Determinants of Perivascular Spaces in the General Population: A Pooled Cohort Analysis of Individual Participant Data.

BACKGROUND AND OBJECTIVES: Perivascular spaces (PVS) are emerging markers of cerebral small vessel disease (CSVD), but research on their determinants has been hampered by conflicting results from small single studies using heterogeneous rating methods. In this study, we therefore aimed to identify determinants of PVS burden in a pooled analysis of multiple cohort studies using 1 harmonized PVS rating method. METHODS: Individuals from 10 population-based cohort studies with adult participants from the Uniform Neuro-Imaging of Virchow-Robin Spaces Enlargement consortium and the UK Biobank were included. On MRI scans, we counted PVS in 4 brain regions (mesencephalon, hippocampus, basal ganglia, and centrum semiovale) according to a uniform and validated rating protocol, both manually and automated using a deep learning algorithm. As potential determinants, we considered demographics, cardiovascular risk factors, APOE genotypes, and other imaging markers of CSVD. Negative binomial regression models were used to examine the association between these determinants and PVS counts. RESULTS: In total, 39,976 individuals were included (age range 20-96 years). The average count of PVS in the 4 regions increased from the age 20 years (0-1 PVS) to 90 years (2-7 PVS). Men had more mesencephalic PVS (OR [95% CI] = 1.13 [1.08-1.18] compared with women), but less hippocampal PVS (0.82 [0.81-0.83]). Higher blood pressure, particularly diastolic pressure, was associated with more PVS in all regions (ORs between 1.04-1.05). Hippocampal PVS showed higher counts with higher high-density lipoprotein cholesterol levels (1.02 [1.01-1.02]), glucose levels (1.02 [1.01-1.03]), and APOE ε4-alleles (1.02 [1.01-1.04]). Furthermore, white matter hyperintensity volume and presence of lacunes were associated with PVS in multiple regions, but most strongly with the basal ganglia (1.13 [1.12-1.14] and 1.10 [1.09-1.12], respectively). DISCUSSION: Various factors are associated with the burden of PVS, in part regionally specific, which points toward a multifactorial origin beyond what can be expected from PVS-related risk factor profiles. This study highlights the power of collaborative efforts in population neuroimaging research.

Endophenotyping in idiopathic adult onset cervical dystonia.

OBJECTIVE: Idiopathic adult onset cervical dystonia (IAOCD) is considered to be a partially penetrant autosomal dominant genetic condition. Dystonia may result from genetic and environmental factors. In this view, part of the physiology should be an endophenotype stemming from the genetic background. We assessed the most discriminative test to separate patients with IAOCD and healthy controls for further endophenotyping in non-affected 1st degree relatives. METHODS: We included patients with IAOCD, their 1st degree relatives and healthy controls. Tests performed: (1) Sensory temporal discrimination (visual, tactile, visuo-tactile), (2) Paired pulse paradigms using transcranial magnetic stimulation (TMS), (3) Mental rotation paradigms. RESULTS: 45 patients with IAOCD, 23 healthy controls and 14 non-affected 1st degree relatives were recruited. Visuo-tactile temporal discrimination separated best between controls and patients as well as between controls and 1st degree relatives. 36% of the latter had an abnormal visuo-tactile temporal discrimination. No difference between patients and healthy controls was found for the other paradigms. CONCLUSIONS: Visuo-tactile temporal discrimination separates controls from patients with IAOCD and its 1st degree relatives. 36% of the latter had abnormal visuo-tactile thresholds supporting the role of visuo-tactile temporal discrimination as an endophenotype for IAOCD. SIGNIFICANCE: Even though the study was of exploratory design, our findings expand the understanding of endophenotypes in IAOCD.

Agreement between TOAST and CCS ischemic stroke classification: the NINDS SiGN study.

OBJECTIVE: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. METHODS: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. RESULTS: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58). CONCLUSION: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.

Sensory tricks in primary cervical dystonia depend on visuotactile temporal discrimination.

A characteristic feature of primary cervical dystonia is the presence of "sensory tricks" as well as the impairment of temporal and spatial sensory discrimination on formal testing. The aim of the present study was to test whether the amount of improvement of abnormal head deviation due to a sensory trick is associated with different performance of temporal sensory discrimination in patients with cervical dystonia. We recruited 32 patients with cervical dystonia. Dystonia severity was assessed using the Toronto Western Spasmodic Torticollis Rating Scale. Patients were rated according to clinical improvement to a sensory trick and assigned to 1 of the following groups: (1) no improvement (n = 6), (2) partial improvement (n = 17), (3) complete improvement (n = 9). Temporal discrimination thresholds were assessed for visual, tactile, and visuotactile modalities. Disease duration was shorter (P = .026) and dystonia severity lower (P = .033) in the group with complete improvement to sensory tricks compared with the group with partial improvement to sensory tricks. A significant effect for group and modality and a significant interaction between group × modality were found, with lower visuotactile discrimination thresholds in the group with complete improvement to sensory tricks compared with the other groups. In primary cervical dystonia, a complete resolution of dystonia during a sensory trick is associated with better visuotactile discrimination and shorter disease duration compared with patients with less effective sensory tricks, which may reflect progressive loss of adaptive mechanisms to basal ganglia dysfunction.

Tremor in inflammatory neuropathies.

BACKGROUND: Tremor is known to occur in patients with neuropathies although its reported prevalence varies widely. Tremor has been shown to cause disability in children with Charcot-Marie-Tooth disease but no data exit about the disability caused by tremor in inflammatory neuropathies. Little is known about the response of neuropathic tremor to treatment and why it selectively occurs in some people and not others. METHODS: This case control study investigates the presence and severity of tremor in 43 consecutively recruited patients with inflammatory neuropathies at the National Hospital for Neurology and Neurosurgery, London. Clinical assessment, including Fahn-Tolosa-Marin Scale for tremor, sensory scores, power scores and Overall Neuropathy Limitations Scale, were recorded. Results of nerve conduction studies were retrieved and assessed. Nine patients' tremors were recorded with accelerometry. RESULTS: Tremor was most common in IgM paraproteinaemic neuropathies, as previously reported, but also occurred in 58% of those with chronic inflammatory demyelinating polyradiculoneuropathy and 56% of those with multifocal motor neuropathy with conduction block. We describe, for the first time, tremor in the majority of patients with multifocal motor neuropathy with conduction block. Tremor in all of these patients seems generally refractory to treatment except in a small number of cases where tremor improves with treatment of the underlying neuropathy. We provide evidence that tremor may add to disability in patients with inflammatory neuropathy. Mean tremor frequency was 6 Hz and did not vary with weight loading. We demonstrate for the first time that although tremor severity correlates with F wave latency, it is not sufficient to distinguish those with, from those without, tremor. CONCLUSION: Tremor in inflammatory neuropathies is common, adds to disability and yet does not often respond to treatment of the underlying neuropathy. When present, tremor severity is associated with F wave latency.

Levodopa changes brain motor network function during ankle movements in Parkinson's disease.

Bradykinesia-the cardinal symptom in Parkinson's disease (PD)-affects both upper and lower limbs. While several functional imaging studies investigated the impact of levodopa on movement-related neural activity in Parkinson's disease during upper limb movements, analogue studies on lower limb movements are rare. We studied 20 patients with PD (mean age 66.8 ± 7.2 years) after at least 12 h drug withdrawal (OFF-state) and a second time approximately 40 min after oral administration of 200 mg levodopa (ON-state) behaviourally and by functional magnetic resonance imaging (fMRI) at 3 T during externally cued active ankle movements of the more affected foot at fixed rate. Results were compared with that obtained in ten healthy controls (HC) to separate pure pharmacological from disease-related levodopa-induced effects and to allow for interaction analyses. Behaviourally, all patients improved by at least 20 % regarding the motor score of the Unified Parkinson's disease rating scale after levodopa-challenge (mean scores OFF-state: 38.4 ± 10.1; ON-state: 25.5 ± 8.1). On fMRI, levodopa application elicited increased activity in subcortical structures (contralateral putamen and thalamus) in the patients. In contrast, no significant levodopa-induced activation changes were found in HC. The interaction between "PD/HC group factor" and "levodopa OFF/ON" did not show significant results. Given the levodopa-induced activation increases in the putamen and thalamus with unilateral ankle movements in patients with PD but not in HC, we speculate that these regions show the most prominent response to levodopa within the cortico-subcortical motor-circuit in the context of nigrostriatal dysfunction.

Is transcranial sonography useful to distinguish scans without evidence of dopaminergic deficit patients from Parkinson's disease?

BACKGROUND: Approximately 10% of patients clinically diagnosed with early Parkinson's disease (PD) subsequently have normal dopaminergic functional imaging. Transcranial sonography (TCS) has been shown to detect midbrain hyperechogenicity in approximately 90% of Parkinson's disease (PD) patients and 10% of the healthy population. The aim of this study was to investigate the prevalence of midbrain hyperechogenicity in patients with suspected parkinsonism and scans without evidence of dopaminergic deficit (SWEDD), in comparison to PD patients. METHODS: TCS was performed in 14 patients with SWEDD and 19 PD patients. RESULTS: There was a significantly increased area of echogenicity in the PD group (0.24 ± 0.06 cm(2) ), compared to the group of patients with SWEDD (0.13 ± 0.06 cm(2) ; P < 0.001). One (9.1%) of these patients, compared to 14 (82.5%) of the PD patients, was found to have hyperechogenicity (P < 0.001). CONCLUSIONS: We conclude that TCS is useful to distinguish PD patients from patients with suspected parkinsonism and SWEDD.

Moving toward "laboratory-supported" criteria for psychogenic tremor.

A confident clinical diagnosis of psychogenic tremor is often possible, but, in some cases, a "laboratory-supported" level of certainty would aid in early positive diagnosis. Various electrophysiological tests have been suggested to identify patients with psychogenic tremor, but their diagnostic reliability has never been assessed "head to head" nor compared to forms of organic tremor other than essential tremor or PD. We compared baseline tremor characteristics (e.g., frequency and amplitude) as well as electrophysiological tests previously reported to distinguish psychogenic and organic tremor in a cohort of 13 patients with psychogenic tremor and 25 patients with organic tremor, the latter including PD, essential-, dystonic-, and neuropathic tremors. We assessed between-group differences and calculated sensitivity and specificity for each test. A number of tests, including entrainment or frequency changes with tapping, pause of tremor during contralateral ballistic movements, increase in tremor amplitude with loading, presence of coherence, and tonic coactivation at tremor onset, revealed significant differences on a group level, but there was no single test with adequate sensitivity and specificity for separating the groups (33%-77% and 84%-100%, respectively). However, a combination of electrophysiological tests was able to distinguish psychogenic and organic tremor with excellent sensitivity and specificity. A laboratory-supported level of diagnostic certainty in psychogenic tremor is likely to require a battery of electrophysiological tests to provide sufficient specificity and sensitivity. Our data suggest such a battery that, if supported in a prospective study, may form the basis of laboratory-supported criteria for the diagnosis of psychogenic tremor.

Abnormal sense of intention preceding voluntary movement in patients with psychogenic tremor.

Psychogenic tremor is the commonest psychogenic movement disorder, yet little is known of its pathophysiology. Given the presence of movements that appear from their physiological properties to be voluntarily produced, and yet are not experienced as such by the patients, we hypothesised that patients might have an abnormal conscious experience of volition with regard to self-generated movement. Nine patients with psychogenic tremor were asked to judge the timing of a self-paced button press relative to a clock displayed on a computer screen. In separate trials they were asked to judge the timing of their internal feeling of intention to move. These results were compared to those of healthy control participants. Patients with psychogenic tremor judged their feeling of intention to move significantly later compared to control participants. As a result, the interval between the perceived time of intention and the perceived time of action, which was highly significant in the control participants, was numerically smaller and non-significant in the patients. This study provides novel data that the sense of volition prior to movement is impaired in patients with psychogenic tremor. This fits with a pathophysiological explanation for this disorder based on an impairment of neural mechanisms that generate the conscious experience of action: actions that are voluntary in terms of their physiological origin might be experienced as involuntary.

Late-onset asymmetric myoclonus: an emerging syndrome.

BACKGROUND: Asymmetric cortical myoclonus is typically thought to be associated with either contralateral cortical structural lesions or degenerative disorders such as corticobasal degeneration when onset is in middle-aged or aged adults. This view has been challenged after a recent case series brought to light a syndrome of senile-onset, asymmetric cortical myoclonus not associated with any such identifiable disorders, thus, named "primary progressive myoclonus of aging." This is rare and no other reports have been published; hence, further such cases need to be highlighted. CASE REPORTS: Here, we describe 3 patients with some similarities, namely, adult-onset, asymmetric myoclonus that is most likely to be cortical, with an unremarkable thorough diagnostic workup, but with younger age at onset and longer follow-up time. CONCLUSIONS: This report expands on previous phenotypical descriptions attempting to further develop and refine this possible diagnostic entity.

Altered functional organization of the motor system related to ankle movements in Parkinson's disease: insights from functional MRI.

Bradykinesia represents one of the cardinal and most incapacitating features of Parkinson's disease (PD). In this context, investigating the cerebral control mechanisms for limb movements and defining the associated functional neuroanatomy is important for understanding the impaired motor activity in PD. So far, most studies have focused on motor control of upper limb movements in PD. Ankle movement functional MRI (fMRI) paradigms have been used to non-invasively investigate supraspinal control mechanisms relevant for lower limb movements in healthy subjects, patients with Multiple sclerosis, and stroke. Using such an active and passive paradigm in 20 PD patients off medication (mean age 66.8 ± 7.2 years) and 20 healthy controls (HC; mean age 62.3 ± 6.9 years), we here wished to probe for possible activation differences between PD and HC and define functional correlates of lower limb function in PD. Active ankle movement versus rest was associated with a robust activation pattern in expected somatotopy involving key motor areas both in PD and HC. However, contrasting activation patterns in patients versus controls revealed excess activation in the patients in frontal regions comprising pre-supplementary motor areas (pre-SMA) and SMA proper. The extent of SMA activation did not correlate with behavioural parameters related to gait or motor function, and no differences were seen with the passive paradigm. This finding might be indicative of higher demand and increased effort in PD patients to ensure adequate motor function despite existing deficits. The missing correlation with behavioural variables and lack of differences with the passive paradigm suggests that this excess activation is not exclusively compensatory and also not hard-wired.

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.

Delayed experience of volition in Gilles de la Tourette syndrome.

Gilles de la Tourette's syndrome (TS) is a neuropsychiatric movement disorder characterised by the presence of multiple tics. Tics have an unusual, intermediate status between voluntary and involuntary movements. This ambiguity might involve not just a disorder of movement generation but also an abnormality of voluntary experience. Here the experience of voluntary movements in adult patients with TS is investigated and compared with healthy controls. A group of adult TS patients and age matched control participants estimated the time of conscious intention to perform a simple keypress movement and movement onset. Patients with TS showed a delayed experience of intention relative to controls whereas estimates of the actual movement onset were similar for patients and controls. These data suggest an abnormal experience of volition in patients with TS. Delayed volition could either be an additional intrinsic feature of the syndrome or it could reflect a cognitive strategy to limit motor excitability, and thus tic generation, during voluntary action.

Patients with primary cervical dystonia have evidence of discrete deficits in praxis.

BACKGROUND: Functional imaging and electrophysiological data from patients with primary dystonia reveal widespread abnormalities in brain areas associated with higher motor functions but to date there has been little investigation of the functional consequences of these abnormalities. The aim of this study was to use a battery of tests of praxis, based on those tests used in routine clinical examination, to uncover evidence of higher motor dysfunction in patients with primary cervical dystonia. METHODS: Praxis was assessed in 13 patients with primary cervical dystonia without hand involvement and in 29 age and sex matched controls. A semiquantitative praxis assessment was used which combined timed tests of meaningful and meaningless movements with copying of transitive and intratransitive hand movements and pantomime of tool use. Control tasks consisted of evaluation of motor speed, strength and a number of additional cognitive tasks. RESULTS: Patients made significantly more errors in copying meaningless gestures and were slow in the performance of meaningless sequences of hand movements. Copying meaningful gestures and performance of meaningful sequences of hand movements were normal. CONCLUSION: This study has identified a discrete deficit in praxis in dystonia patients and suggests additional functional consequences from the widespread pathophysiological abnormalities seen in primary dystonia.

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.

Mental rotation of body parts and sensory temporal discrimination in fixed dystonia.

Fixed dystonia is an uncommon but severely disabling condition typically affecting young women following a minor peripheral injury. There is no evidence of any structural lesions of the central nervous system nor any clear peripheral nerve or root damage. Electrophysiological techniques such as short intracortical inhibition, cortical silent period and a plasticity inducing protocol have revealed similarities but also differences compared to classical mobile dystonia. To further explore the pathophysiology of fixed dystonia we compared mental rotation of body parts and sensory temporal discrimination in 11 patients with fixed dystonia, 11 patients with classical mobile dystonia and 10 healthy controls. In the mental rotation task subjects were presented with realistic photos of left or right hands, feet and the head of a young women with a black patch covering the left or the right eye in six different orientations. Subjects had to verbally report the laterality of the presented stimuli. To assess sensory temporal discrimination subjects were asked to discriminate whether pairs of visual, tactile (electrical), or visuo-tactile stimuli were simultaneous or sequential (temporal discrimination threshold) and in the latter case which stimulus preceded the other (temporal order judgement). In accordance with previous studies patients with mobile dystonia were abnormal in mental rotation and temporal discrimination, whereas patients with fixed dystonia were only impaired in mental rotation. Possible explanations for this deficit may include the influence of the abnormal body posture itself, a shared predisposing pathophysiology for mobile and fixed dystonia, or a body image disturbance. These findings add information to the developing pathophysiological picture of fixed dystonia.

Distinguishing SWEDDs patients with asymmetric resting tremor from Parkinson's disease: a clinical and electrophysiological study.

Approximately 10% of patients diagnosed clinically with early Parkinson's disease (PD) have normal dopaminergic functional imaging (Scans Without Evidence of Dopaminergic Deficit [SWEDDs]). An important subgroup of SWEDDs are those with asymmetric rest tremor resembling parkinsonian tremor. Clinical and pathophysiological features which could help to distinguish SWEDDs from PD have not been explored. We therefore studied clinical details including non-motor symptoms in 25 tremulous SWEDDs patients in comparison to 25 tremor-dominant PD patients. Blinded video rating was used to compare examination findings. Electrophysiological tremor parameters and also response to a cortical plasticity protocol using paired associative stimulation (PAS) was studied in 9 patients with SWEDDs, 9 with tremor-dominant PD (with abnormal dopamine transporter single photon emission computed tomography findings), 8 with segmental dystonia, and 8 with essential tremor (ET). Despite clinical overlap, lack of true bradykinesia, presence of dystonia, and head tremor favored a diagnosis of SWEDDs, whereas re-emergent tremor, true fatiguing or decrement, good response to dopaminergic drugs, and presence of non-motor symptoms favored PD. A single tremor parameter could not differentiate between groups, but the combination of re-emergent tremor and highest tremor amplitude at rest was characteristic of PD tremor. SWEDDs and segmental dystonia patients exhibited an abnormal exaggerated response to the PAS protocol, in contrast to a subnormal response in PD and a normal response in ET. We conclude that despite clinical overlap, there are features that can help to distinguish between PD and SWEDDs which may be useful in clinical practice. The underlying pathophysiology of SWEDDs differs from PD but has similarities with primary dystonia.