Rebound Tremor Frequency as a Potential Diagnostic Marker for Delayed Therapy Escape after Thalamic Deep Brain Stimulation for Essential Tremor-Insights from a Cross-Sectional Study.

Delayed therapy escape (DTE) is frequent after thalamic deep brain stimulation for essential tremor, leading to reduced quality of life, often with ataxic symptoms, and early recognition is challenging. Our goal was to examine whether a low-frequency rebound tremor of the left hand after switching off stimulation is useful as a diagnostic marker for DTE. In this cross-sectional study with additional retrospective analysis, we examined 31 patients with bilateral thalamic DBS ≥ 12 months for essential tremor, using quantitative assessments including video-based motion capture, Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS), and scale for the assessment and rating of ataxia (SARA). If available, preoperative (preOP) and 12-month postoperative assessments were included in the analysis. Evaluations occurred with DBS activated (ON) and deactivated (OFF). A higher ratio FTMTRS nowON/preOP indicated DTE. Preoperative FTMTRS scores were available for 16 patients, including 5 patients with DTE. The receiver operating characteristic analysis found an area under the curve of 0.86 (p = 0.024) for identification of DTE by low-frequency rebound tremor (i.e., OFF) on the left. In conclusion, it could serve as a potential diagnostic marker.

Time to bury the chisel: a continuous dorsal association tract system.

The arcuate fasciculus may be subdivided into a tract directly connecting frontal and temporal lobes and a pair of indirect subtracts in which the fronto-temporal connection is mediated by connections to the inferior parietal lobe. This tripartition has been advanced as an improvement over the centuries-old consensus that the lateral dorsal association fibers form a continuous system with no discernible discrete parts. Moreover, it has been used as the anatomical basis for functional hypotheses regarding linguistic abilities. Ex hypothesi, damage to the indirect subtracts leads to deficits in the repetition of multi-word sequences, whereas damage to the direct subtract leads to deficits in the immediate reproduction of single multisyllabic words. We argue that this partitioning of the dorsal association tract system enjoys no special anatomical status, and the search for the anatomical substrates of linguistic abilities should not be constrained by it. Instead, the merit of any postulated partitioning should primarily be judged on the basis of whether it enlightens or obfuscates our understanding of the behavior of patients in which individual subtracts are damaged.

Cerebral Glucose Metabolism Is a Valuable Predictor of Survival in Patients with Lewy Body Diseases.

OBJECTIVE: Patients with Lewy body diseases have an increased risk of dementia, which is a significant predictor for survival. Posterior cortical hypometabolism on [18F]fluorodeoxyglucose positron emission tomography (PET) precedes the development of dementia by years. We therefore examined the prognostic value of cerebral glucose metabolism for survival. METHODS: We enrolled patients diagnosed with Parkinson's disease (PD), Parkinson's disease with dementia, or dementia with Lewy bodies who underwent [18F]fluorodeoxyglucose PET. Regional cerebral metabolism of each patient was analyzed by determining the expression of the PD-related cognitive pattern (Z-score) and by visual PET rating. We analyzed the predictive value of PET for overall survival using Cox regression analyses (age- and sex-corrected) and calculated prognostic indices for the best model. RESULTS: Glucose metabolism was a significant predictor of survival in 259 included patients (n = 118 events; hazard ratio: 1.4 [1.2-1.6] per Z-score; hazard ratio: 1.8 [1.5-2.2] per visual PET rating score; both p < 0.0001). Risk stratification with visual PET rating scores yielded a median survival of 4.8, 6.8, and 12.9 years for patients with severe, moderate, and mild posterior cortical hypometabolism (median survival not reached for normal cortical metabolism). Stratification into 5 groups based on the prognostic index revealed 10-year survival rates of 94.1%, 78.3%, 34.7%, 0.0%, and 0.0%. INTERPRETATION: Regional cerebral glucose metabolism is a significant predictor of survival in Lewy body diseases and may allow an earlier survival prediction than the clinical milestone "dementia." Thus, [18F]fluorodeoxyglucose PET may improve the basis for therapy decisions, especially for invasive therapeutic procedures like deep brain stimulation in Parkinson's disease. ANN NEUROL 2024;96:539-550.

The connection of motor improvement after deep brain stimulation in Parkinson's disease and microstructural integrity of the substantia nigra and subthalamic nucleus.

BACKGROUND: Nigrostriatal microstructural integrity has been suggested as a biomarker for levodopa response in Parkinson's disease (PD), which is a strong predictor for motor response to deep brain stimulation (DBS) of the subthalamic nucleus (STN). This study aimed to explore the impact of microstructural integrity of the substantia nigra (SN), STN, and putamen on motor response to STN-DBS using diffusion microstructure imaging. METHODS: Data was collected from 23 PD patients (mean age 63 ± 7, 6 females) who underwent STN-DBS, had preoperative 3 T diffusion magnetic resonance imaging including multishell diffusion-weighted MRI with b-values of 1000 and 2000 s/mm2 and records of motor improvement available. RESULTS: The association between a poorer DBS-response and increased free interstitial fluid showed notable effect sizes (rho > |0.4|) in SN and STN, but not in putamen. However, this did not reach significance after Bonferroni correction and controlling for sex and age. CONCLUSION: Microstructural integrity of SN and STN are potential biomarkers for the prediction of therapy efficacy following STN-DBS, but further studies are required to confirm these associations.

Advanced therapies in Parkinson's disease: an individualized approach to their indication.

Device aided therapies (DAT) comprising the intrajejunal administration of levodopa/carbidopa intestinal gel (LCIG) and levodopa/carbidopa/entacapone intestinal gel (LECIG), the continuous subcutaneous application of foslevodopa/foscarbidopa or apomorphine infusion (CSAI) and deep brain stimulation (DBS) are used to treat Parkinson's disease with insufficient symptom alleviation under intensified pharmacotherapy. These DAT significantly differ in their efficacy profiles, indication, invasiveness, contraindications, and potential side effects. Usually, the evaluation of all these procedures is conducted simultaneously at the same point in time. However, as disease progression and symptom burden is extremely heterogeneous, clinical experience shows that patients reach the individual milestones for a certain therapy at different points in their disease course. Therefore, advocating for an individualized therapy evaluation for each DAT, requiring an ongoing evaluation. This necessitates that, during each consultation, the current symptomatology should be analyzed, and the potential suitability for a DAT be assessed. This work represents a critical interdisciplinary appraisal of these therapies in terms of their individual profiles and compares these DAT regarding contraindications, periprocedural considerations as well as their efficacy regarding motor- and non-motor deficits, supporting a personalized approach.

Disbalanced recruitment of crossed and uncrossed cerebello-thalamic pathways during deep brain stimulation is predictive of delayed therapy escape in essential tremor.

BACKGROUND: Thalamic deep brain stimulation (DBS) is an efficacious treatment for drug-resistant essential tremor (ET) and the dentato-rubro-thalamic tract (DRT) constitutes an important target structure. However, up to 40% of patients habituate and lose treatment efficacy over time, frequently accompanied by a stimulation-induced cerebellar syndrome. The phenomenon termed delayed therapy escape (DTE) is insufficiently understood. Our previous work showed that DTE clinically is pronounced on the non-dominant side and suggested that differential involvement of crossed versus uncrossed DRT (DRTx/DRTu) might play a role in DTE development. METHODS: We retrospectively enrolled right-handed patients under bilateral thalamic DBS >12 months for ET from a cross-sectional study. They were characterized with the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) and Scale for the Assessment and Rating of Ataxia (SARA) scores at different timepoints. Normative fiber tractographic evaluations of crossed and uncrossed cerebellothalamic pathways and volume of activated tissue (VAT) studies together with [18F]Fluorodeoxyglucose positron emission tomography were applied. RESULTS: A total of 29 patients met the inclusion criteria. Favoring DRTu over DRTx in the non-dominant VAT was associated with DTE (R2 = 0.4463, p < 0.01) and ataxia (R2 = 0.2319, p < 0.01). Moreover, increasing VAT size on the right (non-dominant) side was associated at trend level with more asymmetric glucose metabolism shifting towards the right (dominant) dentate nucleus. CONCLUSION: Our results suggest that a disbalanced recruitment of DRTu in the non-dominant VAT induces detrimental stimulation effects on the dominant cerebellar outflow (together with contralateral stimulation) leading to DTE and thus hampering the overall treatment efficacy.

[Synergies Instead of Rivalries - Expert Opinion on the Misunderstood Roles of Continuous Intrajejunal Levodopa Therapy and Deep Brain Stimulation in the Treatment of Parkinson̓s Disease]. / Synergien statt Rivalitäten ­ die missverstandenen Rollen von kontinuierlicher intrajejunaler Levodopatherapie und Tiefer Hirnstimulation in der Behandlung des Morbus Parkinson ­ eine Expertenmeinung.

In the therapy of Parkinson̓s disease, both the intrajejunal administration of Levodopa/Carbidopa Intestinal Gel (LCIG) and, more recently, Levodopa/Carbidopa/Entacapone Intestinal Gel (LECIG), as well as deep brain stimulation (DBS), are employed. These approaches differ significantly in their efficacy and side effect profiles, as well as the timing of their use. Yet, the initiation of therapy for both methods is often simultaneously considered when patients have reached an advanced stage of the disease. From the authors' perspective, however, patients may reach the milestones for the indication of one of these respective treatments at different points in the course of the disease. Individual disease progression plays a pivotal role in this regard. The concept that all patients become candidates for a specific treatment at a predefined time appears erroneous to the authors. In the context of this review, therefore, the therapeutic modalities are presented in terms of their efficacy for different symptoms, the notion of simultaneous timing of their initiation is questioned, and an individualized therapy evaluation is derived, with a focus on quality of life and participation.

Complemental Value of Microstructural and Macrostructural MRI in the Discrimination of Neurodegenerative Parkinson Syndromes.

PURPOSE: Various MRI-based techniques were tested for the differentiation of neurodegenerative Parkinson syndromes (NPS); the value of these techniques in direct comparison and combination is uncertain. We thus compared the diagnostic performance of macrostructural, single compartmental, and multicompartmental MRI in the differentiation of NPS. METHODS: We retrospectively included patients with NPS, including 136 Parkinson's disease (PD), 41 multiple system atrophy (MSA) and 32 progressive supranuclear palsy (PSP) and 27 healthy controls (HC). Macrostructural tissue probability values (TPV) were obtained by CAT12. The microstructure was assessed using a mesoscopic approach by diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI), and diffusion microstructure imaging (DMI). After an atlas-based read-out, a linear support vector machine (SVM) was trained on a training set (n = 196) and validated in an independent test cohort (n = 40). The diagnostic performance of the SVM was compared for different inputs individually and in combination. RESULTS: Regarding the inputs separately, we observed the best diagnostic performance for DMI. Overall, the combination of DMI and TPV performed best and correctly classified 88% of the patients. The corresponding area under the receiver operating characteristic curve was 0.87 for HC, 0.97 for PD, 1.0 for MSA, and 0.99 for PSP. CONCLUSION: We were able to demonstrate that (1) MRI parameters that approximate the microstructure provided substantial added value over conventional macrostructural imaging, (2) multicompartmental biophysically motivated models performed better than the single compartmental DTI and (3) combining macrostructural and microstructural information classified NPS and HC with satisfactory performance, thus suggesting a complementary value of both approaches.

Cerebellar, Not Nigrostriatal Degeneration Impairs Dexterity in Multiple System Atrophy.

BACKGROUND: Multiple system atrophy (MSA) clinically manifests with either predominant nigrostriatal or cerebellopontine degeneration. This corresponds to two different phenotypes, one with predominant Parkinson's symptoms (MSA-P [multiple system atrophy-parkinsonian subtype]) and one with predominant cerebellar deficits (MSA-C [multiple system atrophy-cerebellar subtype]). Both nigrostriatal and cerebellar degeneration can lead to impaired dexterity, which is a frequent cause of disability in MSA. OBJECTIVE: The aim was to disentangle the contribution of nigrostriatal and cerebellar degeneration to impaired dexterity in both subtypes of MSA. METHODS: We thus investigated nigrostriatal and cerebellopontine integrity using diffusion microstructure imaging in 47 patients with MSA-P and 17 patients with MSA-C compared to 31 healthy controls (HC). Dexterity was assessed using the 9-Hole Peg Board (9HPB) performance. RESULTS: Nigrostriatal degeneration, represented by the loss of cells and neurites, leading to a larger free-fluid compartment, was present in MSA-P and MSA-C when compared to HCs. Whereas no intergroup differences were observed between the MSAs in the substantia nigra, MSA-P showed more pronounced putaminal degeneration than MSA-C. In contrast, a cerebellopontine axonal degeneration was observed in MSA-P and MSA-C, with stronger effects in MSA-C. Interestingly, the degeneration of cerebellopontine fibers is associated with impaired dexterity in both subtypes, whereas no association was observed with nigrostriatal degeneration. CONCLUSION: Cerebellar dysfunction contributes to impaired dexterity not only in MSA-C but also in MSA-P and may be a promising biomarker for disease staging. In contrast, no significant association was observed with nigrostriatal dysfunction. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Cognitive Deficits in Parkinson's Disease Are Associated with Neuronal Dysfunction and Not White Matter Lesions.

Background: Cognitive deficits considerably contribute to the patient's burden in Parkinson's disease (PD). While cognitive decline is linked to neuronal dysfunction, the additional role of white matter lesions (WML) is discussed controversially. Objective: To investigate the influence of WML, in comparison to neuronal dysfunction, on cognitive deficits in PD. Methods: We prospectively recruited patients with PD who underwent neuropsychological assessment using the Mattis Dementia Rating Scale 2 (DRS-2) or Parkinson Neuropsychometric Dementia Assessment (PANDA) and both MRI and PET with [18F]fluorodeoxyglucose (FDG). WML-load and PD cognition-related covariance pattern (PDCP) as a measure of neuronal dysfunction were read out. Relationship between cognitive performance and rank-transformed WML was analyzed with linear regression, controlling for the patients' age. PDCP subject scores were investigated likewise and in a second step adjusting for age and WML load. Results: Inclusion criteria were met by 76 patients with a mean (± SD) age of 63.5 ± 9.0 years and disease duration of 10.7 ± 5.4 years. Neuropsychological testing revealed front executive and parietal deficits and a median DRS-2 score of 137 (range 119-144)/144 and PANDA score of 22 (range 3-30)/30. No association between WML and cognition was observed, whereas PDCP subject scores showed a trend-level negative correlation with the DRS-2 (P = 0.060) as well as a negative correlation with PANDA (P = 0.049) which persisted also after additional correction for WML (P = 0.039). Conclusion: The present study indicates that microangiopathic WML do not have a relevant impact on neurocognitive performance in PD whereas neuronal dysfunction does.

Understanding the concept of a novel tool requires interaction of the dorsal and ventral streams.

The left hemisphere tool-use network consists of the dorso-dorsal, ventro-dorsal, and ventral streams, each with distinct computational abilities. In the dual-loop model, the ventral pathway through the extreme capsule is associated with conceptual understanding. We performed a learning experiment with fMRI to investigate how these streams interact when confronted with novel tools. In session one, subjects observed pictures and video sequences in real world action of known and unknown tools and were asked whether they knew the tools and whether they understood their function. In session two, video sequences of unknown tools were presented again, followed again by the question of understanding their function. Different conditions were compared to each other and effective connectivity (EC) in the tool-use network was examined. During concept acquisition of an unknown tool, EC between dorsal and ventral streams was found posterior in fusiform gyrus and anterior in inferior frontal gyrus, with a functional interaction between BA44d and BA45. When previously unknown tools were presented for a second time, EC was prominent only between dorsal stream areas. Understanding the concept of a novel tool requires an interaction of the ventral stream with the dorsal streams. Once the concept is acquired, dorsal stream areas are sufficient.

Identifying large vessel occlusion at first glance in telemedicine.

BACKGROUND: Telemedicine has rapidly emerged as an important tool in emergency neurology. In particular, reliable biomarkers of large vessel occlusions (LVOs) are critically necessary in order to identify the need for in-hospital mechanical thrombectomy (MT). Based on pathophysiological factors, we propose that the presence of head and/or gaze deviation alone signifies cortical hypoperfusion and is therefore a highly sensitive marker for the presence of LVO. METHODS: We retrospectively analyzed a cohort of 160 patients, examined via telemedicine and suspected to have had an acute stroke; this included patients with ischemic or hemorrhagic stroke, transient ischemic attack, and stroke mimics. An assessment of head and gaze deviation and NIHSS score evaluation was performed. In a second analysis, patients who only had ischemia in the anterior circulation (n = 110) were evaluated. RESULTS: Head and/or gaze deviation alone was found to be a reliable marker of LVO (sensitivity: 0.66/specificity: 0.92), as well as a sound indicator for MT (0.82/0.91), in patients with suspected ischemic stroke. The performance of this indicator further improved when patients with ischemia in the anterior circulation only were assessed (LVO: 0.70/0.93; MT: 0.86/0.90). In both analyses, head and/or gaze deviation served as a better indicator for LVO or MT compared to the prevalence of motor deficits or aphasia. Of note, in patients who had ischemia in the anterior circulation, head and/or gaze deviation performed better than the NIHSS score as an indicator for MT. CONCLUSION: These findings confirm that the presence of head and/or gaze deviation serves as a reliable biomarker in stroke-based telemedicine for the diagnosis of LVO, as well as a strong indicator for MT. Furthermore, this marker is just as reliable as the NIHSS score but easier to assess. We therefore suggest that any stroke patient who displays head and/or gaze deviation should immediately be scheduled for vessel imaging and subsequently transported to a MT-competent center.

Deep learning segmentation results in precise delineation of the putamen in multiple system atrophy.

OBJECTIVES: The precise segmentation of atrophic structures remains challenging in neurodegenerative diseases. We determined the performance of a Deep Neural Patchwork (DNP) in comparison to established segmentation algorithms regarding the ability to delineate the putamen in multiple system atrophy (MSA), Parkinson's disease (PD), and healthy controls. METHODS: We retrospectively included patients with MSA and PD as well as healthy controls. A DNP was trained on manual segmentations of the putamen as ground truth. For this, the cohort was randomly split into a training (N = 131) and test set (N = 120). The DNP's performance was compared with putaminal segmentations as derived by Automatic Anatomic Labelling, Freesurfer and Fastsurfer. For validation, we assessed the diagnostic accuracy of the resulting segmentations in the delineation of MSA vs. PD and healthy controls. RESULTS: A total of 251 subjects (61 patients with MSA, 158 patients with PD, and 32 healthy controls; mean age of 61.5 ± 8.8 years) were included. Compared to the dice-coefficient of the DNP (0.96), we noted significantly weaker performance for AAL3 (0.72; p < .001), Freesurfer (0.82; p < .001), and Fastsurfer (0.84, p < .001). This was corroborated by the superior diagnostic performance of MSA vs. PD and HC of the DNP (AUC 0.93) versus the AUC of 0.88 for AAL3 (p = 0.02), 0.86 for Freesurfer (p = 0.048), and 0.85 for Fastsurfer (p = 0.04). CONCLUSION: By utilization of a DNP, accurate segmentations of the putamen can be obtained even if substantial atrophy is present. This allows for more precise extraction of imaging parameters or shape features from the putamen in relevant patient cohorts. CLINICAL RELEVANCE STATEMENT: Deep learning-based segmentation of the putamen was superior to currently available algorithms and is beneficial for the diagnosis of multiple system atrophy. KEY POINTS: • A Deep Neural Patchwork precisely delineates the putamen and performs equal to human labeling in multiple system atrophy, even when pronounced putaminal volume loss is present. • The Deep Neural Patchwork-based segmentation was more capable to differentiate between multiple system atrophy and Parkinson's disease than the AAL3 atlas, Freesurfer, or Fastsurfer.

The Role of Ascending Ventral-Tegmental Fibers for Recovery after Stroke.

OBJECTIVES: The integrity of cortical motor networks and their descending effector pathway (the corticospinal tract [CST]) is a major determinant motor recovery after stroke. However, this view neglects the importance of ascending tracts and their modulatory effects on cortical physiology. Here, we explore the role of such a tract that connects dopaminergic ventral tegmental midbrain nuclei to the motor cortex (the VTMC tract) for post-stroke recovery. METHODS: Lesion data and diffusivity parameters (fractional anisotropy) of the ipsi- and contralesional VTMC tract and CST were obtained from 133 patients (63.9 ± 13.4 years, 45 women) during the acute and chronic stage after the first ever ischemic stroke in the middle cerebral artery territory. Degeneration of VTMC tract and CST was quantified and related to clinical outcome parameters (National Institute of Health Stroke Scale with motor and cortical symptom subscores; modified Fugl-Meyer upper extremity score; modified Ranking Scale [mRS]). RESULTS: A significant post-stroke degeneration occurred in both tracts, but only VTMC degeneration was associated with lesion size. Using multiple regression models, we dissected the impact of particular tracts on recovery: Changes in VTMC tract integrity were stronger associated with independence in daily activities (mRS), upper limb motor impairment (modified Fugl-Meyer upper extremity score) and cortical symptoms (aphasia, neglect) captured by National Institute of Health Stroke Scale compared to CST. Changes in CST integrity merely were associated with the degree of hemiparesis (National Institute of Health Stroke Scale motor subscale). INTERPRETATION: Post-stroke outcome is influenced by ascending (VTMC) and descending (CST) fiber tracts. Favorable outcome regarding independence (modified Ranking Scale), upper limb motor function (modified Fugl-Meyer upper extremity score), and cortical symptoms (aphasia, neglect) was more strongly related to the ascending than descending tract. ANN NEUROL 2023;93:922-933.

Disentangling nigral and putaminal contribution to motor impairment and levodopa response in Parkinson's disease.

The extent to which the degeneration of the substantia nigra (SN) and putamen each contribute to motor impairment in Parkinson's disease (PD) is unclear, as they are usually investigated using different imaging modalities. To examine the pathophysiological significance of the SN and putamen in both motor impairment and the levodopa response in PD using diffusion microstructure imaging (DMI). In this monocentric retrospective cross-sectional study, DMI parameters from 108 patients with PD and 35 healthy controls (HC) were analyzed using a voxel- and region-based approach. Linear models were applied to investigate the association between individual DMI parameters and Movement Disorder Society Unified Parkinson's Disease Rating Scale-Part 3 performance in ON- and OFF-states, as well as the levodopa response, controlling for age and sex. Voxel- and region-based group comparisons of DMI parameters between PD and HC revealed significant differences in the SN and putamen. In PD, a poorer MDS-UPDRS-III performance in the ON-state was associated with increased free fluid in the SN (b-weight = 65.79, p = 0.004) and putamen (b-weight = 86.00, p = 0.006), and contrariwise with the demise of cells in both structures. The levodopa response was inversely associated with free fluid both in the SN (b-weight = -83.61, p = 0.009) and putamen (b-weight = -176.56, p < 0.001). Interestingly, when the two structures were assessed together, the integrity of the putamen, but not the SN, served as a predictor for the levodopa response (b-weight = -158.03, p < 0.001). Structural alterations in the SN and putamen can be measured by diffusion microstructure imaging in PD. They are associated with poorer motor performance in the ON-state, as well as a reduced response to levodopa. While both nigral and putaminal integrity are required for good performance in the ON-state, it is putaminal integrity alone that determines the levodopa response. Therefore, the structural integrity of the putamen is crucial for the improvement of motor symptoms to dopaminergic medication, and might therefore serve as a promising biomarker for motor staging.

Nigral glucose metabolism as a diagnostic marker of neurodegenerative parkinsonian syndromes.

Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) are characterized by nigrostriatal degeneration. We used [18F]FDG PET to assess glucose metabolism of the substantia nigra (SN) in patients with these diseases and evaluated its ability to discriminate neurodegenerative parkinsonian syndromes (NP) from controls. We retrospectively evaluated [18F]FDG PET scans of 171 patients with NP (n = 115 PD, n = 35 MSA, n = 21 PSP) and 48 controls (13 healthy controls [HC] and 35 control patients). Mean normalized bilateral [18F]FDG uptake in the SN was calculated and compared between groups with covariance and receiver operating characteristic (ROC) analyses (selection of the optimal cut-off required a minimum specificity of 90% to meet the clinical need of a confirmatory test). PD patients were additionally stratified by the expression of the well-established PD-related metabolic pattern (PDRP; elevated expression defined as 2 standard deviations above the mean value of HC). [18F]FDG uptake was significantly lower in NP (Cohen's d = 1.09, p < 0.001) and its subgroups (PD, d = 1.10, p < 0.001; MSA, d = 0.97, p < 0.001; PSP, d = 1.79, p < 0.001) than in controls. ROC analysis for discriminating NP vs. controls revealed an area under the curve of 0.81 and a sensitivity and specificity of 56 and 92%. Moreover, nigral metabolism was below the cut-off in 60% of PD patients without elevated PDRP expression. Glucose metabolism of the SN can distinguish patients with NP from controls with good diagnostic accuracy and can be used as a marker of nigral degeneration. Its evaluation is particularly valuable in PD patients without elevated PDRP expression and may thus help to narrow the diagnostic gap of [18F]FDG PET in neurodegenerative parkinsonism (i.e., identification of patients with PD without cortical involvement).

Unravelling delayed therapy escape after thalamic deep brain stimulation for essential tremor? - Additional clinical and neuroimaging evidence.

BACKGROUND: Delayed therapy escape after thalamic deep brain stimulation (DBS) for essential tremor is a serious yet frequent condition. It is often difficult to detect this process at onset due to its gradual evolution. OBJECTIVE: Here we aim to identify clinical and neuroimaging hallmarks of delayed therapy escape. METHODS: We retrospectively studied operationalized and quantitative analyses of tremor and gait, as well as [18F]fluorodeoxyglucose (FDG) PET of 12 patients affected by therapy escape. All examinations were carried out with activated DBS (ON) and 72 h after deactivation (OFF72h); gait and tremor were also analyzed directly after deactivation (OFF0h). Changes of normalized glucose metabolism between stimulation conditions were assessed using within-subject analysis of variance and statistical parametric mapping. Additionally, a comparison to the [18F]FDG PET of an age-matched control group was performed. Exploratory correlation analyses were conducted with operationalized and parametric clinical data. RESULTS: Of the immediately accessible parametric tremor data (i.e. ON or OFF0h) only the rebound (i.e. OFF0h) frequency of postural tremor showed possible correlations with signs of ataxia at ON. Regional glucose metabolism was significantly increased bilaterally in the thalamus and dentate nucleus in ON compared to OFF72h. No differences in regional glucose metabolism were found in patients in ON and OFF72h compared with the healthy controls. CONCLUSIONS: Rebound frequency of postural tremor seems to be a good diagnostic marker for delayed therapy escape. Regional glucose metabolism suggests that this phenomenon may be associated with increased metabolic activity in the thalamus and dentate nucleus possibly due to antidromic stimulation effects. We see reasons to interpret the delayed therapy escape phenomenon as being related to long term and chronic DBS.