Elmar H. Pinkhardt

Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology.

Diffusion tensor imaging can identify amyotrophic lateral sclerosis-associated patterns of brain alterations at the group level. Recently, a neuropathological staging system for amyotrophic lateral sclerosis has shown that amyotrophic lateral sclerosis may disseminate in a sequential regional pattern during four disease stages. The objective of the present study was to apply a new methodological diffusion tensor imaging-based approach to automatically analyse in vivo the fibre tracts that are prone to be involved at each neuropathological stage of amyotrophic lateral sclerosis. Two data samples, consisting of 130 diffusion tensor imaging data sets acquired at 1.5 T from 78 patients with amyotrophic lateral sclerosis and 52 control subjects; and 55 diffusion-tensor imaging data sets at 3.0 T from 33 patients with amyotrophic lateral sclerosis and 22 control subjects, were analysed by a tract of interest-based fibre tracking approach to analyse five tracts that become involved during the course of amyotrophic lateral sclerosis: the corticospinal tract (stage 1); the corticorubral and the corticopontine tracts (stage 2); the corticostriatal pathway (stage 3); the proximal portion of the perforant path (stage 4); and two reference pathways. The statistical analyses of tracts of interest showed differences between patients with amyotrophic lateral sclerosis and control subjects for all tracts. The significance level of the comparisons at the group level was lower, the higher the disease stage with corresponding involved fibre tracts. Both the clinical phenotype as assessed by the amyotrophic lateral sclerosis functional rating scale-revised and disease duration correlated significantly with the resulting staging scheme. In summary, the tract of interest-based technique allowed for individual analysis of predefined tract structures, thus making it possible to image in vivo the disease stages in amyotrophic lateral sclerosis. This approach can be used not only for individual clinical work-up purposes, but enlarges the spectrum of potential non-invasive surrogate markers as a neuroimaging-based read-out for amyotrophic lateral sclerosis studies within a clinical context.

The Chemokine CXCL13 Is a Prognostic Marker in Clinically Isolated Syndrome (CIS)

Background There is increasing recognition of the importance of B lymphocytes in the immunopathogenesis of multiple sclerosis (MS), encouraging the evaluation of B cell-associated biomarkers in the cerebrospinal fluid (CSF). We aimed to evaluate the relevance of the B cell chemoattractant CXCL13 as a prognostic marker in patients with clinically isolated syndrome (CIS) regarding conversion to MS, and to compare it to Barkhof criteria in magnetic resonance imaging (MRI), oligoclonal bands (OCB) and the polyspecific intrathecal B cell response against measles, rubella and varicella zoster virus (MRZR). Methodology/Principal Findings CXCL13 was determined in a prospective study over 2 years including 46 patients that remained CIS over follow-up (CIS-CIS), 45 patients that developed MS (CIS-RRMS), and 30 controls using ELISA. CSF CXCL13 was significantly elevated in CIS-RRMS as compared to CIS-CIS and controls (p<0.001). It was significantly elevated in CIS with OCB (p<0.001), positive MRZR (p = 0.04), and gadolinium enhancement in MRI (p = 0.02) and showed a significant correlation with CSF leukocyte count (p<0.001) and QIgG (p<0.001). CXCL13 showed the best positive predictive value (PPV) of all parameters investigated (70%, 95%-CI: 53–84%), which could be further increased by combination with Barkhof criteria in MRI (80%). Conclusions/Significance Our data indicate the relevance of CXCL13 in CIS to predict conversion to MS. It furthermore shows CXCL13 to be an important mediator in the inflammatory cascade associated with the polyspecific intrathecal B cell response that manifests itself in OCB and MRZR.

Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients

Objectives Biomarkers for the diagnosis of motoneuron diseases (MND) are urgently needed to improve the diagnostic pathway, patient stratification and monitoring. The aim of this study was to validate candidate markers for MND in cerebrospinal fluid (CSF) and specify cut-offs based on large patient cohorts by especially considering patients who were seen under the initial differential diagnosis (MND mimics). Methods In a prospective study, we investigated CSF of 455 patients for neurofilament light chain (NfL), phosphorylated heavy chain (pNfH), tau protein (Tau) and phospho-tau protein (pTau). Analysed cohorts included patients with apparently sporadic and familial amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) (MND, n=253), MND mimics (n=85) and neurological control groups. Cut-off values were specified, and diagnostic performance and correlation with progression were analysed. Results Nfs were significantly higher in the MND group compared to the control groups, whereas Tau and pTau did not differ. At a cut-off level of 2200 pg/mL for NfL, a 77% diagnostic sensitivity (CI 71% to 82%), 85% specificity (CI 79% to 90%) and 87% positive predictive value (PPV) (CI 81% to 91%) were achieved. For pNfH, we calculated 83% sensitivity (CI 78% to 88%), 77% specificity (CI 71% to 83%) and 82% PPV (CI 77% to 86%) at 560 pg/mL. There were no significant differences between sporadic and genetic ALS or PLS. Nf levels were elevated at early disease stage, and correlated moderately with MND progression and duration. Conclusions Neurofilaments in CSF have a high relevance for the differential diagnosis of MNDs and should be included in the diagnostic work-up of patients. Their value as prognostic markers should be investigated further.

Differential diagnostic value of eye movement recording in PSP-parkinsonism, Richardson's syndrome, and idiopathic Parkinson's disease

Vertical gaze palsy is a highly relevant clinical sign in parkinsonian syndromes. As the eponymous sign of progressive supranuclear palsy (PSP), it is one of the core features in the diagnosis of this disease. Recent studies have suggested a further differentiation of PSP in Richardsons syndrome (RS) and PSP-parkinsonism (PSPP). The aim of this study was to search for oculomotor abnormalities in the PSP-P subset of a sample of PSP patients and to compare these findings with those of (i) RS patients, (ii) patients with idiopathic Parkinsons disease (IPD), and (iii) a control group. Twelve cases of RS, 5 cases of PSP-P, and 27 cases of IPD were examined by use of video-oculography (VOG) and compared to 23 healthy normal controls. Both groups of PSP patients (RS, PSP-P) had significantly slower saccades than either IPD patients or controls, whereas no differences in saccadic eye peak velocity were found between the two PSP groups or in the comparison of IPD with controls. RS and PSP-P were also similar to each other with regard to smooth pursuit eye movements (SPEM), with both groups having significantly lower gain than controls (except for downward pursuit); however, SPEM gain exhibited no consistent difference between PSP and IPD. A correlation between eye movement data and clinical data (Hoehn & Yahr scale or disease duration) could not be observed. As PSP-P patients were still in an early stage of the disease when a differentiation from IPD is difficult on clinical grounds, the clear-cut separation between PSP-P and IPD obtained by measuring saccade velocity suggests that VOG could contribute to the early differentiation between these patient groups.

Are amygdalar volume alterations in children with Tourette syndrome due to ADHD comorbidity

Recent studies have shown that changes in the basal ganglia circuitry and limbic loops may play an important role both in Tourette syndrome (TS) and attention‐deficit–hyperactivity disorder (ADHD). This study aimed to investigate in vivo possible morphological alterations of the amygdala as a key component of the limbic system. Amygdalar and total brain volumes were measured in three‐dimensional magnetic resonance imaging data sets of 17 male patients with TS (mean age 11y 8mo [SD 2y]; range 9–16y) and 17 age‐matched comparison children (mean age 12y 6mo (SD 2y 1mo); range 9–17y) by volume‐of‐interest‐based volumetry. Eight members of the TS group also fulfilled the diagnostic criteria for ADHD. A significant decrease in the left‐hemispheric amygdalar volumes and in the proportions of amygdalar to total brain volumes was observed in members of the TS group compared with the comparison group. Amygdalar volumes did not correlate with tic severity, but with behavioural impairment and especially with symptoms of ADHD. The amygdalar volume reduction might be the pathoanatomical correlate of an impaired input of the amygdala to the striatum and frontal cortex. Future studies should investigate if the involvement of the amygdala is due to TS or rather caused by the genetically‐linked most frequent comorbidity ADHD.

Ocular motor abnormalities in Parkinsonian syndromes.

Oculomotor abnormalities can be observed in all Parkinsonian syndromes (PS). Nevertheless, due to the considerable overlap of oculomotor pathology in Parkinsonism, oculomotor changes are not generally considered to contribute substantially to the differential diagnosis of PS. Here we review the characteristics of oculomotor disturbances in the major PS, we provide a survey of the current concepts of the underlying neural physiology of oculomotor control and a summary of the major recording techniques for eye movements. The main focus of this review is to outline the subtle differences between apparently similar oculomotor alterations in Parkinsons disease (PD) and atypical neurodegenerative PS that can contribute to the early differential diagnosis of these entities.

Retinal single-layer analysis in Parkinsonian syndromes: an optical coherence tomography study

We report a newly developed analysis algorithm for optical coherence tomography (OCT) that makes a retinal single-layer analysis with calculation of the average thickness of retinal layers possible. The aim of the study was to examine specific patterns of retinal layer pathology as a potential marker of neurodegeneration in Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Spectral domain OCT with a semiautomatic algorithm to calculate the average thickness of single retinal layers was applied to foveal scans of 65 PD, 16 PSP, and 12 MSA patients as well as 41 matched controls. Demographic and clinical data were collected for correlation analysis. Only PSP and MSA showed a significant reduction of retinal layers in comparison to controls. In PD, there were no significant findings in single retinal layer measurement. Most remarkably, the thickening of the outer nuclear layer in PSP and the outer plexiform layer in MSA was highly specific for these disease entities and allowed differentiating PSP from MSA with high sensitivity and specificity. With this analysis algorithm of OCT data, disease-specific retinal layer changes could be observed. Despite a general tendency to whole retinal and single retinal layer thinning that may reflect neurodegeneration in all Parkinsonian syndromes, the specific findings in MSA and PSP may serve as a highly sensitive and specific differential diagnostic tool and as a progression marker in these disease entities. Upcoming studies with a longitudinal setting will have to prove this assumption.

Body Fat Distribution as a Risk Factor for Cerebrovascular Disease: An MRI-Based Body Fat Quantification Study

Background: While adiposity is a well-established risk factor for cardiovascular disease, the association between adiposity and cerebrovascular disease is not entirely understood. For example, common methods to quantify body fat volume such as body mass index, waist circumference and waist-to-hip ratio are not suitable to identify the complex distribution patterns of body fat and its relation to cerebrovascular pathology. In view of a better understanding of the association between fat distribution and cerebrovascular disorders, the aim of the study was to perform measurements of body fat distribution patterns and body fat volumes in correlation to arteriosclerosis of the brain-feeding arteries and white matter lesion load (WMLL). Methods: In this study we performed a magnetic resonance imaging (MRI)-based volumetric differential analysis of subcutaneous and visceral body fat distribution in 25 patients with MRI-proven hyperacute ischemic stroke. For the measurement of adipose tissue volume and tissue distribution automatic labeling analysis software was used. A correlation analysis of MRI volumetric measurements of subcutaneous and visceral body fat, atherosclerotic plaque load of the brain-feeding arteries measured by computed tomography angiography, and WMLL measured by MRI volumetry of the whole brain was performed. Results: The normalized total abdominal adipose tissue and the normalized subcutaneous abdominal adipose tissue showed no significant correlation with either WMLL or total plaque volume. In contrast, the normalized visceral adipose tissue showed a significant correlation with WMLL volume. Visceral adipose tissue as a percentage of total adipose tissue showed a significant correlation with WMLL. In particular, the percentage of visceral adipose tissue rather than total body fat volume strongly correlated with atherosclerosis and ischemic cerebral lesions. Furthermore, the volume of both soft and calcified plaques correlated significantly with WMLL. Conclusions: Our results contribute to existing studies about the association of different patterns of fat distribution with atherosclerosis of the brain-feeding arteries, in particular highlighting the importance of visceral adiposity as a risk factor for cerebrovascular disease. The percentage of visceral adipose tissue in total adipose tissue has the potential of a sensitive parameter and might become a relevant new epidemiological marker, showing highly significant correlations with well-established markers of cerebrovascular disease. In conclusion, the percentage of visceral adipose tissue by itself has to be regarded as a risk factor for both small vessel cerebrovascular disease and cerebral atherosclerosis of the large-to-medium-sized arteries.

Comparison of smooth pursuit eye movement deficits in multiple system atrophy and Parkinson’s disease

Because of the large overlap and quantitative similarity of eye movement alterations in Parkinson’s disease (PD) and multiple system atrophy (MSA), a measurement of eye movement is generally not considered helpful for the differential diagnosis. However, in view of the pathophysiological differences between MSA and PD as well as between the cerebellar (MSA-C) and Parkinsonian (MSA-P) subtypes of MSA, we wondered whether a detailed investigation of oculomotor performance would unravel parameters that could help to differentiate between these entities. We recorded eye movements during sinusoidal pursuit tracking by means of video-oculography in 11 cases of MSA-P, 8 cases of MSA-C and 27 cases of PD and compared them to 23 healthy controls (CTL). The gain of the smooth pursuit eye movement (SPEM) component exhibited significant group differences between each of the three subject groups (MSA, PD, controls) but not between MSA-P and MSA-C. The similarity of pursuit impairment in MSA-P and in MSA-C suggests a commencement of cerebellar pathology in MSA-P despite the lack of clinical signs. Otherwise, SPEM gain was of little use for differential diagnosis between MSA and PD because of wide overlap. However, inspection of the saccadic component of pursuit tracking revealed that in MSA saccades typically correct for position errors accumulated during SPEM epochs (“catch-up saccades”), whereas in PD, saccades were often directed toward future target positions (“anticipatory saccades”). The differences in pursuit tracking between PD and MSA were large enough to warrant their use as ancillary diagnostic criteria for the distinction between these disorders.

Signs of impaired selective attention in patients with amyotrophic lateral sclerosis

The evidence for involvement of extramotor cortical areas in non-demented patients with amyotrophic lateral sclerosis (ALS) has been provided by recent neuropsychological and functional brain imaging studies. The aim of this study was to investigate possible alterations in selective attention, as an important constituent part of frontal brain function in ALS patients. A classical dichotic listening task paradigm was employed to assess event-related EEG potential (ERPs) indicators of selective attention as well as preattentive processing of mismatch, without interference by motor impairment.A total of 20 patients with sporadic ALS according to the revised El Escorial criteria and 20 healthy controls were studied. Additionally a neuropsychological test battery of frontotemporal functions was applied.Compared with the controls, the ALS patients showed a distinct decrease of the fronto-precentral negative difference wave (Nd), i.e., the main ERP indicator of selective attention. Analysis of the P3 component of the ERPs indicated an increased processing of non-relevant stimuli in ALS patients confirming a reduced focus of attention. We conclude impaired selective attention reflects a subtle variant of frontotemporal dementia frequently observed in ALS patients at a relatively early stage of the disease.