Nelly Joseph-Mathurin

In Vivo Cross-sectional Characterization of Cerebral Alterations Induced by Intracerebroventricular Administration of Streptozotocin

Cerebral aging is often associated with the occurrence of neurodegenerative diseases leading to dementia. Animal models are critical to elucidate mechanisms associated to dementia and to evaluate neuroprotective drugs. Rats that received intracerebroventricular injection of streptozotocin (icv-STZ) have been reported as a model of dementia. In these animals, this drug induces oxidative stress and brain glucose metabolism impairments associated to insulin signal transduction failure. These mechanisms are reported to be involved in the pathogenesis of Alzheimers disease and other dementia. Icv-STZ rats also display memory impairments. However, little is known about the precise location of the lesions induced by STZ administration. In this context, the present study characterized the cerebral lesions induced by two-doses of icv-STZ by using high-field magnetic resonance imaging to easily and longitudinally detect cerebral abnormalities and by using immunohistochemistry to evaluate neuronal loss and neuroinflammation (astrocytosis and microgliosis). We showed that, at high doses, icv-STZ induces severe and acute neurodegenerative lesions in the septum and corpus callosum. The lesions are associated with an inflammation process. They are less severe and more progressive at low doses. The relevance of high and low doses of icv-STZ to mimic dementia and evaluate new drugs is discussed in the final part of this article.

Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group

Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer’s Network (DIAN), an autosomal dominant Alzheimer’s disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer’s disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted.

Micro-MRI Study of Cerebral Aging: Ex Vivo Detection of Hippocampal Subfield Reorganization, Microhemorrhages and Amyloid Plaques in Mouse Lemur Primates

Mouse lemurs are non-human primate models of cerebral aging and neurodegeneration. Much smaller than other primates, they recapitulate numerous features of human brain aging, including progressive cerebral atrophy and correlation between regional atrophy and cognitive impairments. Characterization of brain atrophy in mouse lemurs has been done by MRI measures of regional CSF volume and by MRI measures of regional atrophy. Here, we further characterize mouse lemur brain aging using ex vivo MR microscopy (31 µm in-plane resolution). First, we performed a non-biased, direct volumetric quantification of dentate gyrus and extended Ammons horn. We show that both dentate gyrus and Ammons horn undergo an age-related reorganization leading to a growth of the dentate gyrus and an atrophy of the Ammons horn, even in the absence of global hippocampal atrophy. Second, on these first MR microscopic images of the mouse lemur brain, we depicted cortical and hippocampal hypointense spots. We demonstrated that their incidence increases with aging and that they correspond either to amyloid deposits or to cerebral microhemorrhages.

A novel PSEN1 (S230N) mutation causing early-onset Alzheimer's Disease associated with prosopagnosia, hoarding, and Parkinsonism.

We describe clinical and biomarker findings in an index patient with the onset of Alzheimers disease (AD) symptoms at age 57 and a family history consistent with an autosomal dominant pattern of inheritance. She had the atypical early features of visual agnosia and prosopagnosia followed by hoarding behavior and Parkinsonism. Structural MRI revealed global atrophy that was most severe in the lateral temporal lobes and insular cortex bilaterally. CSF biomarker assessment showed Aβ42, p-tau181, and total tau levels consistent with AD. Genetic assessment revealed a novel mutation in the PSEN1 gene (S230N) in the index patient and her affected brother which was absent in her two clinically unaffected and AD-biomarker negative sisters. The serine residue at codon 230 in PSEN1 is highly conserved across species and in PSEN2, providing strong evidence for its pathogenicity in this family.

OCCIPITAL TO GLOBAL PIB UPTAKE IS ASSOCIATED WITH THE PRESENCE OF MICROHEMORRHAGES AND MUTATIONS ASSOCIATED WITH CEREBRAL AMYLOID ANGIOPATHY IN THE DOMINANTLY INHERITED ALZHEIMER’S NETWORK

contact) and overall social network size in 86 community-dwelling older adults without ADRDs – after adjusting for age, sex, education, global health, and total intracranial volume. Results: The mean age was 75.20 years, mean years of education 15.66, and 53% identified as female. On average, participants reported 5.26 high-contact social relationships, and 22.98 individuals in their overall social network. We identified gray matter volume covariance networks associated with both high-contact social relationships and overall social network size. We also found that greater expression of these networks were associated with better episodic memory, but not with processing speed or executive function. Shared nodes in these networks included medial, lateral and orbital prefrontal cortex, hippocampal, precuneus, insular and cingulate regions. A more extended network of brain regions was associated with high-contact social relationships than overall social network size – also including parahippocampal, amygdala, and entorhinal cortex regions. Conclusions: Social networks in older adults is associated with distributed gray matter volume networks that are closely linked with episodic memory performance and are composed of regions previously linked to both normal and ADRD-related aging. High-contact social relationships may also be a more sensitive measure of age-related and ADRD-related changes in the brain than overall social network size.

Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease

18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimers disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C‐Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET.

CLINICAL RISK RELATED TO CEREBRAL MICROHEMORRHAGES IN AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE: LONGITUDINAL RESULTS FROM THE DIAN STUDY

IC-P-057 CLINICAL RISK RELATED TO CEREBRAL MICROHEMORRHAGES IN AUTOSOMAL DOMINANTALZHEIMER’S DISEASE: LONGITUDINAL RESULTS FROM THE DIAN STUDY Nelly Joseph-Mathurin, Kejal Kantarci, Clifford R. Jack Jr., John M. Ringman, Stephen Salloway, Eric McDade, David Clifford, Tyler Blazey, Karl A. Friedrichsen, Yi Su, Brian A. Gordon, Russ C. Hornbeck, Susan Mills, Beau M. Ances, Marcus E. Raichle, Daniel S. Marcus, Nigel J. Cairns, Chengjie Xiong, Carlos Cruchaga, Alison Goate, Virginia Buckles, Katrina L. Paumier, John C. Morris, Randall J. Bateman, Tammie L. S. Benzinger and Dominantly Inherited Alzheimer Network, Washington University School of Medicine, St. Louis, MO, USA; Mayo Clinic, Rochester, MN, USA; Mayo Clinic College of Medicine, Rochester, MN, USA; University of Southern California, Los Angeles, CA, USA; Alpert Medical School of Brown University, Providence, RI, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA. Contact e-mail: mathurinn@npg.wustl.edu

Widespread white matter and conduction defects in PSEN1-related spastic paraparesis

The mechanisms underlying presenilin 1 (PSEN1) mutation-associated spastic paraparesis (SP) are not clear. We compared diffusion and volumetric magnetic resonance measures between 3 persons with SP associated with the A431E mutation and 7 symptomatic persons with PSEN1 mutations without SP matched for symptom duration. We performed amyloid imaging and central motor and somatosensory conduction studies in 1 subject with SP. We found decreases in fractional anisotropy and increases in mean diffusivity in widespread white-matter areas including the corpus callosum, occipital, parietal, and frontal lobes in PSEN1 mutation carriers with SP. Volumetric measures were not different, and amyloid imaging showed low signal in sensorimotor cortex and other areas in a single subject with SP. Electrophysiological studies demonstrated both slowed motor and sensory conduction in the lower extremities in this same subject. Our results suggest that SP in carriers of the A431E PSEN1 mutation is a manifestation of widespread white-matter abnormalities not confined to the corticospinal tract that is at most indirectly related to the mutations effect on amyloid precursor protein processing and amyloid deposition.

NEURONAL INJURY AND DEGENERATION EVALUATED WITH IMAGING AND CSF BIOMARKERS IN AUTOSOMAL DOMINANT ALZHEIMER'S DISEASE: RESULTS FROM THE DIAN STUDY

plete work-ups were differently represented for the two diagnoses. No statistically significant change emerged in diagnosis, diagnostic confidence or clinical management between complete, intermediate or incomplete assessments (Table). Stratifying patients for etiopathology (AD-FTD) or clinical severity (MCI-dementia) led to the same results. Conclusions:Collection of additional core bio-markers does not seem to affect the incremental value of amyloid-PET in naturalistic clinical setting. The clinicians combinations and use of instrumental examination needs to be better understood and elucidated in view of the definition of an evidence-based diagnostic algorithm.

SIMILARITIES AND DIFFERENCES IN PATTERNS OF [F18]-AV-1451 AND [F18]-FDG IN FRONTOTEMPORAL DEMENTIA

cohort.Methods:18 participants were included. 80-100minute [F] AV-1451 images were normalized to SUVR units by cerebellar grey matter. Measures from antecedent cross-sectional [F]FDG-PET, baseline [F]Florbetapir PET and MRI that were approximately 3yrs before the [F]AV-1451 scan (mean 1⁄4 3.2yrs; range 1⁄4 2.05.1yrs), and two-year change in florbetapir and MRI measures were explored as independent predictors of [F]AV-1451 SUVR values extracted from the whole cortex and the medial temporal lobe (MTL). [F]Florbetapir and []FDG scans were pre-processed as described [1]. [F]Florbetapir scans were intensity normalized by the whole cerebellum (baseline) and a composite of the cerebral white matter, brainstem, and whole cerebellum (longitudinal). [F]FDG intensity was normalized to the pons. Baseline global cortical [F]Florbetapir and mean parietal [F]FDG SUVR, as well as 2yr annualized percent change (APC) in global [F]Florbetapir were extracted. Baseline and 2-year hippocampal volumes (HV) were estimated using Freesurfer v5.1. Step-wise linear models predicting cortical or MTL [F]AV-1451 SUVR with the following predictors were assessed: cortical [F]Florbetapir SUVR, annual percent change (APC) in cortical [F]Florbetapir SUVR, mean parietal [F]FDG SUVR, HV, APC in HV, diagnosis (control or MCI/AD), age, gender, and time between scans. Results:Mean cortical [F]AV-1451 uptake was predicted only by diagnosis and cross-sectional mean cortical [F]Florbetapir SUVR. However, MTL [F]AV-1451 uptake was predicted by both mean cross-sectional cortical [F]Florbetapir uptake and cross-sectional HV. Conclusions: Overall, [F]AV-1451 uptake (representative of tau deposition) was predicted by the extent of cortical amyloid deposition ([F]Florbetapir uptake) approximately three years prior. Hippocampal atrophy may interact with this process. [1] Risacher et al. (2015) Alzheimer’s & Dementia, (11): 1417.