Characterising in vivo tau-related white matter deficits in Alzheimer's disease
Nicolas Nicastro (Geneve | CH)
To examine the relationship between [18F]-AV1451 binding (tau) and diffusion tensor imaging (DTI) of white matter changes in Alzheimer’s disease (AD).
19 people with clinically probable AD and 14 people with mild cognitive impairment (MCI, with amyloid positive PET imaging) and 24 similarly-aged healthy controls underwent 3T DTI to estimate parameters of Fractional Anisotropy (FA), Mean Diffusivity (MD), Axial Diffusivity (AD), and Radial Diffusivity (RD). A subset of 24 people with AD/MCI also underwent [18F]-AV1451 PET imaging, with PetSurfer quantification of cortical binding potential. Tract Based Spatial Statistics (TBSS) with non-parametric permutations testing were performed to compare DTI parameters in AD/MCI against healthy controls and identify associations of [18F]-AV1451 binding with DTI parameters.
TBSS confirmed widespread changes in FA, MD and RD parameters in the AD/MCI group compared to controls while adjusting for age and gender (Threshold Free Cluster Enhancement, TFCE p < 0.05). Among people with AD/MCI, the cortical [18F]-AV1451 binding estimates of the Tau burden correlated with widespread reductions in FA and increased RD (TFCE p < 0.05).
The use of multimodal brain imaging provides in vivo evidence to link tau pathology to changes in white matter. Our findings corroborated previous evidence from histopathology and CSF studies to implicate cortical neurodegeneration as a potential pathophysiological mechanism underpinning white matter pathologies in AD.
Ischaemic stroke despite oral anticoagulant therapy in patients with AF – what is the risk of recurrent events and how to prevent further events?
David Seiffge (Basel | CH)
Background/Aim: We investigated whether patients with atrial fibrillation (AF) having a stroke despite oral anticoagulant therapy a) are at increased risk for further events and b) changing the type of anticoagulant is associated with a decreased risk of further events.
Methods: We conducted an individual patient data analysis of 7 prospective cohort studies recruiting patients with AF and an index event (ischaemic stroke or TIA). We compared patients taking oral anticoagulants (Vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior) with those without prior anticoagulation (OACnaive). We further compared those who changed the type (i.e. VKA or DOAC) of anticoagulation (OACchanged) with those who continued the same anticoagulation after the event (OACunchanged). We followed-up patients for at least 90 days for recurrent ischaemic stroke (AIS), intracerebral haemorrhage (ICH) or mortality. Time-to-endpoint was analysed using multivariate cox proportional hazard regression models with frailty term for study and calculating hazard ratios (HR) with corresponding 95% confidence intervals.
Results: We included 5413 patients in this study (median age 78years [IQR 71-84years], 5136 [96.7%] had ischaemic stroke as index event, median NIHSS-on-admission 6 [IQR 2-12]). During follow-up of 6128 patient years, 289 patients had AIS (4.7%/year, 95%CI 4.2-5.3%), 90 patients had ICH (1.5%/year, 95%CI 1.2-1.8%) and 624 patient died (10.2%/year, 95%CI 9.4-11.0%). priorOAC (n=1195) was associated with an increased risk of recurrent AIS (HR 1.6 95%CI 1.1-2.1, p=0.006) compared to OACnaive (n=4119). OACchanged (n=307) was not associated with decreased risk of recurrent AIS (HR 1.3, 95%CI 0.8-2.2, p=0.326) compared to OACunchanged (n=585).
Conclusion: Patients having a stroke despite anticoagulation therapy are at increased risk of further events. More research is needed to investigate mechanisms of recurrent stroke and improve secondary prevention in these patients.
MOG-IgG antibodies in autoimmune demyelinating CNS disorders – retrospective analysis of a monocentric patient cohort
Anke Salmen (Bern | CH)
The discovery of the pathogenic antibody directed against Aquaporin-4 (AQP4) re-defined neuromyelitis optica spectrum disorders (NMOSD). The antibody directed against myelin-oligodendrocyte-glycoprotein (MOG-IgG) might define another disease entity. An approach to define diagnostic criteria for so-called “MOG encephalomyelitis” (MOG-EM) has recently been published.
Clinical and paraclinical data of patients with positive (>1:10) or borderline positive (=1:10, test cut-off) results of serum MOG-IgG, tested in a cell-based assay, were analyzed in a retrospective study.
We identified 40 patients. Of these, 3 patients did not demonstrate findings compatible with a demyelinating CNS disorder (qualified as unspecific, not included in analyses). For the remaining 37 patients, median age at onset was 28 years (IQR 18.5-40.5). All patients below 18 years at onset (9, 11, 14, 15, 16, 17, 17 years) experienced a first manifestation with a spinal cord or optic nerve syndrome.
The female:male ratio was 1.6:1. The last EDSS score was 2.0 (median, IQR 1.5-3.0; max. EDSS 8.0). Classified by EDSS functional systems (FS), onset was monosymptomatic in 18/34, polysymptomatic in 16/34 patients with the majority of patients exhibiting a visual and/or sensory onset (n=13 each), followed by pyramidal symptoms (n=9). In 2 patients with (meningo-) encephalomyelitis, FS classification was not appropriate (multifocal, reduced consciousness, seizures, movement disorder). The first manifestation was an optic nerve or spinal cord syndrome (n=12 each), followed by cerebral and brainstem syndromes (n=6 each) and cerebellar involvement (n=1).
All patients were seronegative for AQP4 antibodies.
In 4 patients, onset of symptoms was para-/postinfectious, 2 with unknown pathogen after extensive work-up, 1 with VZV and 1 with EHEC, respectively. In the patient with EHEC-associated sepsis and consecutive relapsing bilateral optic neuritis, serum available from the acute phase of infection was retrospectively tested negative for MOG-IgG.
MOG-EM is not limited to a predominant involvement of optic nerve and spinal cord; brainstem and cerebellar involvement and (atypical) encephalitis can occur. As recently suggested, MOG-IgG testing should thus not be limited to AQP4 antibody negative NMOSD.
The para-/postinfectious disease onset of MOG-EM not resembling ADEM has not been described, yet. It may provide hints to the underlying immunological mechanisms.
Cervical Spinal Cord Gray and White Matter Atrophy in Patients with Post-Polio Syndrome
Maria Janina Wendebourg (Basel | CH)
Aims: Post-polio syndrome (PPS) is defined as a progressive persistent new muscle weakness or fatigability occurring after a stable interval, years to decades after the initial viral infection of spinal cord (SC) motor neurons (Baj et al. Int J Infect Dis. 2015:35:107). The precise mechanisms underlying PPS are yet to be known. Recent advances in MR sequence development now allow for reliable quantitation of SC gray matter (GM) and white matter (WM) in vivo. The aim of this study was to quantitate SC GM and WM in PPS patients in comparison to healthy age and sex matched control subjects and to correlate GM areas to segmental muscle strength.
Methods: 20 patients with PPS (mean age 66.5 years [SD 4.53], 12 men) and 20 age and sex-matched healthy controls (HC) were investigated clinically (including quantitative muscle strength assessments of selected target muscles by dynamometer) and at 3T by axial 2D-AMIRA imaging (in plane resolution 0.5x0.5mm) (Weigel & Bieri. Magn Reson Med. 2018:79:1870) perpendicular to the SC at the intervertebral disc levels C2/C3, C3/C4, C4/C5, C5/C6 and C6/C7. Total cord areas (TCA) were segmented semi-automatically via JIM 7 (www.xinapse.com). SC GM areas were segmented manually. SC WM areas were calculated by subtracting GM area from TCA.
Results: Compared to the HC subjects, PPS patients showed significant SC GM atrophy at all levels (C2/C3 p=0.0405, C3/C4 p=0.0002, C4/C5 p < 0.0001, C5/C6 p=0.0006, C6/C7 p=0.0356) and significant SC WM atrophy at the levels C2/C3 (p=0.0175), C3/C4 (0.0134) and C4/C5 (0.0288). GM area at C2/C3 correlated with neck flexor muscle strength measured by dynamometer (r= 0.64, p=0.0223).
Conclusion: AMIRA imaging is a sensitive method to quantitate SC GM and WM atrophy in vivo. Cervical SC GM and WM areas were reduced in PPS compared to HC. Spinal cord GM at C2/C3 correlated with muscle strength in the corresponding myotome in PPS. Longitudinal studies are necessary to investigate atrophy over time, its relation to symptom evolution and possible prognostic value. The methodology used here is promising for the development of novel imaging surrogates not only for PPS, but also for other neurodegenerative, genetic or autoimmune mediated diseases of the spinal cord.
Vitamin D Supplementation: A therapeutic strategy to augment steroid treatment of acute Multiple Sclerosis Relapses
Maud Bagnoud (Bern | CH)
Objective: Limited efficacy of glucocorticoids (GCs) during acute relapse of multiple sclerosis (MS) leads to increase of MS associated disability in approximately 40% of patients. We investigated the potential of vitamin D (VD) to enhance steroid efficacy for MS relapse therapy.
Methods: T-cell apoptosis was analysed by FACS. Glucocorticoid receptor (GR) protein was measured using ELISA. MOG35-55 Experimental autoimmune encephalomyelitis (EAE) was performed in wt animals and in those with T-cells deficient for GR-/mTORc1-expression. VD-levels (immunoassay) were analysed in MS patients with stable disease (n=56), relapse responsive (n=30) or resistant to GC treatment (n=24). Gene expression of human T-cells (microarrays, n=112) were correlated with VD-levels.
Results: In vitro, VD induced the expression of GR protein resulting in a significant increase of Glucocorticoid-induced T-cell apoptosis. VD/GC combination therapy ameliorated EAE disease course more efficiently than respective monotherapies. This effect was dependent on the presence of the GR in T-cells. In the human situation, VD-deficiency was significantly more sever in MS patients during relapse resistant to GC treatment and resulted in a reduced expression of the T-cell GR. The signaling pathway beyond this GR upregulation was via mTORc1 as VD inhibited mTORc1 activity in murine T-cells in vitro. Furthermore, hypovitaminosis D was associated with reduced expression of mTORc1 inhibiting TSC-1 in human T-cells. Finally the upregulation of the GR by VD as well as the functional VD/GC synergism in vitro and in vivo were absent in mice with mTORc1 deficient T-cells and pharmacological inhibition of mTORc1 (everolimus) augmented GC effects in wt animals during EAE even more potent than VD co-administration.
Interpretation: VD increases therapeutic effects of GCs. The mechanism behind the described synergism is an mTORc1 dependent upregulation of the GR. Our data should stimulate clinical studies investigating the efficacy of a VD/mTOR based approach to treat MS relapses.
Why do patients on anticoagulants bleed in the brain? - Small vessel disease burden in intracerebral haemorrhage associated with oral anticoagulants
David Seiffge (Basel | CH)
Objectives: We thought to determine the burden of small vessel disease (SVD) and its association with functional outcome in patients with intracerebral haemorrhage (ICH) associated with the use of oral anticoagulants (OAC, OAC-ICH).
Methods: In a prospective cohort study of ICH patients with (OAC-ICH) and without (non-OAC ICH) prior use of OAC (Vitamin K antgonists or direct oral anticoagulants), we assessed the association of SVD markers (white matter lesions, lacunes, cortical and deep atrophy, perivascular spaces, cerebral microbleeds and cortical superficial siderosis) and poor functional outcome (defined as modified Rankin Scale score 4-6 at 6 month) using univariate and multivariate logistic regression models with odds ratio (OR) and 95% confidence intervals (95%CI).
Results: We included 1030 patients (all with CT and 234/22.7% had an additional MRI): 421 (40.9%) with OAC-ICH and 609 (59.1%) with non-OAC ICH. Patients with OAC-ICH were older (median age 79 years, IQR 72-84 years vs. 72 years IQR 62-80 years, p < 0.001) and had more often cardiovascular comorbidities (i.e. diabetes mellitus, hypertension, hypercholesterolemia) but there was no difference in ICH-volume (OAC-ICH: 7.2ml IQR 2.4-20.6ml vs. non-OAC ICH: 6.9ml, IQR 2.1-16.0ml, p=0.22).
Patients with OAC-ICH had more often white matter lesions and atrophy on CT and MRI and perivascular spaces and lobar microbleeds on MRI. The median SVD score was higher in patients with OAC-ICH using both, CT (OR 1.3, 95%CI 1.1-1.5, p=0.001) and MRI (OR 1.5, 95%CI 1.1-2.1, p=0.010). However, after adjusting for confounders, we did not find differences in SVD markers or burden between both groups. In multivariate analysis, poor functional outcome was associated with SVD burden on CT (OR 1.5 95%CI 1.1-2.1, p=0.009) but not with OAC-ICH.
Interpretation: Patients with OAC-ICH have a high burden of SVD which is driven by older age and a higher prevalence of vascular risk factors. SVD burden but not OAC-ICH is associated with poor outcome.
Outcome of patients with large vessel occlusion, mild symptoms, and reperfusion therapies: analysis of the Swiss Stroke Registry (SSR).
Concetta Manno (Lugano | CH)
Aims:Efficacy and safety of endovascular treatment (EVT) in patients with acute ischaemic stroke, large vessel occlusion (LVO) and mild symptoms have not been proven. Randomized controlled (RC) EVT trials have mainly excluded patients with NIHSS ≤ 5. We aimed at comparing functional outcome and safety after 90 days in patients with LVO and low NIHSS (≤ 5) undergoing EVT vs intravenous thrombolysis (IVT).Methods: We performed a multicentre retrospective analysis of data from the Swiss Stroke Registry. Primary endpoint was favourable functional outcome (modified Rankin Scale [mRS] 0-1) at 3 months. Secondary outcomes were mRS shift analysis at 3 months, independence (mRS 0-2), survival with high disability (mRS 4-5), mortality and symptomatic intracerebral haemorrhage (sICH). IVT and EVT patients were matched 1:1 by using propensity scores (PS) based on age, sex, baseline NIHSS, pre-stroke mRS, time to treatment, occlusion site and anticoagulation therapy. Differences in outcomes were tested using multivariate logistic and ordinal regression models.Results:Out of 11’356 acute stroke patients, 339 met inclusion criteria (n=153 were treated with EVT [n=74 with direct EVT, n=79 with bridging therapy, IVT + EVT] and n=186 were treated with IVT only). After matching by PS, 126 in both groups were available for analyses. A similarly large proportion of EVT and IVT patients reached a favourable outcome at 3 months (57% vs 66% respectively; OR= 0.65, 95%CI= 0.36-1.17, p=0.15). The proportion of patients reaching independence was slightly lower in EVT than IVT (77% vs 87%; OR= 0.47, 95%CI= 0.22-1.01, p=0.054). EVT patients also had greater mRS at 3 months by shift analysis (OR= 1.60; 95%CI= 1.02-2.54, p=0.043). This was largely mediated by higher mortality rates among EVT than IVT (10% vs 3%; OR= 3.51, 95%CI= 1.04-11.85, p= 0.043), while the proportion of survived patients with high disability was similarly low (6% vs 3%; OR=2.56, 95%CI=0.68-9.61, p=0.165). sICH were overall relatively rare in two groups (EVT 5% vs IVT 1%, OR= 5.58, 95%CI= 0.57-54.86, p=0.140. Age was inversely associated with independency (OR= 0.94, 95%CI= 0.91-0.98, p=0.002).Conclusion: In acute stroke patients with LVO and mild neurological symptoms, EVT and IVT appear similarly effective in terms of achieving a favourable functional outcome at 3 months, but EVT might be inferior to IVT with regard to mortality and outcome across all levels of disability. Further research is needed.
Buzzing Sympathetic Nerves: A New Test to Enhance Reflex Pupil Dilation in Suspected Horner Syndrome
Rawan Omary (Zurich | CH)
Introduction: Patients with suspected Horner syndrome and equivocal pupil dilation lag and pharmacologic testing might undergo unnecessary MR imaging. Our purpose was to increase the diagnostic sensitivity of pupillometry by accentuating sympathetic innervation to the iris dilator by surface electrical stimulation of the median nerve using a standard electromyography machine. We hypothesized that any difference in sympathetic innervation to the right and left eye would be accentuated.
Methods: Ten healthy volunteers tested before and after monocular instillation of brimonidine 0.2% to induce pharmacological Horner syndrome were compared to ten patients with proven Horner syndrome. Pupillary responses were measured with binocular pupillometry (DP-2000, Neuroptics; Irvine, CA) in response to sympathetic activation by electrical stimulation (0.2ms, 50mA) of the median nerve in darkness and at various times after extinction of a 3log lux light stimulus (1 vs. 4 seconds). Sudomotor sympathetic responses from the palm were recorded simultaneously.
Results: In subjects with Horner syndrome or pharmacologically induced unilateral sympathetic deficit, electrical stimulation in combination with the extinction of light greatly enhanced the anisocoria during the evoked pupil dilation and was well tolerated. The asymmetric sympathetic response was greatest when the electrical stimulus was given 1-2s after termination of the light. Two discernible reflex dilation responses appeared; an initial symmetric dilation due to central inhibition of the Edinger-Westphal nucleus followed by an accentuated asymmetric dilation due to enhanced peripheral sympathetic stimulation.
Conclusions: Electrical sympathetic stimulation given at the termination of a short light stimulus appears to greatly enhance the sensitivity for diagnosing asymmetric pupil dilation due to Horner syndrome.
This strategy may improve upon the ability to rule in or rule out a unilateral oculosympathetic deficit, especially if the results of topical pharmacological testing are inconclusive.
Penumbra salvage and infarct growth in acute ischemic stroke: Multiple factors explain high interindividual variability
Gaia Sirimarco (Lausanne | CH)
Introduction. Effective treatment of ischemic stroke requires reperfusion of the penumbral brain tissue. We aimed at investigating predictors of penumbra salvage and infarct growth.
Methods. In the Acute STroke Registry and Analysis of Lausanne (ASTRAL) from 2003 to 2016, we selected all middle cerebral artery (MCA) strokes with availability of a good quality CT-angiography < 24h and thresholded CT-perfusion. Penumbra salvage (PS) and infarct growth (IG) over 24 hours were correlated in multivariate analyses with clinical, radiological and biochemical variables, and in adjusted analysis with clinical outcome.
Results. In the 551 MCA strokes included, 49.2% were females, median age (± IQR) was 68.7 ± 21, admission NIHSS 14 ± 12, and onset-to-imaging time 169.5 ± 283 minutes.
More PS was associated with higher BMI, hemineglect, absence of early ischemic changes, leukoaraiosis and other vascular territory involvement, larger baseline penumbra and a lower clot burden. Less IG was associated with current smoking, lower admission glycemia, larger baseline infarct core, absence of early ischemic changes, chronic vascular brain lesions and other territory involvement, absence of extracranial arterial pathology and hyperdense MCA sign, and lower clot burden. Adding subacute variables to these analyses, recanalisation were associated with more PS and less IG, and the absence of parenchymal haemorrhage with less IG. More PS and less IG were independently correlated with better 12 months functional outcome.
Conclusions. Penumbra salvage and infarct growth depend on multiple clinical, metabolic, parenchymal, and arterial variables. These findings may explain variability of treatment response and outcome, and may help select patients for late or more aggressive management.