Quantification of tremor severity with a mobile tremor pen.

BACKGROUND: An objective evaluation of tremor severity is necessary to document the course of disease, the efficacy of treatment, or interventions in clinical trials. Most available objective quantification devices are complex, immobile, or not validated. NEW METHOD: We used the TREMITAS-System that comprises a pen-shaped sensor for tremor quantification. The Power of Main Peak and the Total Power were used as surrogate markers for tremor amplitude. Tremor severity was assessed by the TREMITAS-System and relevant subscores of the MDS-UPDRS and TETRAS rating scales in 14 patients with Parkinson's disease (PD) and 16 patients with Essential tremor (ET) off and on therapy. We compared tremor amplitudes assessed during wearable and hand-held constellations. RESULTS: We found significant correlations between tremor amplitudes captured by TREM and tremor severity assessed by the MDS-UPDRS in PD (r = 0.638-0.779) and the TETRAS in ET (r = 0.597-0. 704) off and on therapy. The TREMITAS-System captured the L-Dopa-induced improvement of tremor in PD patients (p = 0.027). Tremor amplitudes did not differ between the handheld and wearable constellation (p > 0.05). COMPARISON WITH EXISTING METHODS: We confirm the results of previous studies using inertial based sensors that tremor severity and drug-induced changes of tremor severity can be quantified using inertial based sensors. The assessment of tremor amplitudes was not influenced by using a handheld or wearable constellation. CONCLUSIONS: The TREMITAS-System can be used to quantify rest tremor in PD and postural tremor in ET and is capable of detecting clinically relevant changes in tremor in clinical and research settings.

Minor Structural Differences in the Cervical Spine Between Patients With Cervical Dystonia and Age-Matched Healthy Controls.

Background: Cervical dystonia is the most common form of focal dystonia. The frequency and pattern of degenerative changes of the cervical spine in patients with cervical dystonia and their relation to clinical symptoms remain unclear as no direct comparison to healthy controls has been performed yet. Here, we used magnetic resonance imaging (MRI) to investigate (1) whether structural abnormalities of the cervical spine are more common in patients with cervical dystonia compared to age-matched healthy controls, (2) if there are clinical predictors for abnormalities on MRI, and (3) to calculate the inter-rater reliability of the respective radiological scales. Methods: Twenty-five consecutive patients with cervical dystonia and 20 age-matched healthy controls were included in the study. MRI scans of the cervical spine were analyzed separately by three experienced raters blinded to clinical information, applying different MRI rating scales. Structural abnormalities were compared between groups for upper, middle, and lower cervical spine segments. The associations between scores differentiating both groups and clinical parameters were assessed in dystonia patients. Additionally, inter-rater reliability of the MRI scales was calculated. Results: Comparing structural abnormalities, we found minor differences in the middle cervical spine, indicated by a higher MRI total score in patients but no significant correlation between clinical parameters and MRI changes. Inter-rater reliability was satisfying for most of the MRI rating scales. Conclusion: Our results do not provide evidence for a role of MRI of the cervical spine in the routine work-up of patients with cervical dystonia in the absence of specific clinical signs or symptoms.

Nigral iron deposition in common tremor disorders.

OBJECTIVE: We investigated R2* relaxation rates as a marker of iron content in the substantia nigra in patients with common tremor disorders and explored their diagnostic properties. METHODS: Mean nigral R2* rates were measured in 40 patients with tremor-dominant Parkinson's disease (PD), 15 with tremor in dystonia, 25 with essential tremor, and 25 healthy controls. RESULTS: Tremor-dominant PD patients had significantly higher nigral R2* values (34.1 ± 5.7) than those with tremor in dystonia (30.0 ± 3.9), essential tremor (30.6 ± 4.8), and controls (30.0 ± 2.8). An R2* threshold of 31.15 separated tremor-dominant PD from controls with a sensitivity and specificity of 67.5% and 72%. The sensitivity and specificity for discrimination between PD and non-PD tremor patients was 67.5% and 60%. CONCLUSION: Iron content in the substantia nigra is significantly higher in tremor-dominant PD than in tremor in dystonia, essential tremor, and controls. Because of the considerable overlap, nigral R2* cannot be suggested as a useful diagnostic tool. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Quantitative Susceptibility Mapping in Parkinson's Disease.

BACKGROUND: Quantitative susceptibility mapping (QSM) and R2* relaxation rate mapping have demonstrated increased iron deposition in the substantia nigra of patients with idiopathic Parkinson's disease (PD). However, the findings in other subcortical deep gray matter nuclei are converse and the sensitivity of QSM and R2* for morphological changes and their relation to clinical measures of disease severity has so far been investigated only sparsely. METHODS: The local ethics committee approved this study and all subjects gave written informed consent. 66 patients with idiopathic Parkinson's disease and 58 control subjects underwent quantitative MRI at 3T. Susceptibility and R2* maps were reconstructed from a spoiled multi-echo 3D gradient echo sequence. Mean susceptibilities and R2* rates were measured in subcortical deep gray matter nuclei and compared between patients with PD and controls as well as related to clinical variables. RESULTS: Compared to control subjects, patients with PD had increased R2* values in the substantia nigra. QSM also showed higher susceptibilities in patients with PD in substantia nigra, in the nucleus ruber, thalamus, and globus pallidus. Magnetic susceptibility of several of these structures was correlated with the levodopa-equivalent daily dose (LEDD) and clinical markers of motor and non-motor disease severity (total MDS-UPDRS, MDS-UPDRS-I and II). Disease severity as assessed by the Hoehn & Yahr scale was correlated with magnetic susceptibility in the substantia nigra. CONCLUSION: The established finding of higher R2* rates in the substantia nigra was extended by QSM showing superior sensitivity for PD-related tissue changes in nigrostriatal dopaminergic pathways. QSM additionally reflected the levodopa-dosage and disease severity. These results suggest a more widespread pathologic involvement and QSM as a novel means for its investigation, more sensitive than current MRI techniques.

Microstructural tissue damage in normal appearing brain tissue accumulates with Framingham Stroke Risk Profile Score: magnetization transfer imaging results of the Austrian Stroke Prevention Study.

BACKGROUND AND PURPOSE: Magnetization transfer imaging detects cerebral microstructural tissue alterations. We examined the association between the Framingham Stroke Risk Profile (FSRP) score and magnetization transfer imaging (MTI) measures in pathological and normal appearing brain tissue in clinically normal elderly subjects to determine if stroke risk leads to brain tissue destruction beyond what is visible in conventional MRI scans. METHODS: The study cohort is from the Austrian Stroke Prevention Study (ASPS). A total of 316 subjects underwent MTI and had a complete risk factor assessment sufficient to calculate the FSRP score. There were 205 women and 111 men with a mean age of 70.2 years ranging from 54 to 82 years. Subjects were grouped into four categories of stroke risk probability ranging from 3% to 88% for men and 1% to 84% for women. RESULTS: A higher FSRP score was significantly and independently associated with a MTR peak position shift indicating global microstructural alterations in brain tissue (BT) and in normal appearing brain tissue (NABT). The mean MTR in white matter hyperintensities (WMH) correlated inversely with increasing stroke risk. Age explained most of the variance in MTR peak position, all other risk factors of the FSRP score contributed significantly but explained an additional 2% of the variance of this MRI measure, only. CONCLUSION: Increasing risk for stroke leads to microstructural brain changes invisible by standard MRI. The validity, the underlying pathogenic mechanisms and the clinical importance of these abnormalities needs to be further determined.

B vitamins and magnetic resonance imaging-detected ischemic brain lesions in patients with recent transient ischemic attack or stroke: the VITAmins TO Prevent Stroke (VITATOPS) MRI-substudy.

BACKGROUND AND PURPOSE: Elevated concentrations of homocysteine are associated with cerebral small vessel disease (CSVD). B-vitamin supplementation with folate and vitamins B12 and B6 reduces homocysteine concentrations. In a substudy of the VITAmins TO Prevent Stroke (VITATOPS) trial, we assessed the hypothesis that the addition of once-daily supplements of B vitamins would reduce the progression of CSVD-related brain lesions. METHODS: A total of 359 patients with recent stroke or transient ischemic attack, who were randomly allocated to double-blind treatment with placebo or b vitamins, underwent brain MRI at randomization and after 2 years of B-vitamin supplementation. MR images were analyzed blinded to treatment allocation. Outcomes related to the prespecified hypothesis were progression of white matter hyperintensities and incident lacunes. We also explored the effect of B-vitamin supplementation on the incidence of other ischemic abnormalities. RESULTS: After 2 years of treatment with b vitamins or placebo, there was no significant difference in white matter hyperintensities volume change (0.08 vs 0.13 cm3; P=0.419) and incidence of lacunes (8.0% vs 5.9%, P=0.434; odds ratio=1.38). In a subanalysis of patients with MRI evidence of severe CSVD at baseline, b-vitamin supplementation was associated with a significant reduction in white matter hyperintensities volume change (0.3 vs 1.7 cm3; P=0.039). CONCLUSIONS: Daily B-vitamin supplementation for 2 years did not significantly reduce the progression of brain lesions resulting from presumed CSVD in all patients with recent stroke or transient ischemic attack but may do so in the subgroup of patients with recent stroke or transient ischemic attack and severe CSVD. CLINICAL TRIAL REGISTRATION: http://vitatops.highway1.com.au/. Unique identifier: NCT00097669 and ISRCTN74743444.

MRI-detected white matter lesions: do they really matter?

Despite extensive research over the last decades the clinical significance of white matter lesions (WMLs) is still a matter of debate. Here, we review current knowledge of the correlation between WMLs and cognitive functioning as well as their predictive value for future stroke, dementia, and functional decline in activities of daily living. There is clear evidence that age-related WMLs relate to all of these outcomes on a group level, but the inter-individual variability is high. The association between WMLs and clinical phenotypes exists particularly for early confluent to confluent changes, which are ischaemic in aetiology and progress quickly over time. One reason for the variability of the relationship between WMLs and clinic on an individual level is probably the complexity of the association. Numerous factors such as cognitive reserve, concomitant loss of brain volume, and ultrastructural changes have been identified as mediators between white matter damage and clinical findings, and need to be incorporated in the consideration of WMLs as visible markers of these detrimental processes.

Metabolic syndrome, brain magnetic resonance imaging, and cognition.

OBJECTIVE: We explored cognitive impairment in metabolic syndrome in relation to brain magnetic resonance imaging (MRI) findings. RESEARCH DESIGN AND METHODS: We studied 819 participants free of clinical stroke and dementia of the population-based Austrian Stroke Prevention Study who had undergone brain MRI, neuropsychological testing, and a risk factor assessment relevant to National Cholesterol Education Program Adult Treatment Panel III criteria-defined metabolic syndrome. High-sensitivity C-reactive protein (hs-CRP) was also determined. RESULTS: Of 819 subjects, 232 (28.3%) had metabolic syndrome. They performed worse than those without metabolic syndrome on cognitive tests assessing memory and executive functioning after adjustment for possible confounders. Stratification by sex demonstrated that metabolic syndrome was related to cognitive dysfunction in men but not in women. Only in men was an increasing number of metabolic syndrome components associated with worse cognitive performance. MRI showed no significant differences in focal ischemic lesions and brain volume between subjects with and without metabolic syndrome, and MRI abnormalities failed to explain impaired cognition. Cognitive performance was most affected in male subjects with metabolic syndrome who also had high hs-CRP levels. CONCLUSIONS: Metabolic syndrome exerts detrimental effects on memory and executive functioning in community-dwelling subjects who have not had a clinical stroke or do not have dementia. Men are more affected than women, particularly if they have high inflammatory markers. MRI-detected brain abnormalities do not play a crucial role in these relationships.

Vascular dementia and Alzheimer's disease - are we in a dead-end road?

BACKGROUND: Diagnostic criteria separating vascular dementia from other dementias, particularly Alzheimer's disease (AD) neglect the real world in which most AD cases present with at least some vascular brain lesions. Most importantly, vascular lesions, even if subtle, exert significant effects on the patients' cognitive functioning if they coexist with AD pathology. OBJECTIVES: To emphasize the need for an integrative dementia concept in which the vascular component represents an important end point in trial planning and a possibility for disease modification along the whole spectrum of combined vascular and primary degenerative pathology. METHODS: Review of the literature on possible surrogate markers to study the contribution of vascular brain damage in dementia. RESULTS: The longitudinal change in volume of white matter lesions is the best elaborated putative surrogate marker for the study of the vascular component in dementia. Validation of the role of lacunes and microbleeds as surrogate end points is poor. Loss of brain volume is an important adjunct outcome measure even though the vascular origin of atrophy remains uncertain. CONCLUSIONS: A focus on pure vascular dementia distracts from the importance of vascular factors in dementia. Consideration of the vascular component in future clinical trials will improve our pathophysiological understanding and provide options for treatment.