Longitudinal brain atrophy distribution in advanced Parkinson's disease: What makes the difference in "cognitive status" converters?

We investigated the brain atrophy distribution pattern and rate of regional atrophy change in Parkinson's disease (PD) in association with the cognitive status to identify the morphological characteristics of conversion to mild cognitive impairment (MCI) and dementia (PDD). T1-weighted longitudinal 3T MRI data (up to four follow-up assessments) from neuropsychologically well-characterized advanced PD patients (n = 172, 8.9 years disease duration) and healthy elderly controls (n = 85) enrolled in the LANDSCAPE study were longitudinally analyzed using a linear mixed effect model and atlas-based volumetry and cortical thickness measures. At baseline, PD patients presented with cerebral atrophy and cortical thinning including striatum, temporoparietal regions, and primary/premotor cortex. The atrophy was already observed in "cognitively normal" PD patients (PD-N) and was considerably more pronounced in cognitively impaired PD patients. Linear mixed effect modeling revealed almost similar rates of atrophy change in PD and controls. The group comparison at baseline between those PD-N whose cognitive performance remained stable (n = 42) and those PD-N patients who converted to MCI/PDD ("converter" cPD-N, n = 26) indicated suggested cortical thinning in the anterior cingulate cortex in cPD-N patients which was correlated with cognitive performance. Our results suggest that cortical brain atrophy has been already expanded in advanced PD patients without overt cognitive deficits while atrophy progression in late disease did not differ from "normal" aging regardless of the cognitive status. It appears that cortical atrophy begins early and progresses already in the initial disease stages emphasizing the need for therapeutic interventions already at disease onset.

Cognitive decline in Parkinson's disease: the impact of the motor phenotype on cognition.

OBJECTIVES: Parkinson's disease (PD) is the second most common neurodegenerative disorder and is further associated with progressive cognitive decline. In respect to motor phenotype, there is some evidence that akinetic-rigid PD is associated with a faster rate of cognitive decline in general and a greater risk of developing dementia.The objective of this study was to examine cognitive profiles among patients with PD by motor phenotypes and its relation to cognitive function. METHODS: Demographic, clinical and neuropsychological cross-sectional baseline data of the DEMPARK/LANDSCAPE study, a multicentre longitudinal cohort study of 538 patients with PD were analysed, stratified by motor phenotype and cognitive syndrome. Analyses were performed for all patients and for each diagnostic group separately, controlling for age, gender, education and disease duration. RESULTS: Compared with the tremor-dominant phenotype, akinetic-rigid patients performed worse in executive functions such as working memory (Wechsler Memory Scale-Revised backward; p=0.012), formal-lexical word fluency (p=0.043), card sorting (p=0.006), attention (Trail Making Test version A; p=0.024) and visuospatial abilities (Leistungsprüfungssystem test 9; p=0.006). Akinetic-rigid neuropsychological test scores for the executive and attentive domain correlated negatively with non-tremor motor scores. Covariate-adjusted binary logistic regression analyses showed significant odds for PD-mild cognitive impairment for not-determined as compared with tremor-dominant (OR=3.198) and akinetic-rigid PD (OR=2.059). The odds for PD-dementia were significant for akinetic-rigid as compared with tremor-dominant phenotype (OR=8.314). CONCLUSION: The three motor phenotypes of PD differ in cognitive performance, showing that cognitive deficits seem to be less severe in tremor-dominant PD. While these data are cross-sectional, longitudinal data are needed to shed more light on these differential findings.

T1 mapping with the variable flip angle technique: A simple correction for insufficient spoiling of transverse magnetization.

PURPOSE: The variable flip angle method derives T1 maps from radiofrequency-spoiled gradient-echo data sets, acquired with different flip angles α. Because the method assumes validity of the Ernst equation, insufficient spoiling of transverse magnetization yields errors in T1 estimation, depending on the chosen radiofrequency-spoiling phase increment (Δϕ). This paper presents a versatile correction method that uses modified flip angles α' to restore the validity of the Ernst equation. METHODS: Spoiled gradient-echo signals were simulated for three commonly used phase increments Δϕ (50°/117°/150°), different values of α, repetition time (TR), T1 , and a T2 of 85 ms. For each parameter combination, α' (for which the Ernst equation yielded the same signal) and a correction factor CΔϕ (α, TR, T1 ) = α'/α were determined. CΔϕ was found to be independent of T1 and fitted as polynomial CΔϕ (α, TR), allowing to calculate α' for any protocol using this Δϕ. The accuracy of the correction method for T2 values deviating from 85 ms was also determined. The method was tested in vitro and in vivo for variable flip angle scans with different acquisition parameters. RESULTS: The technique considerably improved the accuracy of variable flip angle-based T1 maps in vitro and in vivo. CONCLUSIONS: The proposed method allows for a simple correction of insufficient spoiling in gradient-echo data. The required polynomial parameters are supplied for three common Δϕ. Magn Reson Med 79:3082-3092, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Evaluation of brain ageing: a quantitative longitudinal MRI study over 7 years.

OBJECTIVES: T1 relaxometry is a promising tool for the assessment of microstructural changes during brain ageing. Previous cross-sectional studies demonstrated increasing T1 values in white and decreasing T1 values in grey matter over the lifetime. However, these findings have not yet been confirmed on the basis of a longitudinal study. In this longitudinal study over 7 years, T1 relaxometry was used to investigate the dynamics of age-related microstructural changes in older healthy subjects. METHODS: T1 mapping was performed in 17 healthy subjects (range 51-77 years) at baseline and after 7 years. Advanced cortical and white matter segmentation was used to determine mean T1 values in the cortex and white matter. RESULTS: The analysis revealed a decrease of mean cortical T1 values over 7 years, the rate of T1 reduction being more prominent in subjects with higher age. T1 decreases were predominantly localized in the lateral frontal, parietal and temporal cortex. In contrast, mean white matter T1 values remained stable. CONCLUSIONS: T1 mapping is shown to be sensitive to age-related microstructural changes in healthy ageing subjects in a longitudinal setting. Data of a cohort in late adulthood and the senescence period demonstrate a decrease of cortical T1 values over 7 years, most likely reflecting decreasing water content and increased iron concentrations. KEY POINTS: • T1 mapping is sensitive to age-related microstructural changes in a longitudinal setting. • T1 decreases were predominantly localized in the lateral frontal, parietal and temporal cortex. • The rate of T1 reduction was more prominent in subjects with higher age. • These changes most likely reflect decreasing cortical water and increasing iron concentrations.

Quantitative T1 and proton density mapping with direct calculation of radiofrequency coil transmit and receive profiles from two-point variable flip angle data.

Quantitative T1 mapping of brain tissue is frequently based on the variable flip angle (VFA) method, acquiring spoiled gradient echo (GE) datasets at different excitation angles. However, accurate T1 calculation requires a knowledge of the sensitivity profile B1 of the radiofrequency (RF) transmit coil. For an additional derivation of proton density (PD) maps, the receive coil sensitivity profile (RP) must also be known. Mapping of B1 and RP increases the experiment duration, which may be critical when investigating patients. In this work, a method is presented for the direct calculation of B1 and RP from VFA data. Thus, quantitative maps of T1 , PD, B1 and RP can be obtained from only two spoiled GE datasets. The method is based on: (1) the exploitation of the linear relationship between 1/PD and 1/T1 in brain tissue and (2) the assumption of smoothly varying B1 and RP, so that a large number of data points can be fitted across small volume elements where B1 and RP are approximately constant. The method is tested and optimized on healthy subjects. Copyright © 2016 John Wiley & Sons, Ltd.

Ultrasound-based motion analysis demonstrates bilateral arm hypokinesia during gait in heterozygous PINK1 mutation carriers.

Carriers of a single heterozygous PINK1 (PTEN-induced putative kinase 1) gene mutation provide an ideal opportunity to study the development of parkinsonian motor signs from the very beginning. Measuring tools that reliably represent mild motor symptoms could also facilitate the assessment of future neuroprotective therapies and early diagnosis of Parkinson's disease (PD). We investigated nine family members carrying a heterozygous PINK1 mutation in comparison with 25 age-matched healthy controls. Arm kinematics were quantified during treadmill walking at four different speeds using ultrasound-based motion analysis. Heterozygous PINK1 mutation carriers showed a bilateral reduction of arm swing amplitudes (P = 0.003) and arm anteversion (P = 0.001), which was more pronounced on the predominantly affected body side but also was present, albeit to a lesser degree, contralaterally (amplitude P = 0.01, anteversion P = 0.002, repeated measures analysis of covariance [rmANCOVA]). Single post-hoc comparisons revealed similar results for all speeds on both body sides (P < 0.05) except for 2.0 km/h on the less affected side. A single heterozygous mutation in the PINK1 gene is associated with a bilateral dopaminergic dysfunction in this family. Ultrasound-based three-dimensional motion analysis of arm swing during gait is a suitable tool to quantify even subtle hypokinesia in mildly affected PINK1 mutation carriers, which tends to be easily overlooked on the less affected body side during clinical examination. Therefore, this technique is a promising application in early stage PD and in at-risk populations for the disease.

The value of putaminal diffusion imaging versus 18-fluorodeoxyglucose positron emission tomography for the differential diagnosis of the Parkinson variant of multiple system atrophy.

Differentiating the Parkinson variant of multiple system atrophy (MSA-P) from idiopathic Parkinson's disease (PD) and other forms of atypical parkinsonism can be difficult because symptoms overlap considerably. 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) is a powerful imaging technique that can assist in the diagnosis of MSA-P via detection of putaminal and cerebellar hypometabolism. Recent studies suggest that diffusion-weighted imaging (DWI) might be of similar diagnostic value, as it can detect microstructural damage in the putamen by means of an increased mean diffusivity (MD). The aim of this study was a direct comparison of DWI and FDG-PET by using both methods on the same subject cohort. To this end, combined DWI and FDG-PET were employed in patients with MSA-P (n = 11), PD (n = 13), progressive supranuclear palsy (n = 8), and in 6 control subjects. MD values and FDG uptake ratios were derived from volumetric parcellations of the putamen and subjected to further analysis of covariance (ANCOVA) and receiver operating characteristics analyses. MSA-P was found to be associated with an increased posterior putaminal MD (P < 0.001 in all subgroup comparisons) that correlated strongly with local reductions in FDG uptake (r = -0.85, P = 0.002). DWI discriminated patients with MSA-P from other subgroups nearly as accurately as FDG-PET (area under the curve = 0.89 vs 0.95, P = 0.27 [pooled data]). Our data suggest a close association between the amount of putaminal microstructural damage and a reduced energy metabolism in patients with MSA-P. The clinical use of DWI for the differential diagnosis of MSA-P is encouraged.

Diurnal variation of hypothalamic function and chronic subthalamic nucleus stimulation in Parkinson's disease.

BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) improves quality of life in patients with advanced Parkinson's disease (PD), but is associated with neuropsychiatric side effects and weight gain in some individuals. The pathomechanisms of these phenomena are still unknown. Considering anatomical and functional connections of the STN with the hypothalamic-pituitary (HP) system, we prospectively investigated whether chronic STN-DBS alters HP functioning in 11 PD patients. METHODS: Basal hormone levels of the HP-adrenal (HPA), HP-gonadal and HP-somatotropic axis were determined before surgery as well as 3 and 6 months after electrode implantation. In addition, 24-hour cortisol profiles and dexamethasone suppression tests were obtained. Postoperative hormone changes were correlated with individual neuropsychological test performance, psychiatric status and anthropometric measures. RESULTS: While PD patients experienced weight gain (p = 0.025) at follow-up, most neuropsychological data and basal HP hormone levels did not change over time. HPA regulation and diurnal rhythmicity of cortisol remained intact in all patients. The 24-hour mean cortisol levels decreased 6 months after surgery (p = 0.002) correlating with improved postoperative depression (p = 0.02). CONCLUSIONS: Chronic application of high-frequency electrical stimuli in the STN was not associated with HP dysfunction in patients with advanced PD. The diurnal variability of peripheral cortisol secretion as one important element of the endogenous biological clock remained intact. Evening cortisol levels decreased after surgery reflecting a favorable regulation of the cortisol setpoint. STN-DBS can be considered safe from a neuroendocrine perspective, but the origin of unwanted side effects warrants further elucidation.

Necessity of MRI-compatible deep brain stimulation systems - Hits and hints for decision making.

OBJECTIVES: Deep brain stimulation (DBS) is a safe and effective treatment option for patients with movement disorders as Parkinson's disease, essential tremor and dystonia[1]. For many of these patients the need for imaging may arise in the following years after implantation. The study's aim was to get an overview of the amount of patients with a DBS system who needed an MRI after successful implantation, and if they did, whether the imaging led to a surgical consequence. MATERIALS AND METHODS: In this retrospective descriptive work patients were included if they had their DBS implantation for at least 12 months at the time of analysis. Data were collected by retrospective analysis of the electronic patient files as well as a telephone interview. The reason of each imaging performed was assessed, if patients got MRI after the implantation, it was additionally recorded whether imaging led to a consequence (conservative treatment or surgery). An independent neurologist assessed if an MRI would have been better than a CT for the particular indication. RESULTS: From 54 included patients, 28 patients received imaging after implantation, either CT or MRI. 7 patients underwent MRIs, of whom 3 patients received cranial MRIs and 4 patients received lumbar spine MRIs. All cranial MRIs led to conservative therapy, in 2 lumbar MRIs the diagnosis led to surgery. Nearly 13 % of the imaging performed in our study population occurred because of fall events, 9 of the included patients developed or have had a tumor diagnosis. CONCLUSIONS: Safety of MRI for patients with implanted DBS-systems is and remains an important consideration. Since it can be assumed that patients at a younger age are more likely to get an MRI in the course of their disease, we suggest paying particular attention to the MRI's suitability of the DBS device by patients age. In the end it remains always an individual decision for the surgeon or the consulting physician, which system to use.

Brain age and Alzheimer's-like atrophy are domain-specific predictors of cognitive impairment in Parkinson's disease.

Recently, it was shown that patients with Parkinson's disease (PD) who exhibit an "Alzheimer's disease (AD)-like" pattern of brain atrophy are at greater risk for future cognitive decline. This study aimed to investigate whether this association is domain-specific and whether atrophy associated with brain aging also relates to cognitive impairment in PD. SPARE-AD, an MRI index capturing AD-like atrophy, and atrophy-based estimates of brain age were computed from longitudinal structural imaging data of 178 PD patients and 84 healthy subjects from the LANDSCAPE cohort. All patients underwent an extensive neuropsychological test battery. Patients diagnosed with mild cognitive impairment or dementia were found to have higher SPARE-AD scores as compared to patients with normal cognition and healthy controls. All patient groups showed increased brain age. SPARE-AD predicted impairment in memory, language and executive functions, whereas advanced brain age was associated with deficits in attention and working memory. Data suggest that SPARE-AD and brain age are differentially related to domain-specific cognitive decline in PD. The underlying pathomechanisms remain to be determined.

Long-Term Cognitive Decline Related to the Motor Phenotype in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is associated with various non-motor symptoms, including cognitive deterioration. OBJECTIVE: Here, we used data from the DEMPARK/LANDSCAPE cohort to describe the association between progression of cognitive profiles and the PD motor phenotypes: postural instability and gait disorder (PIGD), tremor-dominant (TR-D), and not-determined (ND). METHODS: Demographic, clinical, and neuropsychological six-year longitudinal data of 711 PD-patients were included (age: M = 67.57; 67.4% males). We computed z-transformed composite scores for a priori defined cognitive domains. Analyses were controlled for age, gender, education, and disease duration. To minimize missing data and drop-outs, three-year follow-up data of 442 PD-patients was assessed with regard to the specific role of motor phenotype on cognitive decline using linear mixed modelling (age: M = 66.10; 68.6% males). RESULTS: Our study showed that in the course of the disease motor symptoms increased while MMSE and PANDA remained stable in all subgroups. After three-year follow-up, significant decline of overall cognitive performance for PIGD-patients were present and we found differences for motor phenotypes in attention (ß= -0.08, SE = 0.003, p < 0.006) and memory functions showing that PIGD-patients deteriorate per months by -0.006 compared to the ND-group (SE = 0.003, p = 0.046). Furthermore, PIGD-patients experienced more often difficulties in daily living. CONCLUSION: Over a period of three years, we identified distinct neuropsychological progression patterns with respect to different PD motor phenotypes, with early executive deficits yielding to a more amnestic profile in the later course. Here, in particular PIGD-patients worsened over time compared to TR-D and ND-patients, highlighting the greater risk of dementia for this motor phenotype.

fMRI of the brainstem using dual-echo EPI.

The brainstem is the part of the human brain that plays a pivotal role in the maintenance of many critical body functions. Due to the elevated level of cardiogenic noise, few fMRI studies have investigated the brainstem so far. Cardiac-gated echo-planar imaging with acquisition of two echoes per excitation (dual-echo EPI) is one method that significantly reduces cardiogenic noise and, thus, allows for fMRI measurements of the brainstem. As information on optimal preprocessing approaches for brainstem-fMRI data is still scarce, the goal of this study was to compare different combinations of normalization and smoothing procedures as implemented in standard fMRI software packages and to identify the combinations yielding optimal results for dual-echo EPI. 21 healthy subjects were measured while executing a simple motor paradigm to activate the facial and trigeminal motor nucleus in the brainstem. After motion correction and calculation of T(2)*-maps the data were preprocessed with 24 combinations of standard normalization (SPM classic, SPM unified, FSL, ABC) and smoothing procedures (pre-/post-smoothing with 3mm-, 4.5mm- and 6mm-kernel) before undergoing first- and second-level statistical analysis. Activation results were compared for first-level and second-level statistics using two anatomically defined regions of interest. Five methods were found to be sensitive for activation of both nuclei. These included FSL normalization with 3mm and 4.5mm pre-smoothing as well as 3mm post-smoothing, SPM unified normalization with 3mm pre-smoothing and ABC normalization with 4.5mm pre-smoothing. All these methods can be recommended for normalization and smoothing when analyzing fMRI data of the brainstem acquired by cardiac-gated dual-echo EPI.

Resting state fMRI reveals increased subthalamic nucleus-motor cortex connectivity in Parkinson's disease.

Parkinson's disease (PD) is associated with abnormal hypersynchronicity in basal ganglia-thalamo-cortical loops. The clinical effectiveness of subthalamic nucleus (STN) high frequency stimulation indicates a crucial role of this nucleus within the affected motor networks in PD. Here we investigate alterations in the functional connectivity (FC) profile of the STN using resting state BOLD correlations on a voxel-by-voxel basis in functional magnetic resonance imaging (fMRI). We compared early stage PD patients (n=31) during the medication-off state with healthy controls (n=44). The analysis revealed increased FC between the STN and cortical motor areas (BA 4 and 6) in PD patients in accordance with electrophysiological studies. Moreover, FC analysis of the primary motor cortex (M1) hand area revealed that the FC increase was primarily found in the STN area within the basal ganglia. These findings are in good agreement with recent experimental data, suggesting that an increased STN-motor cortex synchronicity mediated via the so called hyperdirect motor cortex-subthalamic pathway might play a fundamental role in the pathophysiology of PD. An additional subgroup analysis was performed according to the presence (n=16) or absence (n=15) of tremor in patients. Compared to healthy controls tremor patients showed increased STN FC specifically in the hand area of M1 and the primary sensory cortex. In non-tremor patients, increased FC values were also found between the STN and midline cortical motor areas including the SMA. Taken together our results underline the importance of the STN as a key node for the modulation of BG-cortical motor network activity in PD patients.

Diffusion tensor imaging of white matter involvement in essential tremor.

This study set out to determine whether there is white matter involvement in essential tremor (ET), the most common movement disorder. We collected diffusion MRI and analysed differences in fractional anisotropy (FA) and mean diffusivity (MD) between ET patients and control subjects as markers of white matter integrity. We used both classical ROI-based statistics and whole-brain analysis techniques, including voxel-wise analysis with SPM5 and tract-based spatial statistics (TBSS). Using region of interest (ROI) analysis, we found increased MD bilaterally in the inferior cerebellar peduncles (ICP) and reduced FA in the right-sided ICP of ET patients. Whole-brain analyses with TBSS detected increased MD distributed in both motor and nonmotor white matter fibers of ET patients predominantly in the left parietal white matter, while there were no significant FA differences in these areas between ET patients and controls. Voxel-wise analysis with SPM detected significant increase of MD congruent with the highest probability of difference as detected by TBSS. VBM analysis of T1 images did not detect significant differences in either gray or white matter density between our study groups. In summary, we found evidence for changes in white matter MRI properties in ET. The circumscript pathology of the ICP corroborates the pathogenetic concept of the cerebellum and its projections as key structures for tremor generation in ET. Moreover, increased diffusivity in white matter structures of both hemispheres suggests widespread alterations of fiber integrity in motor and nonmotor networks in ET patients. The underlying cause of the DTI changes observed remains to be elucidated.

Multiparametric Quantitative MRI in Neurological Diseases.

Magnetic resonance imaging (MRI) is the gold standard imaging technique for diagnosis and monitoring of many neurological diseases. However, the application of conventional MRI in clinical routine is mainly limited to the visual detection of macroscopic tissue pathology since mixed tissue contrasts depending on hardware and protocol parameters hamper its application for the assessment of subtle or diffuse impairment of the structural tissue integrity. Multiparametric quantitative (q)MRI determines tissue parameters quantitatively, enabling the detection of microstructural processes related to tissue remodeling in aging and neurological diseases. In contrast to measuring tissue atrophy via structural imaging, multiparametric qMRI allows for investigating biologically distinct microstructural processes, which precede changes of the tissue volume. This facilitates a more comprehensive characterization of tissue alterations by revealing early impairment of the microstructural integrity and specific disease-related patterns. So far, qMRI techniques have been employed in a wide range of neurological diseases, including in particular conditions with inflammatory, cerebrovascular and neurodegenerative pathology. Numerous studies suggest that qMRI might add valuable information, including the detection of microstructural tissue damage in areas appearing normal on conventional MRI and unveiling the microstructural correlates of clinical manifestations. This review will give an overview of current qMRI techniques, the most relevant tissue parameters and potential applications in neurological diseases, such as early (differential) diagnosis, monitoring of disease progression, and evaluating effects of therapeutic interventions.

Dual-echo EPI for non-equilibrium fMRI - implications of different echo combinations and masking procedures.

Dual-echo EPI is based on the acquisition of two images with different echo times per excitation, thus allowing for the calculation of purely T2(*) weighted data. The technique can be used for the measurement of functional activation whenever the prerequisite of constant equilibrium magnetization cannot be fulfilled due to variable inter-volume delays. The latter is the case when image acquisition is triggered by physiological parameters (e.g. cardiac gating) or by the subject's response. Despite its frequent application, there is currently no standardized way of combining the information obtained from the two acquired echoes. The goal of this study was to quantify the implication of different echo combination methods (quotients of echoes and quantification of T(2)(*)) and calculation modalities, either pre-smoothing data before combination or subjecting unsmoothed combined data to masking (no masking, volume-wise masking, joint masking), on the theoretically predicted signal-to-noise ratio (SNR) of the BOLD response and on activation results of two fMRI experiments using finger tapping and visual stimulation in one group (n=5) and different motor paradigms to activate motor areas in the cortex and the brainstem in another group (n=21). A significant impact of echo combination and masking procedure was found for both SNR and activation results. The recommended choice is a direct calculation of T(2)(*) values, either using joint masking on unsmoothed data, or pre-smoothing images prior to T(2)(*) calculation. This method was most beneficial in areas close to the surface of the brain or adjacent to the ventricles and may be especially relevant to brainstem fMRI.

Quantitative mapping of T1 and T2* discloses nigral and brainstem pathology in early Parkinson's disease.

Quantitative magnetic resonance imaging is a promising in vivo imaging technique revealing insights into different aspects of brain morphology in neurodegenerative diseases based on the determination of physical tissue parameters. Using combined T1- and T2*-mapping, we investigated changes of local relaxation times in the midbrain and lower brainstem of 20 patients with early Parkinson's disease (PD) compared to 20 healthy controls. Voxelwise statistical parametric mapping disclosed a widespread reduction of midbrain T1 values contralateral to the clinically more severely affected limbs. Within the SN, the T1 decrease matched the known pattern of selective neuronal loss as examined in various post-mortem studies, suggesting that T1 is a marker for PD related tissue pathology. However, the spatial extent of T1 reductions exceeded the SN and reached non-dopaminergic areas in the pontomesencephalic junction potentially involved in early non-motor symptoms of PD. In contrast, T2*-mapping revealed a bilateral decrease of T2* values restricted to the SN, indicating a local increase in total iron content. We conclude that, particularly in longitudinal studies, quantitative T1 may be a valuable marker for the monitoring of progressive neuronal loss in PD, whereas nigral T2* reductions might be more closely associated with an increased general vulnerability for the development of the disorder.

Comparing Programming Sessions of Vim-DBS.

Background: Essential Tremor (ET) is a progressive neurological disorder characterized by postural and kinetic tremor most commonly affecting the hands and arms. Medically intractable ET can be treated by deep brain stimulation (DBS) of the ventral intermediate nucleus of thalamus (VIM). We investigated whether the location of the effective contact (most tremor suppression with at least side effects) in VIM-DBS for ET changes over time, indicating a distinct mechanism of loss of efficacy that goes beyond progression of tremor severity, or a mere reduction of DBS efficacy. Methods: We performed programming sessions in 10 patients who underwent bilateral vim-DBS surgery between 2009 and 2017 at our department. In addition to the intraoperative (T1) and first clinical programming session (T2) a third programming session (T3) was performed to assess the effect- and side effect threshold (minimum voltage at which a tremor suppression or side effects occurred). Additionally, we compared the choice of the effective contact between T1 and T2 which might be affected by a surgical induced "brain shift." Discussion: Over a time span of about 4 years VIM-DBS in ET showed continuous efficacy in tremor suppression during stim-ON compared to stim-OFF. Compared to immediate postoperative programming sessions in ET-patients with DBS, long-term evaluation showed no relevant change in the choice of contact with respect to side effects and efficacy. In the majority of the cases the active contact at T2 did not correspond to the most effective intraoperative stimulation site T1, which might be explained by a brain-shift due to cerebral spinal fluid loss after neurosurgical procedure.

Effect of thalamic deep brain stimulation on swallowing in patients with essential tremor.

OBJECTIVE: Deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) is a mainstay treatment for severe and drug-refractory essential tremor (ET). Although stimulation-induced dysarthria has been extensively described, possible impairment of swallowing has not been systematically investigated yet. METHODS: Twelve patients with ET and bilateral VIM-DBS with self-reported dysphagia after VIM-DBS were included. Swallowing function was assessed clinically and using by flexible endoscopic evaluation of swallowing in the stim-ON and in the stim-OFF condition. Presence, severity, and improvement of dysphagia were recorded. RESULTS: During stim-ON, the presence of dysphagia could be objectified in all patients, 42% showing mild, 42% moderate, and 16 % severe dysphagia. During stim-OFF, all patients experienced a statistically significant improvement of swallowing function. INTERPRETATION: VIM-DBS may have an impact on swallowing physiology in ET-patients. Further studies to elucidate the prevalence and underlying pathophysiological mechanisms are warranted.

Cortical aging - new insights with multiparametric quantitative MRI.

Understanding the microstructural changes related to physiological aging of the cerebral cortex is pivotal to differentiate healthy aging from neurodegenerative processes. The aim of this study was to investigate the age-related global changes of cortical microstructure and regional patterns using multiparametric quantitative MRI (qMRI) in healthy subjects with a wide age range. 40 healthy participants (age range: 2nd to 8th decade) underwent high-resolution qMRI including T1, PD as well as T2, T2* and T2' mapping at 3 Tesla. Cortical reconstruction was performed with the FreeSurfer toolbox, followed by tests for correlations between qMRI parameters and age. Cortical T1 values were negatively correlated with age (p=0.007) and there was a widespread age-related decrease of cortical T1 involving the frontal and the parietotemporal cortex, while T2 was correlated positively with age, both in frontoparietal areas and globally (p=0.004). Cortical T2' values showed the most widespread associations across the cortex and strongest correlation with age (r= -0.724, p=0.0001). PD and T2* did not correlate with age. Multiparametric qMRI allows to characterize cortical aging, unveiling parameter-specific patterns. Quantitative T2' mapping seems to be a promising imaging biomarker of cortical age-related changes, suggesting that global cortical iron deposition is a prominent process in healthy aging.