thalamic atrophy in MS and normal aging, and to estimate sample sizes for study design. METHODS: Six hundred one subjects (2,632 MRI scans) were analyzed. Five hundred twenty subjects with relapse-onset MS (clinically isolated syndrome, n = 90; relapsing-remitting MS, n = 392; secondary progressive MS, n = 38) underwent annual standardized 3T MRI scans for an average of 4.1 years, including a 1mm3 3-dimensional T1-weighted sequence (3DT1; 2,485 MRI scans). Eighty-one healthy controls (HC) were scanned longitudinally on the same scanner using the same protocol (147 MRI scans). 3DT1s were processed using FreeSurfer's longitudinal pipeline after lesion inpainting. Rates of normalized thalamic volume loss in MS and HC were compared in linear mixed effects models. Simulation-based sample size calculations were performed incorporating the rate of atrophy in HC. RESULTS: Thalamic volume declined significantly faster in MS subjects compared to HC, with an estimated decline of -0.71% per year (95% confidence interval [CI] = -0.77% to -0.64%) in MS subjects and -0.28% per year (95% CI = -0.58% to 0.02%) in HC (p for difference = 0.007). The rate of decline was consistent throughout the MS disease duration and across MS clinical subtypes. Eighty or 100 subjects per arm (α = 0.1 or 0.05, respectively) would be needed to detect the maximal effect size with 80% power in a 24-month study. INTERPRETATION: Thalamic atrophy occurs early and consistently throughout MS. Preliminary sample size calculations appear feasible, adding to its appeal as an MRI marker associated with neurodegeneration. Ann Neurol 2018;83:223-234.

Heterogeneous pathological processes account for thalamic degeneration in multiple sclerosis: Insights from 7 T imaging.

BACKGROUND: Thalamic degeneration impacts multiple sclerosis (MS) prognosis. OBJECTIVE: To investigate heterogeneous thalamic pathology, its correlation with white matter (WM), cortical lesions and thickness, and as function of distance from cerebrospinal fluid (CSF). METHODS: In 41 MS subjects and 17 controls, using 3 and 7 T imaging, we tested for (1) differences in thalamic volume and quantitative T2* (q-T2*) (2) globally and (3) within concentric bands originating from the CSF/thalamus interface; (4) the relation between thalamic, cortical, and WM metrics; and (5) the contribution of magnetic resonance imaging (MRI) metrics to clinical scores. We also assessed MS thalamic lesion distribution as a function of distance from CSF. RESULTS: Thalamic lesions were mainly located next to the ventricles. Thalamic volume was decreased in MS versus controls ( p < 10-2); global q-T2* was longer in secondary progressive multiple sclerosis (SPMS) only ( p < 10-2), indicating myelin and/or iron loss. Thalamic atrophy and longer q-T2* correlated with WM lesion volume ( p < 0.01). In relapsing-remitting MS, q-T2* thalamic abnormalities were located next to the WM ( p < 0.01 (uncorrected), p = 0.09 (corrected)), while they were homogeneously distributed in SPMS. Cortical MRI metrics were the strongest predictors of clinical outcome. CONCLUSION: Heterogeneous pathological processes affect the thalamus in MS. While focal lesions are likely mainly driven by CSF-mediated factors, overall thalamic degeneration develops in association with WM lesions.

Brain signal intensity changes as biomarkers in amyotrophic lateral sclerosis.

OBJECTIVES: To evaluate the contribution of the demographical, clinical, analytical and genetic factors to brain signal intensity changes in T2-weighted MR images in amyotrophic lateral sclerosis (ALS) patients and controls. METHODS: Susceptibility-weighted and FLAIR sequences were obtained in a 3T MR scanner. Iron-related hypointensities in the motor cortex (IRhMC) and hyperintensities of the corticospinal tract (HCT) were qualitatively scored. Age, gender, family history and clinical variables were recorded. Baseline levels of ferritin were measured. C9orf72 was tested in all patients and SOD1 only in familial ALS patients not carrying a C9orf72 expansion. Patients who carried a mutation were categorized as genetic. Associations of these variables with visual scores were assessed with multivariable analysis. RESULTS: A total of 102 ALS patients (92 non-genetic and 10 genetic) and 48 controls (28 ALS mimics and 20 healthy controls) were recruited. In controls, IRhMC associated with age, but HCT did not. In ALS patients, both HTC and IRhMC strongly associated with clinical UMN impairment and bulbar onset. The intensity/extent of IRhMC in the different motor homunculus regions (lower limbs, upper limbs and bulbar) were linked to the symptoms onset site. Between genetic and sporadic patients, no difference in IRhMC and HCT was found. CONCLUSIONS: IRhMC and HCT are reliable markers of UMN degeneration in ALS patients and are more frequent in bulbar onset patients, independently of the mutation status. Age should be considered when evaluating IRhMC. The regional measurement of IRhMC following the motor homunculus could be used as a measure of disease progression.

Risky driving and pedunculopontine nucleus-thalamic cholinergic denervation in Parkinson disease.

BACKGROUND: It is unknown whether driving difficulty in Parkinson disease (PD) is attributable to nigrostriatal dopaminergic or extranigral non-dopaminergic neurodegeneration. OBJECTIVE: To investigate in vivo imaging differences in dopaminergic and cholinergic innervation between PD patients with and without a history of risky driving. METHODS: Thirty non-demented PD subjects (10 women/20 men) completed a driving survey. These subjects had previously undergone (+)-[(11)C] dihydrotetrabenazine vesicular monoamine transporter 2 and [(11)C] methyl-4-piperidinyl propionate acetylcholinesterase PET imaging. Acetylcholinesterase PET imaging assesses cholinergic terminal integrity with cortical uptake largely reflecting basal forebrain and thalamic uptake principally reflecting pedunculopontine nucleus integrity. RESULTS: Eight of thirty subjects reported a history of risky driving (been pulled over, had a traffic citation, or been in an accident since PD onset) while 22 had no such history (safe drivers). There was no difference in striatal dihydrotetrabenazine vesicular monoamine transporter uptake between risky and safe drivers. There was significantly less thalamic acetylcholinesterase activity in the risky drivers compared to safe drivers (0.0513 ± 0.006 vs. 0.0570 ± 0.006, p = 0.022) but no difference in neocortical acetylcholinesterase activity. Using multivariable logistic regression, decreased thalamic acetylcholinesterase activity remained an independent predictor of risky driving in PD even after controlling for age and disease duration. CONCLUSIONS: Risky driving is related to pedunculopontine nucleus-thalamic but not neocortical cholinergic denervation or nigrostriatal dopaminergic denervation in PD. This suggests that degeneration of the pedunculopontine nucleus, a brainstem center responsible for postural and gait control, plays a role in the ability of PD patients to drive.

The implication of nigrostriatal dopaminergic degeneration in the pathogenesis of REM sleep behavior disorder.

BACKGROUND AND PURPOSE: The pathogenesis of rapid eye movement (REM) sleep behavior disorder (RBD) is not clear despite its frequent association with Parkinson's disease (PD). We investigated whether the nigrostriatal dopaminergic system is involved in the development of idiopathic RBD. METHODS: Fourteen patients with RBD, 14 patients with PD and 12 normal controls were included in the study. The diagnosis of RBD was confirmed on polysomnography. All the participants performed single-photon emission computed tomography imaging 3 h after injection of [(123)I]FP-CIT. During REM sleep of the RBD patients, each 30-s epoch was rated as 'tonic' when there was at least 50% of tonically maintained chin electromyography (EMG) activity in the epoch. Phasic EMG activities were calculated as the percentage of 3-s mini-epoch containing phasic EMG events (leg and chin, separately). RESULTS: The RBD patients showed a trend of lower binding in the striatum than the normal controls (P = 0.07), and the significance was revealed in the putamen (P = 0.02). However, in 11 individual cases of the 14 RBD patients, the dopamine transporter (DAT) densities in the putamen still remained within the normal range. In the RBD patients, there was no correlation between EMG activities and DAT densities. CONCLUSIONS: Nigrostriatal dopaminergic degeneration could be a part of the pathogenesis of RBD, but not essential for the development of RBD. The lack of correlation between RBD severity and DAT densities suggests that another pathogenic process not related to nigrostriatal dopaminergic transmission may be implicated in RBD.

Sleep microstructure and neurodegeneration as measured by [123I]beta-CIT SPECT in treated patients with Parkinson's disease.

OBJECTIVES: Along with spindles, K-complexes are well known hallmarks of stage 2 (S2) sleep. However, little is known about their quantity in S2 sleep of patients with Parkinson's disease (PD). SETTING: Sleep laboratory, Department of Neurology, University of Vienna, Austria. PATIENTS AND METHODS: Whole-night polysomnography (PSG) was performed in twelve treated PD patients and ten healthy controls without history of sleep complaints. The quantity of spontaneous K-complexes, K-alpha-complexes, and sleep spindles in one hour S2 sleep, distributed in four epochs of 15 minutes all through the night, were visually selected and analysed. The quantity and the temporal course of these phasic events were compared with the quantity in age-matched healthy controls. Nine of the twelve PD patients underwent [123I]beta-CIT SPECT for calculating dopamine transporter binding in the striatum and serotonin transporter density in the thalamus-hypothalamus region. RESULTS: There was no difference between the quantity of K-complexes, K-alpha-complexes, and sleep spindles in PD patients and in the healthy control group. K-complexes but not sleep spindles decreased over the night in both groups. The number of sleep spindles did not correlate with the dopamine transporter binding in the striatum or the serotonin binding in the thalamic/hypothalamic region. CONCLUSION: K-complexes and sleep spindles are not reduced and do not seem to be related to the degree of dopaminergic degeneration in treated PD patients.

Contributions of PET and SPECT to the understanding of the pathophysiology of Parkinson's disease.

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) provide the means to studying in vivo the neurochemical, hemodynamic or metabolic consequences of the degeneration of the nigrostriatal dopaminergic system in Parkinson's disease (PD). The extent of striatal dopaminergic denervation can be quantified with radiotracers as [18F]FDopa for PET and [123I]tropanes for SPECT. There are other radiotracers such as [11C]Dopa and meta-tyrosines as well as PET tracers for uptake sites. Striatal uptake of [18F]FDopa and [123I]tropanes is markedly decreased in PD, more in the putamen than in the caudate nucleus, and inversely correlates with the severity of motor signs and with duration of disease. PET and SPECT make possible the assessment by noninvasive means of the changes in dopamine receptor density, the effect of neuronal transplants or neuroprotective treatments in PD patients, or the nigrostriatal dopaminergic function in at-risk subjects. Activation studies using cerebral blood flow and metabolism measurements during a motor task reveal an impaired ability to activate the supplementary motor area and dorsolateral prefrontal cortex in PD. This functional disability is reversed by the use of dopaminergic medication or by surgical treatment by pallidotomy or deep brain stimulation. The differential diagnosis between PD and multiple system atrophy, progressive supranuclear palsy or corticobasal degeneration is not yet clearly established by PET and SPECT, even though these syndromes have some particular neurochemical and metabolic profiles. On the other hand, PET and SPECT are useful for distinguishing PD from Dopa-responsive dystonia, or for assessing the integrity of the nigrostriatal dopaminergic pathway in atypical cases of postural tremor or iatrogenic parkinsonian syndromes.