Bayesian meta-analysis of phase 3 results of aducanumab, lecanemab, donanemab, and high-dose gantenerumab in prodromal and mild Alzheimer's disease.

INTRODUCTION: Phase 3 trials using the anti-amyloid antibodies aducanumab, lecanemab, donanemab, and high-dose gantenerumab in prodromal and mild Alzheimer's disease dementia were heterogeneous in respect to statistical significance of effects. However, heterogeneity of results has not yet directly be quantified. METHODS: We used Bayesian random effects meta-analysis to quantify evidence for or against a treatment effect, and assessed the size of the effect and its heterogeneity. Data were extracted from published studies where available and Web based data reports, assuming a Gaussian data generation process. RESULTS: We found moderate evidence in favor of a treatment effect (Bayes factor = 13.2). The effect was moderate to small with -0.33 (95% credible interval -0.54 to -0.10) points on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) scale. The heterogeneity parameter was low to moderate with 0.21 (0.04 to 0.45) CDR-SB points. DISCUSSION: Heterogeneity across studies was moderate despite some trials reaching statistical significance, while others did not. This suggests that the negative aducanumab and gantenerumab trials are in full agreement with the expected effect sizes.

Verbal expressive language minimally affected in non-demented people living with amyotrophic lateral sclerosis.

Objective: Language dysfunction is one of the most common cognitive impairments in amyotrophic lateral sclerosis (ALS). Although discourse capacities are essential for daily functioning, verbal expressive language has not been widely investigated in ALS. The existing research available suggests that discourse impairments are prevalent. This study investigates verbal expressive language in people living with ALS (plwALS) in contrast to healthy controls (HC).Methods: 64 plwALS and 49 age, gender and education-matched healthy controls were ask to describe the Cookie Theft Picture Task. The recordings were analyzed for discourse productivity, discourse content, syntactic complexity, speech fluency and verb processing. We applied the Bayesian hypothesis-testing framework, incorporating the effects of dysarthria, cognitive impairment status (CIS), and premorbid crystalline verbal IQ.Results: Compared to HC, plwALS only showed a single impairment: speech dysfluency. Discourse productivity, discourse content, syntactic complexity and verb processing were not impaired. Cognition and dysarthria exceeded the influence of verbal IQ for total words spoken and content density. Cognition alone seemed to explain dysfluency. Body-agent verbs were produced at even higher rates than other verb types. For the remaining outcomes, verbal IQ was the most decisive factor.Conclusions: In contrast to existing research, our data demonstrates no discernible impairment in verbal expressive language in ALS. What our findings show to be decisive is accounting for the influence of dysarthria, cognitive impairment status, and verbal IQ as variables on spontaneous verbal expressive language. Minor impairments in verbal expressive language appear to be influenced to a greater degree by executive dysfunctioning and dysarthria than by language impairment.

Cognitive reserve protects ALS-typical cognitive domains: A longitudinal study.

BACKGROUND AND OBJECTIVES: To determine whether cognitive reserve (CR) as measured by verbal intelligence quotient, educational length, and achievement protects amyotrophic lateral sclerosis (ALS) patients' verbal fluency, executive functioning, and memory against brain volume loss over a period of 12 months. METHODS: This cohort study was completed between 2013 and 2016 with a follow-up duration of 12 months. ALS patients were recruited from two specialist out-patient clinics in Rostock and Magdeburg in Germany. Participants underwent cognitive testing and magnetic resonance imaging both at baseline and again after 12 months. The cognitive domains assessed included verbal memory in addition to executive functions such as verbal fluency, working memory, shifting and selective attention. RESULTS: Thirty-eight ALS patients took part; 25 patients had no cognitive impairment (ALSni), and 13 were cognitively impaired (ALSci). On average, patients lost 294 mm3 in their superior frontal gyri, 225 mm3 in their orbitofrontal gyri, and 15.97 mm3 in their hippocampi over 12 months. There was strong evidence that CR protected letter fluency from further decline (Bayes factor [BF] >10) and moderate evidence that it supported learning effects in letter flexibility (BF >3). However, there is a lack of evidence supporting the notion that working memory, shifting, selective attention or verbal memory (BF = 1) are protected. DISCUSSION: As CR is easily determined and protects ALS-specific cognitive domains over time, it should be regarded as a valuable predictive marker.

Applied Bayesian Approaches for Research in Motor Neuron Disease.

Statistical evaluation of empirical data is the basis of the modern scientific method. Available tools include various hypothesis tests for specific data structures, as well as methods that are used to quantify the uncertainty of an obtained result. Statistics are pivotal, but many misconceptions arise due to their complexity and difficult-to-acquire mathematical background. Even though most studies rely on a frequentist interpretation of statistical readouts, the application of Bayesian statistics has increased due to the availability of easy-to-use software suites and an increased outreach favouring this topic in the scientific community. Bayesian statistics take our prior knowledge together with the obtained data to express a degree of belief how likely a certain event is. Bayes factor hypothesis testing (BFHT) provides a straightforward method to evaluate multiple hypotheses at the same time and provides evidence that favors the null hypothesis or alternative hypothesis. In the present perspective, we show the merits of BFHT for three different use cases, including a clinical trial, basic research as well as a single case study. Here we show that Bayesian statistics is a viable addition of a scientist's statistical toolset, which can help to interpret data.

A Bayesian perspective on Biogen's aducanumab trial.

This perspective is a companion to a recent editorial on the use of Bayesian analysis in clinical research. We aim to introduce and highlight the relevance and advantages that Bayesian inference offers to clinical trials using the data on the amyloid antibody aducanumab presented at a Food and Drug Administration hearing in November 2020 as an applied example. We apply Bayesian analysis of model plausibility and effect sizes based on simulated data of the two phase 3 trials of aducanumab in prodromal and mild dementia stages of Alzheimer's disease (AD). Bayesian analysis can quantify evidence in favor of, or against, the presence of an effect (i.e., provide evidence of absence), as well as assess the strength of the effect. This is in contrast to the binary conclusions provided by frequentist tests.

Loss of "insight" into behavioral changes in ALS: Differences across cognitive profiles.

OBJECTIVE: Behavioral impairment occurs in amyotrophic lateral sclerosis (ALS) and ALS-fronto-temporal dementia (ALS-FTD). It has been proposed that ALS patients without FTD retain an awareness of their behavioral impairment while ALS-FTD patients lose this awareness (referred to as retention vs. loss of "insight"). Loss of insight has not yet been studied across the entire ALS-FTD spectrum; our study addresses this gap by including patients with all the ALS cognitive-behavioral profiles. METHODS: Eighty-three ALS patients (and their informants) took part in this bicentric study involving two German recruitment sites. Patients and informants completed the Frontal Systems Behavior Scale covering the domains of apathy, disinhibition, and executive dysfunctioning. Patients were classified into five groups according to the Strong and Rascovsky criteria: cognitively unimpaired (ALSni), cognitively impaired without dementia (ALSci), behaviorally impaired (ALSbi), a combination of behaviorally and cognitively impaired (ALScbi), and ALS-FTD. We applied Bayesian two-way ANOVA to test whether there were subgroup differences regarding insight into their behavioral decline. RESULTS: All patient subgroups experienced behavioral decline (Bayes factor > 3). Only ALS-FTD patients lost insight into disinhibition and executive dysfunctioning. ALSbi patients exhibited worse insight than ALSni and ALSci patients (Bayes factor > 10). Evidence regarding the ALScbi patients was inconclusive. Higher IQ was associated with worse insight (Bayes factor > 3). CONCLUSIONS: Our findings provide solid support for the notion that ALS patients without dementia experience behavioral decline regardless of their cognitive-behavioral profile and retain different levels of insight into this decline. The inverse association of premorbid verbal intelligence with insight was unexpected, leaving room for further investigation.

Cognitive Profiles of Amyotrophic Lateral Sclerosis Differ in Resting-State Functional Connectivity: An fMRI Study.

BACKGROUND: Half of all amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) patients are classified as cognitively impaired, of which 10% have frontotemporal dementia (FTD), and an additional 40% suffer from a frontotemporal syndrome not severe enough to be described as dementia (cognitively impaired/ALSci). As changes in cerebral function measured by resting-state magnet resonance imaging (rs-fMRI) are known in ALS, we investigated whether group differences in resting-state functional connectivity (RSFC) networks could be observed between ALS patients with different cognitive profiles against healthy controls (HC). Furthermore, we correlated cognition and motor functioning with network connectivity. METHODS: Healthy controls, 69, and 97 ALS patients underwent functional MRI scanning and cognitive assessment. The ALS patients were categorized as non-impaired (ALSni; n = 68), cognitively impaired (ALSci; n = 21), and ALS-FTD (n = 8). Group differences in connectivity of the default mode network (DMN), motor network (MN), and ventral attention network (VAN) were investigated using a full-factorial model; correlations between global cognitive performance, shifting, and motor symptom severity were established using Pearson's correlation. RESULTS: At a liberal alpha level of uncorrected p < 0.005 and a cluster size exceeding 20 voxels, we found widespread decreases in functional connectivity in all three networks when comparing ALS patients to HC. Similar patterns of hypoconnectivity in the bilateral motor cortices and frontotemporal emerged when comparing the ALSci and ALS-FTD patients to those not cognitively impaired. Hyperconnectivity in the DMN temporal gyrus correlated with worse global cognition; moreover, hyperconnectivity in the VAN thalamus, insula, and putamen correlated with worse shifting ability. Better-preserved motor function correlated with higher MN connectivity. Only the motor-related effects prevailed at a more conservative significance level of p FDR < 0.001. CONCLUSION: Resting-state functional connectivity differs between cognitive profiles of ALS and is directly associated with clinical presentation, specifically with motor function, and cognitive shifting.

Case Report: Cognitive Conversion in a Non-brazilian VAPB Mutation Carrier (ALS8).

Amyotrophic lateral sclerosis 8 (ALS8) is a predominantly lower motor neuron syndrome originally described in a Portuguese-Brazilian family, which originated from a common founder. ALS8 is caused by a VAPB mutation and extremely rare in Central Europe. We present a 51-year-old German man with ALS8 who had the P56S VAPB mutation independently of the founder effect. In the final 4 years of his life (disease duration 10 years), the patient had five MRI scans and four in-depth neuropsychological assessments. This paper addresses the course of the patient's cognitive status and relates cognitive performance to structural brain changes in order to determine whether this ALS8 case showed a different pattern of cognitive decline compared with sporadic ALS. The executive functions, verbal fluency, and memory of the patient and 17 age-, sex-, and education-matched controls were assessed on four different occasions. His cognitive performance and decline were investigated for abnormality using cross-sectional and longitudinal matched case-control analysis. We obtained five T1-weighted MRI, which we analyzed using voxel-wise non-parametric analysis with statistical non-parametric mapping in Matlab. Moreover, we conducted a single-subject correlation between cognitive performance and brain atrophy. The cognitive profile of the index patient featured executive dysfunction. Notably, his working memory and shifting ability declined from a healthy baseline to an impaired performance, leading to a transition from cognitively non-impaired (ALSni) to cognitively impaired (ALSci). The correlations we observed between cerebellar atrophy and verbal fluency in addition to fusiform gyrus atrophy and shifting are novel findings. We found that the conversion from ALSni to ALSci was associated with widespread cerebral atrophy, which extended beyond the primary motor and premotor cortex and affected, among others, the cerebellum and left fusiform gyrus. The index patients' cognitive profile resembles that of other ALS phenotypes, but the extensive atrophy beyond extra-motor areas has not yet been described.

Cognitive reserve and regional brain volume in amyotrophic lateral sclerosis.

OBJECTIVE: We investigated whether cognitive reserve measured by education and premorbid IQ allows amyotrophic lateral sclerosis patients to compensate for regional brain volume loss. METHODS: This was a cross-sectional study. We recruited sixty patients with amyotrophic lateral sclerosis from two specialist out-patient clinics. All participants underwent neuropsychological assessment; the outcomes were standardized z-scores reflecting verbal fluency, executive functions (shifting, planning, working memory), verbal memory and visuo-constructive ability. The predictor was regional brain volume. The moderating proxies of cognitive reserve were premorbid IQ (estimated by vocabulary) and educational years. We hypothesized that higher cognitive reserve would correlate with better performance on a cognitive test battery, and tested this hypothesis with Bayesian analysis of covariance. RESULTS: The analyses provided moderate to very strong evidence in favor of our hypothesis with regard to verbal fluency functions, working memory, verbal learning and recognition, and visuo-constructive ability (all BF01 > 3): higher cognitive reserve was associated with a mild increase in performance. For shifting and planning ability, the evidence was anecdotal. CONCLUSIONS: These results indicate that cognitive reserve moderates the effect of brain morphology on cognition in ALS. Patients draw small but meaningful benefits from higher reserve, preserving fluency, memory and visuo-constructive functions. Executive functions presented a dissociation: verbally assessed functions benefitted from cognitive reserve, non-verbally assessed functions did not. This motivates future research into cognitive reserve in ALS and practical implications, such as strengthening reserve to delay decline.

Association of PET-based stages of amyloid deposition with neuropathological markers of Aß pathology.

OBJECTIVE: To determine if PET-based stages of regional amyloid deposition are associated with neuropathological phases of Aß pathology. METHODS: We applied data-driven regional frequency-based and a-priori striatum-based PET staging approaches to ante-mortem 18F-Florbetapir-PET scans of 30 cases from the Alzheimer's Disease Neuroimaging Initiative autopsy cohort, and used Bayesian regression analysis to study the associations of these in vivo amyloid stages with neuropathological Thal phases of regional Aß plaque distribution and with semi-quantitative ratings of neocortical and striatal plaque densities. RESULTS: Bayesian regression revealed extreme evidence for an association of both PET-based staging approaches with Thal phases, and these associations were about 44 times more likely for frequency-based stages and 89 times more likely for striatum-based stages than for global cortical 18F-Florbetapir-PET signal. Early (i.e., neocortical-only) PET-based amyloid stages also predicted the absence of striatal/diencephalic cored plaques. Receiver operating characteristics curves revealed highly accurate discrimination between low/high Thal phases and the presence/absence of regional plaques. The median areas under the curve were 0.99 for frequency-based staging (95% credibility interval 0.97-1.00), 0.93 for striatum-based staging (0.83-1.00), and 0.87 for global 18F-Florbetapir-PET signal (0.72-0.98). INTERPRETATION: Our data indicate that both regional frequency- and striatum-based amyloid-PET staging approaches were superior to standard global amyloid-PET signal for differentiating between low and high degrees of regional amyloid pathology spread. Despite this, we found no evidence for the ability of either staging scheme to differentiate between low and moderate degrees of amyloid pathology which may be particularly relevant for early, preclinical stages of Alzheimer's disease.