Jolien Schaeverbeke

Core auditory processing deficits in primary progressive aphasia

The extent to which deficits in non-verbal auditory processing contribute to the clinical phenotype of primary progressive aphasia (PPA) is unclear. Grube et al. reveal impairments in processing the timing of brief sequences of non-linguistic stimuli, particularly in the non-fluent variant, indicative of a core central auditory impairment in PPA.

3D Shape Perception in Posterior Cortical Atrophy: A Visual Neuroscience Perspective

Posterior cortical atrophy (PCA) is a rare focal neurodegenerative syndrome characterized by progressive visuoperceptual and visuospatial deficits, most often due to atypical Alzheimers disease (AD). We applied insights from basic visual neuroscience to analyze 3D shape perception in humans affected by PCA. Thirteen PCA patients and 30 matched healthy controls participated, together with two patient control groups with diffuse Lewy body dementia (DLBD) and an amnestic-dominant phenotype of AD, respectively. The hierarchical study design consisted of 3D shape processing for 4 cues (shading, motion, texture, and binocular disparity) with corresponding 2D and elementary feature extraction control conditions. PCA and DLBD exhibited severe 3D shape-processing deficits and AD to a lesser degree. In PCA, deficient 3D shape-from-shading was associated with volume loss in the right posterior inferior temporal cortex. This region coincided with a region of functional activation during 3D shape-from-shading in healthy controls. In PCA patients who performed the same fMRI paradigm, response amplitude during 3D shape-from-shading was reduced in this region. Gray matter volume in this region also correlated with 3D shape-from-shading in AD. 3D shape-from-disparity in PCA was associated with volume loss slightly more anteriorly in posterior inferior temporal cortex as well as in ventral premotor cortex. The findings in right posterior inferior temporal cortex and right premotor cortex are consistent with neurophysiologically based models of the functional anatomy of 3D shape processing. However, in DLBD, 3D shape deficits rely on mechanisms distinct from inferior temporal structural integrity. SIGNIFICANCE STATEMENT Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive visuoperceptual dysfunction and most often an atypical presentation of Alzheimers disease (AD) affecting the ventral and dorsal visual streams rather than the medial temporal system. We applied insights from fundamental visual neuroscience to analyze 3D shape perception in PCA. 3D shape-processing deficits were affected beyond what could be accounted for by lower-order processing deficits. For shading and disparity, this was related to volume loss in regions previously implicated in 3D shape processing in the intact human and nonhuman primate brain. Typical amnestic-dominant AD patients also exhibited 3D shape deficits. Advanced visual neuroscience provides insight into the pathogenesis of PCA that also bears relevance for vision in typical AD.

Amnestic MCI Patients’ Perspectives toward Disclosure of Amyloid PET Results in a Research Context

BackgroundResearchers currently are not obligated to share individual research results (IRR) with participants. This non-disclosure policy has been challenged on the basis of participants’ rights to be aware and in control of their personal medical information. Here, we determined how patients view disclosure of research PET results of brain amyloid and why they believe it is advantageous or disadvantageous to disclose.MethodAs a part of a larger diagnostic trial, we conducted semi-structured interviews with patients with amnestic Mild Cognitive Impairment (aMCI). Participants had the option to receive their brain amyloid PET scan result (i.e., their IRR). Interviews were conducted before they received their IRR.ResultsA total of 38 aMCI patients (100% of study participants) wanted to know their IRR. The two most frequently mentioned reasons for choosing IRR disclosure were to better understand their brain health status and to be better able to make informed decisions about future personal arrangements (e.g., inheritance tax, moving into a smaller house, end-of-life decisions, etc.). Emotional risk was mentioned as the primary disadvantage of knowing one’s IRR. On the other hand, non-disclosure was considered to be emotionally difficult also, as patients would be uncertain about their future health condition.ConclusionsMany patients diagnosed clinically with aMCI want to know their brain amyloid test results, even though this knowledge may be disadvantageous to them. Knowing what is going on with their health and the ability to make informed decisions about their future were the two principal advantages mentioned for obtaining their amyloid PET results. Because of the overwhelming consensus of aMCI patients was to disclose their brain amyloid PET scan results, researchers should strongly consider releasing this information to research subjects.

Cholinergic depletion and basal forebrain volume in primary progressive aphasia

Primary progressive aphasia (PPA) is a heterogeneous syndrome with various neuropathological causes for which no medical treatment with proven efficacy exists. Basal forebrain (BF) volume loss has been reported in PPA but its relation to cholinergic depletion is still unclear. The primary objective of this study was to investigate whether cholinergic alterations occur in PPA variants and how this relates to BF volume loss. An academic memory clinic based consecutive series of 11 PPA patients (five with the semantic variant (SV), four with the logopenic variant (LV) and two with the nonfluent variant (NFV)) participated in this cross-sectional in vivo PET imaging study together with 10 healthy control subjects. Acetylcholinesterase (AChE) activity was quantitatively measured in the neo- and allocortex using N-[11C]-Methylpiperidin-4-yl propionate (PMP)-PET with arterial sampling and metabolite correction. Whole brain and BF volumes were quantified using voxel-based morphometry on high-resolution magnetic resonance imaging (MRI) scans. In the PPA group, only LV cases showed decreases in AChE activity levels compared to controls. Surprisingly, a substantial number of SV cases showed significant AChE activity increases compared to controls. BF volume did not correlate with AChE activity levels in PPA. To conclude, in our sample of PPA patients, LV but not SV was associated with cholinergic depletion. BF atrophy in PPA does not imply cholinergic depletion.

Amnestic MCI Patients’ Perspectives on Volunteer Participation in a Research Context

Background: Inclusion of patients in research studies is immensely important when evaluating new biomarkers for Alzheimer’s disease (AD) and when the efficacy of possible treatment options is under trial investigation. If medical treatment is to advance in slowing the progression of AD, or even preventing it, voluntary participation of patients is not only important but also their reliable participation is key. To get closer in achieving this goal, researchers need to understand better what motivates research participants to enroll in a clinical trial and get insight into participants’ expectations about their participation. Furthermore, what researchers perceive as benefits and risks of a study can differ from participants’ view. This difference could lead to a situation in which researchers recruit fewer subjects than they expected or result in unreliable research subject participation.Method: We conducted semi-structured in-depth interviews in 38 patients with amnestic mild cognitive impairment (aMCI) as part of a clinical trial (EUDRACT no. 2013-004671-12) on the predictive value of biomarkers for AD. Patients had the option of receiving their Individual Research Results (IRR; visual binary read amyloid PET results). In this study, the motivations and perceived advantages and disadvantages of trial participation were investigated from the patients’ perspective. Before deciding to participate, patients received an information brochure describing the possible benefits and risks of participation.Results: The two most frequently mentioned reasons for volunteering for the trial were to contribute to scientific progress and to receive their IRRs. Participating to ameliorate scientific progress was not solely motivated by altruistic reasons; it was mostly mentioned along with the possibility of receiving a valuable result about their health condition, suggesting that self-interest also motivated patients to participate. The two most frequently mentioned disadvantages were the possible risks related to being subjected to invasive medical procedures and that volunteering was considered to be time consuming. Most patients felt that their partner and children supported their decision to enroll in the biomarker study.Conclusion: aMCI patients have several reasons for wanting to volunteer in a clinical trial, with the option of IRR disclosure being the primary motivation for enrolling. Most of our patients felt that family members supported their decision to volunteer. However, researchers need to be cautious when recruiting subjects for clinical trials by ensuring that they truly desire to participate in the study and those family members are not coercing them into doing so. In addition, what the information brochure mentions as possible benefits and risks of trial participation was not always perceived similarly by patients.

Distinct [18F]THK5351 binding patterns in primary progressive aphasia variants

PurposeTo assess the binding of the PET tracer [18F]THK5351 in patients with different primary progressive aphasia (PPA) variants and its correlation with clinical deficits. The majority of patients with nonfluent variant (NFV) and logopenic variant (LV) PPA have underlying tauopathy of the frontotemporal lobar or Alzheimer disease type, respectively, while patients with the semantic variant (SV) have predominantly transactive response DNA binding protein 43-kDa pathology.MethodsThe study included 20 PPA patients consecutively recruited through a memory clinic (12 NFV, 5 SV, 3 LV), and 20 healthy controls. All participants received an extensive neurolinguistic assessment, magnetic resonance imaging and amyloid biomarker tests. [18F]THK5351 binding patterns were assessed on standardized uptake value ratio (SUVR) images with the cerebellar grey matter as the reference using statistical parametric mapping. Whole-brain voxel-wise regression analysis was performed to evaluate the association between [18F]THK5351 SUVR images and neurolinguistic scores. Analyses were performed with and without partial volume correction.ResultsPatients with NFV showed increased binding in the supplementary motor area, left premotor cortex, thalamus, basal ganglia and midbrain compared with controls and patients with SV. Patients with SV had increased binding in the temporal lobes bilaterally and in the right ventromedial frontal cortex compared with controls and patients with NFV. The whole-brain voxel-wise regression analysis revealed a correlation between agrammatism and motor speech impairment, and [18F]THK5351 binding in the left supplementary motor area and left postcentral gyrus. Analysis of [18F]THK5351 scans without partial volume correction revealed similar results.Conclusion[18F]THK5351 imaging shows a topography closely matching the anatomical distribution of predicted underlying pathology characteristic of NFV and SV PPA. [18F]THK5351 binding correlates with the severity of clinical impairment.

A POLYGENIC AD RISK SCORE PREDICTS AMYLOID ACCUMULATION OVER A 6-YEAR INTERVAL IN COGNITIVELY INTACT OLDER ADULTS

campus-connectivity was associated with attenuated decreases in memory recall and MMSE, controlled for gender, site, education and hippocampal volume. Results:In the MC group, we found a significant interaction BDNFVal66MetxEYO on right hippocampus connectivity within the bilateral mediofrontal cortex (Figure 1A; voxel-wise p<0.005, FWE-cluster-corrected). That is, BDNFValcarriers exhibited an attenuated decline in hippocampus-mediofrontal connectivity during the course of AD when compared to BDNFMet-carriers (Figure 1B). In MC, lower right hippocampusmediofrontal connectivity was associated with attenuated decrease in delayed recall (p<0.05, Figure 1C) and MMSE scores (p<0.001). No effects were found in NC. Conclusions: The BDNFVal66Met-SNP moderates hippocampal connectivity decline in ADAD, where BDNFVal-carriage is associated with a relatively preserved hippocampal-mediofrontal connectivity that may ameliorate episodic memory impairment during AD.

From information to follow-up: Ethical recommendations to facilitate the disclosure of amyloid PET scan results in a research setting

In the field of Alzheimers disease research, the use of biomarkers such as amyloid positron emission tomography (PET) has become widespread over a relatively brief period of time. There is an increasing tendency in research studies and trials to switch from no disclosure under any condition toward a qualified disclosure of individual research results, such as amyloid PET scan results. This perspective article aims to evaluate the possible need for a modification of the available recommendations on amyloid PET scan disclosure, based on recent empirical evidence obtained within the field of amyloid PET. This article also applies the International Guideline for Good Clinical Practice to the field of amyloid PET disclosure. Hence, we propose several recommendations to facilitate amyloid PET disclosure while minimizing possible risks of amyloid disclosure in a research context.

VISUAL READING OF AMYLOID-PET IN MCI CHALLENGED: SHOULD WE CONSIDER ALTERNATIVE METHODS?

healthy controls (HC) and patients with amnestic mild cognitive impairment (MCI) were dichotomized into groups of low amyloid (Aß-, HC: n 1⁄4 165, MCI: n 1⁄4188) and high amyloid status (Aß+, HC: n 1⁄4 73, MCI: n 1⁄4 231), with AD dementia group (n 1⁄4 98). Grey matter volume and FDG-PET were obtained within 90 ROIs of the Desikan-Killiany atlas. Feature selection and classification was based on a combination of inner and outer-loop 10-fold cross-validation scheme. Within each fold of a 10-fold cross-validation (outer-loop), feature selection based on the Information Gain criterion was determined within an inner-loop 10-fold cross-validation. The most discriminative features were then tested in the unseen test sample of the outer-loop fold. Overall classification accuracy via support vector machine was calculated as the average outerloop cross-validation accuracy. Results:Classification accuracy for the discrimination between AD and HC Aßwas > 90% for any single modality, and did not significantly benefit from a combination of modalities. For predicting conversion from MCI to AD (median follow-up time 1⁄4 36 months), the highest classification accuracy was 80.4%, when applying a combination of FDG-PET (for best features see Figure) and neuropsychological variables (world recall, Benton naming, tests of executive function). For discriminating Aß status in HC or MCI as well as conversion from HC to MCI, we observed classification accuracies between 60 – 70%. Conclusions:The combination of FDG-PET and neuropsychological variables produced clinically useful classification accuracy to predict conversion of AD dementia at MCI stage, but remained still below clinical utility for the detection of preclinical AD.

IN VIVO VISUALIZATION OF [ 18 ]F-THK5351 BINDING IN PRIMARY PROGRESSIVE APHASIA

Jolien Schaeverbeke, Rose Bruffaerts, Charlotte Evenepoel, Silvy Gabel, Karen Meersmans, Karen Van Bouwel, Eva Dries, Ronald Peeters, Koen Van Laere, Rik Vandenberghe, Alzheimer Research Centre, KU Leuven, Leuven, Belgium; Laboratory for Cognitive Neurology, KU Leuven, Leuven, Belgium; Neurology Department, University Hospitals Leuven (UZ Leuven, Campus Gasthuisberg), Leuven, Belgium; Radiology Department, UZ Leuven, Leuven, Belgium; Nuclear Medicine Department, UZ Leuven, Leuven, Belgium. Contact e-mail: jolien.schaeverbeke@kuleuven.be