Modeling synapses and synaptic neuropsychiatric disorders using human brain organoids
Abraam Yakoub (Boston | US)
Human cerebral organoids currently represent a state-of-the-art human-brain model to study human neuropsychiatric and neurodevelopmental disorders for which mouse models show major limitations. Synaptic connections in the human brain define neural circuits, and their deficits cause neuropsychiatric disorders. Harnessing the full power of the cerebral organoid model requires the ability to visualize and analyze synapses in the cerebral organoids. Here, we report an optimized method to develop human cerebral organoids, and investigate the possibility of modeling synapses in the organoids. We give evidence for synaptogenesis in the cerebral organoids. We show that optimal cerebral organoids express mature-neuron markers, including synaptic proteins and neurotransmitter receptors and transporters. Moreover, we describe various assays to visualize and analyze synapses in the organoids. These results indicate that cerebral organoids can be used to model human brain synaptopathies and understand the molecular bases for neuropsychiatric disorders.
Deconstructing frontal gait in normal pressure hydrocephalus
Eric Morel (Burgdorf | CH)
Gait disturbance in idiopathic normal pressure hydrocephalus (iNPH) is classically described as slow, magnetic and wide-based, also known as frontal gait. However, the clinical gait abnormalities found in iNPH are unspecific and also found in alternate neurological conditions mimicking iNPH (also called iNPH mimics), such as vascular dementia or dementia with Lewy bodies. This study aims to compare the prevalence of clinical gait abnormalities between iNPH and iNPH mimics.
A total of 140 patients with a suspicion of iNPH (76.3 ± 6.8 yo; 30.7 % female) were included in this retrospective study. Eighty patients (57.1 %) fulfilled the NPH consensus guidelines criteria; and the remaining sixty patients were classified as iNPH mimics (23 neurodegenerative condition, 13 multifactorial conditions, 10 vascular dementia, 7 toxic cause, and 7 mixed dementia).
The clinical gait characteristics were rated by two independent clinicians blinded for the diagnosis (EM and GA, kappa, 0.73). Clinical gait characteristics included four categories: frontal gait (short step, wide-based, reduced step height), parkinsonian gait (short and/or shuffling steps, flexed posture, reduced arm swing and narrow base), other clinical gait abnormalities and normal gait.
Clinical characteristics were similar between iNPH and iNPH mimics. Frontal gait was not the most prevalent clinical gait abnormalities among both groups (only a quarter of both groups). The prevalence of frontal gait was similar between iNPH and iNPH mimics; while parkinsonian gait was more prevalent among the iNPH mimics (32 % versus 15 %; p-value: 0.032). This association between parkinsonian gait and iNPH mimics remains significant after adjusting for age, gender, comorbidities and white matter changes (OR: 0.416; 95 % CI: [0.18 – 0.98]; p value: 0.044).
Frontal gait is not the most prevalent clinical gait abnormalities among patients with suspicion of iNPH and does not help to identify iNPH from iNPH mimics. Parkinsonian gait differentiates the mimics from the iNPH patients and may represent a red flag for an alternate condition when assessing a patient with suspicion of iNPH.
The caudal vermis and the dentate nucleus are critical structures for determining the directional asymmetry in gaze-evoked nystagmus in unilateral cerebellar lesions
Alexander Tarnutzer (Zurich | CH)
Aims: Stabilizing the eyes in space when looking at a target is provided by a brainstem/cerebellar gaze-holding network. While lesion studies in non-human primates pointed to a key role of the flocculus/paraflocculus complex in gaze holding, observations in humans indicated an involvement of the caudal vermis, the biventer lobule and the inferior semilunar lobule. Previous research suggested that acute lateralized cerebellar lesions preferentially lead to gaze-evoked nystagmus (GEN) on ipsilesional gaze. We aimed to further characterize GEN-asymmetry in unilateral cerebellar stroke and hypothesized that the direction of gaze-holding impairment depends on the location of the lateralized lesions.
Methods: Nine patients (aged 31-62y, 2 females) with acute/subacute (less than 10d old) MRI-confirmed unilateral cerebellar stroke were included. Horizontal gaze holding was quantified (range=±40° gaze) while a flashing target was slowly (0.5°/s) moving. Asymmetry in eye-drift velocity was calculated and compared to the different patterns in cerebellar lesions.
Results: Individual peak eye drift velocities ranged from 3.9°/s to 17.4°/s and occurred at the most eccentric eye positions (30-40° of lateral gaze). We found significantly asymmetric GEN in 7/9 patients, which increased progressively with increasing eccentricity of eye position, indicating a non-linear behavior similar to the one observed in patients with degenerative cerebellar disease. Those patients with MRI-confirmed involvement of the caudal vermis and the dentate nucleus all presented with predominantly ipsilesional GEN (n=4), while in those with lesions restricted to the cerebellar hemisphere GEN was stronger on contralesional gaze in three out of four patients.
Conclusion: Involvement of the caudal vermis (uvula, nodulus) and the dentate nucleus is critical for determining the directional asymmetry in GEN in unilateral cerebellar lesions, while the flocculus played a minor role only in human gaze-holding in our study. Specifically, the asymmetry in GEN in relation to the side of the lesion predicted which cerebellar structures have been damaged.
CT imaging markers of cerebral amyloid angiopathy, APOE genotype and recurrent ICH risk – the Edinburgh CAA criteria
David Seiffge (Basel | CH)
Background: We analysed the rate of recurrent intracerebral haemorrhage (ICH) applying the Edinburgh criteria for cerebral amyloid angiopathy (CAA).
Methods: In a prospective ICH cohort study, we analysed CT scans for presence of subarachnoid haemorrhage (SAH) and “finger-like projections” (FLP). We used blood samples to determine APOE genotype. Patients were followed up for at least 6 months for recurrent ICH. We calculated annualized rate of recurrent ICH (=total of observed ICH/patient-years of follow-up) and assessed association with recurrent ICH using multivariate (adjusted for age and sex) cox regression models. We calculated hazard ratios (HR) and corresponding 95% confidence intervals (95%CI).
Results: The final cohort contained 339 patients with lobar ICH (median age 77 years, IQR 70-83; median ICH-volume 14.8mL IQR 5.3-31.0mL). SAH was present in 135 patients (39.8%), FLP in 80 (23.6%) and 104 (30.7%) patients had at least one APOE e4 allele. During a total follow-up period of 490 patient years, 22 patients had recurrent ICH (4.5%/year, CI95% 2.8-6.7%). Patients fulling the full Edinburgh criteria (22 patients/6.5%), had the highest rate of recurrent ICH (11.2%/year, 95%CI 3.1-26.3%) and were over 3 times more likely to have a recurrent ICH than those who did not fulfil the full criteria (HR 3.3, 95%CI 1.1-9.9, p=0.034). Patient with CT only Edinburgh criteria (n=52 patients/15.3%) had similar rates of recurrent ICH as the full criteria (12.2%/year, 95%CI 5.4-22.6%, HR 3.4, 95%CI 1.4-8.2, p=0.006).
Conclusion: The Edinburgh criteria identify patients at high risk of recurrent ICH. If genetic testing is unavailable, using the CT only criteria is also suitable.
Direct oral anticoagulants versus Vitamin K antagonists after a recent ischaemic stroke or TIA– a pooled individual patient data analysis
Gian Marco De Marchis (Basel | CH)
Background: We compared clinical outcomes after treatment with direct oral anticoagulants (DOAC) and Vitamin-K antagonists (VKA) in patients with atrial fibrillation (AF) with a recent ischaemic stroke or TIA.
Methods: We conducted an individual patient data analysis of 7 prospective cohort studies. We included patients with AF and a recent ischaemic stroke or TIA ( < 3 months before starting oral anticoagulation) and a minimum follow-up of 3 month. We analyzed the association between type of anticoagulation (DOAC vs. VKA) with the composite primary endpoint (recurrent ischaemic stroke [AIS], intracerebral haemorrhage [ICH], or mortality) using mixed effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HRadj) with 95% confidence intervals (95% CI).
Findings: We included 4912 patients (median age 78 years [IQR71-84]; 2331 [47.5%] women) of whom 4739 (96.5 %) had ischaemic stroke as the index event (median NIHSS-at-onset 5 [IQR2-12]); 2256 (45.9 %) patients received VKA and 2656 (54.1 %) DOAC. The median time from index event to starting oral anticoagulation was 5 days (IQR 2-14) for VKA and 5 days (IQR 2-11) for DOAC (p = 0.53). There were 262 AIS (4.4 %/year), 71 ICH (1.2 %/year) and 439 deaths (7.4 %/year) during the total follow-up of 5970 patient-years. Compared to VKA, DOAC treatment was associated with reduced risks of the composite endpoint (HRadj 0.81, 95%CI 0.66-0.98, p = 0.03), ICH (HRadj 0.33, 95%CI 0.16-0.70, p < 0.01) and mortality (HRadj 0.73, 95%CI 0.57-0.93, p = 0.01); for the risk of recurrent AIS, we found no difference in risk (HRadj 1.02, 95%CI 0.74-1.40, p = 0.91).
Conclusion: DOAC treatment initiated after a median of 5 days after cerebral ischaemia related to AF was associated with reduced risk of poor outcome compared to VKA, mainly due to lower risks of ICH and mortality.
Effectiveness of fingolimod as first-line and second-line treatment for RRMS patients in Switzerland
Guillaume Perriard (Rotkreuz | CH)
Fingolimod is indicated as first-line treatment of relapsing-remitting multiple scleroses (RRMS) in Switzerland.1 In the following analysis, we utilized real world evidence data to compare effectiveness of fingolimod in previously naïve and pre-treated patients.
The study is based on a sub-analysis of a cross-sectional, retrospective study conducted in 19 centers in Switzerland. Included RRMS patients received fingolimod for a minimum of 7 and up to 58 months.2 Demographic as well as clinical data was collected. Effectiveness of treatment was evaluated by freedom from relapses and Gd+-enhancing lesions. Analyses were performed using Wilcoxon- and paired t-tests (SAS® package, version 9.2 or higher).
From 274 analyzed RRMS patients, 79 (28.7%) patients were treatment-naïve and the remaining 196 (71.3%) patients were switched to fingolimod from another therapy. 2
Seventy-six (97.4%) treatment-naïve and 120 (61.2%) pre-treated patients experienced at least one relapse in the 2 years preceding fingolimod initiation. After a mean (SD) fingolimod treatment duration of 32 (11.8) months, 58 (74.4%) treatment naïve and 155 (79.1%) pre-treated patients remained free from relapses. Within pre-treated individuals, the proportion of relapse-free patients was increased under fingolimod as compared to the 2 years preceding treatment switch: 33/42 (78.6%) vs 25/42 (59.5%) in those switching from natalizumab, 119/150 (79.3%) vs 48/150 (32%) in those switching from IFNβ or glatiramer acetate (p < 0.001 for both comparisons). The proportion of patients experiencing more than 1 relapse changed from 50% to 3.8% and from 22.4% to 7.1% when comparing before vs under fingolimod, in previously naïve and pretreated patients, respectively (p < 0.001 for both comparisons). Similarly, the proportion of patients remaining free from Gd+ lesions before vs after fingolimod start increased from 41.6% to 87.9% in naïve, and from 78.7% to 91.7% in pre-treated patients (p < 0.001 for both comparisons).
In this Swiss cohort, fingolimod demonstrated a good efficacy profile in terms of both clinical relapses and MRI activity in naïve as well as pre-treated patients, supporting its use for both indications.