#20
Laura Jonkman

MRI signatures of neuropathology

Abstract: In neurodegenerative diseases, neuroimaging outcome measures are increasingly added as (secondary) end-points in research and clinical trials of therapeutic interventions. Neuroimaging is also more frequently included in the biological definition of disease, such as the ATN framework for Alzheimer’s disease, and SynNeurGe classification for Parkinson’s disease. Broad attempts to explore how pathological measures of disease state and progression influence these imaging end-points remain challenging. One promising avenue is postmortem in-situ (brain still in cranium) MRI with subsequent neuropathological assessment. Postmortem in-situ MRI has shown to be a good proxy for in-vivo MRI, with the added benefit of neuropathological examination from the same time point as MRI acquisition.

A brief introduction to brain banking, in-situ MRI and neuropathological data collection in neurodegenerative diseases will be given. As well as a showcase of studies addressing three research pillars: studying the influence of neuropathological (Aβ, pTau, α-synuclein), axonal and synaptic markers on neuroimaging measures of (i) cortical alterations (volume, thickness, single- and multi-shell diffusion imaging markers), (ii) specific nuclei and their projections (fractional anisotropy and mean diffusivity of the nucleus basalis of Meynert, substantia nigra, locus coeruleus, and their projections), and (ii) the integrating and segregating brain network (structural network construction with graph theoretical characteristics).

A better understanding of the pathological sensitivity of MRI outcome measures will translate MRI signatures of neuropathology and neurodegeneration to the clinical setting. This will facilitate a better interpretation of MRI datasets, contributing to a better defined disease state, monitoring of disease progression, and possible treatment strategies.

Keywords: neuroimaging, neuropathology, Alzheimer’s disease, Parkinson’s disease

#21
Valentina Perosa

Leveraging high-resolution ex vivo neuroimaging to gain insight into the pathophysiology of cerebral small vessel disease 

Asbtract: In this presentation, I will provide an overview of three studies that used high-resolution ex vivo MRI and micro-CT to delve into the pathophysiology of cerebral small vessel disease (CSVD).  The first study examined the histopathological correlates of enlarged perivascular spaces (EPVS) and their association with vascular amyloid-β (Aβ) in cerebral amyloid angiopathy (CAA), a common form of CSVD, which co-exists with Alzheimer’s disease (AD) pathology. Using ex vivo MRI, semi-automatic segmentation, and validated deep-learning-based models, we quantified EPVS and related histopathological abnormalities. Our findings reveal a significant correlation between the severity of EPVS during life and on ex vivo MRI in formalin-fixed intact hemispheres, corresponding with PVS enlargement on histopathology in the same areas. Notably, EPVS predominantly surround the white matter portion of perforating cortical arterioles and their burden correlates with CAA severity in the overlying cortex. These results suggest that EPVS may signify impaired arteriolar flow, shedding light on perivascular clearance mechanisms crucial to the pathophysiology of CAA and AD. In the second study, we focus on achieving 3D histology of the medial temporal lobe (MTL) utilizing ex vivo MRI and micro-CT. This ongoing investigation aims to: I) map the course and morphology of small vessels in the MTL relative to typical AD-related protein accumulation patterns; II) determine the association between CSVD burden in penetrating arterioles of the MTL and accumulation of AD-related proteinopathies in the supplied (sub)regions; and III) utilize quantitative susceptibility mapping (QSM) as a marker of blood-brain barrier leakage on ex vivo MRI. Our analysis will cover cases across Braak-stages and three-dimensional histological reconstructions will be achieved using Imaris® software. Lastly, an exploratory third study delves into the pathological correlates of MRI-observed lobar cerebral microbleeds (CMBs) in false-positive CAA cases. Our investigation confirmed the absence of vascular Aβ accumulation at the lesion site. Instead, utilizing ultra-high-resolution ex vivo MRI and serial sectioning, we gained insight into the probable role of arteriolosclerosis in this context.

Authors:

Valentina Perosa MD PhD¹, Jan Oltmer MD², Lydia Mroz¹, Corinne A. Auger BM³, Matthew P. Frosch MD PhD⁴, Ted Zwang PhD³, Steven M. Greenberg MD PhD¹, Bradley T. Hyman MD PhD², Susanne J. van Veluw PhD^1,3

¹J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

²Department of Digital Health & Innovation, Vivantes Netzwerk für Gesundheit GmbH, Berlin, Germany

³MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA

⁴Neuropathology Service, C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

#22
Marc Suárez-Calvet

New plasma biomarkers related to PET imaging

Abstract: In recent years, several plasma biomarkers for Alzheimer’s disease (AD) and neurodegeneration have been developed, demonstrating high accuracy in distinguishing between individuals with AD and those without. Many of these biomarkers also correlate with amyloid and tau PET imaging, though the degree of agreement varies among biomarkers.

In alignment with the new Revised Criteria for the Diagnosis and Staging of Alzheimer’s Disease, which incorporates blood biomarkers, we will discuss the concordance between plasma and PET biomarkers in both cognitively unimpaired and impaired individuals. This discussion aims to highlight the potential and limitations of plasma biomarkers in reflecting PET imaging findings, ultimately contributing to more accessible and less invasive diagnostic tools for Alzheimer’s disease.

#23
Alexa Pichet Binette

Associations between misfolded alpha-synuclein aggregates and Alzheimer’s disease pathology in vivo

Background: Until recently, biomarkers that could measure α-synuclein pathology in vivo with high accuracy and sensitivity were lacking. With recent improvement in seed amplification assays, it is now possible to indirectly detect misfolded α-synuclein aggregates in cerebrospinal fluid (CSF), enabling to better understand the clinicopathological relations between α-synuclein and AD pathologies. Here we examined the relations of alpha-synuclein pathology with cross-sectional and longitudinal levels of Alzheimer’s disease (AD) pathology in two large independent cohorts covering the AD spectrum.

Methods: We included BioFINDER-2 and ADNI participants (n=2315, Table 1) who had cross-sectional CSF alpha-synuclein measurement as well as cross-sectional and longitudinal Aβ and tau levels (measured in CSF and/or by PET). We fitted logistic regressions to investigate associations between α-synuclein status as outcome (Positive or Negative) and measures of AD pathology (using PET or CSF) as predictors. To evaluate the effect of α-synuclein status on longitudinal AD pathology, we fitted separate linear mixed effect models with longitudinal PET measures (global Aβ SUVR and temporal meta-ROI tau-PET SUVR in BioFINDER-2, Aβ Centiloids in ADNI) as outcome, including random slopes and intercepts. All models were adjusted for age, sex and cognitive status.

Results: Across cohorts, the main pathology associated with alpha-synuclein positivity at baseline was higher levels of Aβ pathology (all p-values£0.02), but not tau, beyond the effects of age, sex and cognitive status (Fig.1). These effects were consistent using PET markers (Fig.1a) or CSF markers (Fig.1b) of AD. Looking at longitudinal measures of AD pathology, alpha-synuclein positive participants had a statistically significant faster increase of Aβ load, although of modest magnitude (1.11 Centiloid/year, p=0.02), compared to alpha-synuclein negative participants in BioFINDER-2 (Fig.2a). However, no difference beween alpha-synuclein groups were seen on longitudinal tau-PET in BioFINDER-2 (Fig.2b) or on Aβ-PET in ADNI (Fig.3b).

Conclusions: We provide novel evidence for in vivo associations between Aβ and alpha-synuclein in the AD continuum. Future studies should investigate if there are potential additive or synergistic effects of abnormal α-synuclein and Aβ accumulation in the brain and the molecular mechanisms that are at play.

Keywords: Lewy body, amyloid-beta, tau, PET, co-pathology

Table 1. Demographics

Data are presented as mean ± standard deviation unless specified otherwise. α-Synuclein status was determined using seed assay amplification in CSF. Aβ status was determined based on CSF Aβ42/40 ratio in BioFINDER-2 and on Aβ-PET in ADNI.

¹Missing for 17 participants in BioFINDER-2 and 49 in ADNI

²Missing for 143 participants in BioFINDER-2 and 49 in ADNI

Abbreviations: Ab= beta-amyloid; APOEe4= apolipoprotein E genotype (carrying at least one e4 allele); F=female; MCI= mild cognitive impairment; MMSE= Mini-Mental State Examination; ROI=region of interest; SUVR= standardized uptake value ratio

 Authors and affiliations: Alexa Pichet Binette¹, Angela Mammana², Laura Wisse³, Marcello Rossi², Olof Strandberg¹, Ruben Smith^1,6, Niklas Mattsson-Carlgren^1,4,5, Shorena Janelidze¹, Sebastian Palmqvist^1,6, ADNI, Alice Ticca⁷, Erik Stomrud^1,6, Piero Parchi^2,7, Oskar Hansson^1,6 

1. Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund
   University, Lund, Sweden
2. IRCCS, Istituto delle Scienze Neurologiche di Bologna (ISNB), Bologna, Italy
3. Diagnostic Radiology Unit, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
4. Department of Neurology, Skåne University Hospital, Malmö, Sweden
5. Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
6. Memory Clinic, Skåne University Hospital, Malmö, Sweden
7. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy