Maria B. Mejia

Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery.

Alzheimers disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstems locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]).

Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's Disease

Hyperphosphorylated tau neuronal cytoplasmic inclusions (ht‐NCI) are the best protein correlate of clinical decline in Alzheimers disease (AD). Qualitative evidence identifies ht‐NCI accumulating in the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht‐NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the impact of AD pathology in these nuclei with a focus on early stages.

Selective Vulnerability of Brainstem Nuclei in Distinct Tauopathies: A Postmortem Study

The brainstem nuclei of the reticular formation (RF) are critical for regulating homeostasis, behavior, and cognition. RF degenerates in tauopathies including Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Although the burden of phopho-tau inclusion is high across these diseases, suggesting a similar vulnerability pattern, a distinct RF-associated clinical phenotype in these diseases indicates the opposite. To compare patterns of RF selective vulnerability to tauopathies, we analyzed 5 RF nuclei in tissue from 14 AD, 14 CBD, 10 PSP, and 3 control cases. Multidimensional quantitative analysis unraveled discernable differences on how these nuclei are vulnerable to AD, CBD, and PSP. For instance, PSP and CBD accrued more tau inclusions than AD in locus coeruleus, suggesting a lower vulnerability to AD. However, locus coeruleus neuronal loss in AD was so extreme that few neurons remained to develop aggregates. Likewise, tau burden in gigantocellular nucleus was low in AD and high in PSP, but few GABAergic neurons were present in AD. This challenges the hypothesis that gigantocellular nucleus neuronal loss underlies REM behavioral disorders because REM behavioral disorders rarely manifests in AD. This study provides foundation for characterizing the clinical consequences of RF degeneration in tauopathies and guiding customized treatment.

APOPTOSIS AND AUTOPHAGY CHANGES CORRELATE WITH ALZHEIMER'S DISEASE PROGRESSION IN HUMANS: A STEREOLOGICAL POSTMORTEM STUDY

in the limbic system and progressively spreads into primary processing and sensory regions such as the primary visual cortex and the retina. For the first time, here we assess the propagation of Ab42 peptide-mediated amyloidogenesis and pro-inflammatory gene expression (at the level of miRNA, mRNA and protein) in the neocortical-thalamic-retinal visual pathway of 5xFAD Tg-AD amyloid-overexpressing mice whose diets were supplemented with aluminum (sulfate). Methods:5xFAD Tg-AD murine models, RNA sequencing, GeneChip (microRNA and mRNA), RT-PCR, LED-Northern, Western, ELISA and bioinformatics analysis. Results:The three most significant findings were (i) in aluminum-supplemented animals, markers for inflammatory neuropathology appeared in both the brain and the retina as evidenced by an evolving presence of Ab42 peptides; (ii) increases in Ab42 peptide abundance in these animals were accompanied by the up-regulation of several pro-inflammatory markers including cyclooxygenase-2 (COX-2) and C-reactive protein (CRP); and (iii) that as similarly reported in other Tg-AD murine models, there was a significantly accelerated development of Ab42-mediated inflammatory neuropathology in 5xFAD Tg-AD mice fed aluminum. Conclusions: Taken together the results indicate that in the 5xFAD Tg-ADmodel aluminum not only enhances an Ab42-mediated inflammatory neurodegeneration in the brain but also significantly induces AD-type neuropathology in anatomically-linked primary sensory areas that involve the acquisition and processing of visual signals.

Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans

Clarifying the mechanisms connecting neurofibrillary tangle (NFT) neurotoxicity to neuronal dysfunction in humans is likely to be pivotal for developing effective treatments for Alzheimers disease (AD). To model the temporal progression of AD in humans, we used a collection of brains with controls and individuals from each Braak stage to quantitatively investigate the correlation between intraneuronal caspase activation or macroautophagy markers, NFT burden, and neuronal loss, in the dorsal raphe nucleus and locus coeruleus, the earliest vulnerable areas to NFT accumulation. We fit linear regressions with each count as outcomes, with Braak score and age as the predictors. In progressive Braak stages, intraneuronal active caspase-6 positivity increases both alone and overlapping with NFTs. Likewise, the proportion of NFT-bearing neurons showing autophagosomes increases. Overall, caspases may be involved in upstream cascades in AD and are associated with higher NFTs. Macroautophagy changes correlate with increasing NFT burden from early AD stages.

INVESTIGATING THE SELECTIVE VULNERABILITY OF ALZHEIMER’S DISEASE IN FIVE SUBCORTICAL NUCLEI AS COMPARED TO FOUR REPEAT TAUOPATHIES

and paper. Computerized tests hold, however, potential for more flexible testing with less resources. Our aim is to validate a webbased cognitive test battery, Muistikko, developed for the early detection of cognitive problems. Methods:Muistikko is a relative short cognitive battery (duration about 30 mins) that consists of seven subtasks assessing verbal episodic memory, processing speed and executive functions. We validated Muistikko in three cohorts (Table 1): PredictND and VPH-DARE@IT cohorts (memory clinic patients) and FINGER cohort (healthy cases at risk). To quantify cognitive disorders, we developed first a global cognitive score (GCS) composed of age, sex, MMSE, digit span, RAVLT, trail-making and animal fluency tests. GCS was defined as the disease-state index computed for the group of cognitively normal (CN, N1⁄4138) and Alzheimer’s disease subjects (N1⁄4275) from the independent Amsterdam Dementia Cohort. Thereafter, GCS was computed for all cases in the three cohorts. Finally, GCS (independent variable) was estimated from five (dependent) Muistikko variables, representing Muistikko GCS (MGCS), using linear regression with the PredictND data. In validation, correlation coefficients between GCS and MGCS were defined. In addition, classification accuracies betweenCN andmild-cognitive impairment (MCI), and CN and dementia subjects were computed for MMSE, GCS, and MGCS using cross-validation. Results: Figure 1 shows the distribution of GCS and MGCS in different diagnostic groups in the PredictND cohort. The correlation coefficients between GCS and MGCS were 0.79, 0.76 and 0.62 for the PredictND, VPH-DARE@IT and FINGER cohorts, respectively, using the regression model developed from the PredictND data. Table 2 shows classification results when using MMSE, GCS and MGCS to separate subjects with CN fromMCI and dementia subjects. The accuracy of MGCSwas superior toMMSE andGCS (p<0.05).Conclusions:This study shows that Muistikko web-based cognitive test battery provides useful information about cognitive decline and is able to classify CN fromMCI and dementia. 1 Ngandu, Lancet 2015; 2 Mattila JAlzheimers Dis 2011; 3 van der Flier J Alzheimers Dis 2014.

TAU BURDEN IN OREXINERGIC WAKE-PROMOTING NEURONS IN ALZHEIMER'S DISEASE IN COMPARISON TO CORTICAL BASAL DEGENERATION AND PROGRESSIVE SUPRANUCLEAR PALSY: A NEUROPATHOLOGICAL IMPLICATION IN SLEEP DISTURBANCES

AD 42127 55808 12430 96433 M 60 AD 11511 18442 3589 26487 M 70 AD 7365 13075 2814 18040 M 59 AD 13236 18530 3223 28543 F 60 Jun Yeop Oh, Rana April Eser, Alexander J. Ehrenberg, Sara RoseDunlop, Maria B.Mejia, Cathrine Petersen, Panos Theofilas, William W. Seeley, Christine Walsh, Thomas Neylan, Bruce L. Miller, Helmut Heinsen, Eduardo Alho, Lea T. Grinberg, University of California, San Francisco, San Francisco, CA, USA; University of California, Berkeley, Berkeley, CA, USA; Universiy of W€uerzburg, W€uerzburg, Germany; University of S~ao Paulo, S~ao Paulo, Brazil; University of S~ao Paulo Medical School, S~ao Paulo, Brazil. Contact e-mail: josephoh0517@berkeley.edu

THE SUBCORTICAL SEROTONERGIC DORSAL RAPHE'S LINK TO PROGRESSIVE ALZHEIMER'S DISEASE

O3-04-01 THE SUBCORTICAL SEROTONERGIC DORSAL RAPHE’S LINK TO PROGRESSIVE ALZHEIMER’S DISEASE Austin K. Nguy, Alexander J. Ehrenberg, Panos Theofilas, Sara Dunlop, Ana T. Alho, Renata Elaine Paraizo Leite, Roberta Diehl Rodriguez, Maria B. Mejia, Claudia K. Suemoto, JoseM. Farfel, Renata Eloah de Lucena Ferretti-Rebustini, Livia Polichiso, Camila F. Nascimento, William W. Seeley, Ricardo Nitrini, Carlos Augusto Pasquallucci, Wilson Jacob-Filho, Udo Rueb, Helmut Heinsen, Lea T. Grinberg, University of California, Berkeley, Berkeley, CA, USA; 2 University of California, San Francisco, San Francisco, CA, USA; Hospital Albert Einstein, S~ao Paulo, Brazil; 4 University of S~ao Paulo Medical School, S~ao Paulo, Brazil; 5 University of S~ao Paulo, School of Nursing, S~ao Paulo, Brazil; University of Sao Paulo Medical School, Sao Paulo, Brazil; University of Table 1 Assosiation of grey matter voxels to specific cognitive domains. Number in cell represents the cluster size of significant voxels in specific brain region. Clusters formed based on p-value threshold 3x10 estimated from permutations.

Locus ceruleus volume changes are a promising biomarker for detecting Alzheimer's disease progression in pre-symptomatic stages

with non-fluent variant primary progressive aphasia showed asymmetric binding in the left inferior frontal and parietal cortex (Figure 2). Tracer binding was unexpectedly seen in all 3 patients with FTD due to presumed tau-negative, TDP43-posistive inclusions, particularly in degenerating white matter (Figure 3). 1/2 patients at risk for CTE showed focal AV1451 binding in the left anterior temporal lobe (Figure 4). Conclusions:AV1451 uptake largely conformed to the expected distribution of pathology in non-AD tauopathies, though subcortical signal overlapped with binding in NC. Unexpected AV1451 uptake was also found in patients with presumed tau-negative, FTD-TDP pathology. PET-to-autopsy correlation studies are needed to better characterize these findings.

Lc caudal cells show the earliest vulnerability to Alzheimer's disease

46.4% had low likelihood AD and only 3.8% had intermediate or high likelihood AD. The frequency of AD pathology increased linearly with age (p<0.01) (Figure 1). Ninety-four subjects (51.9%) were free of NFTs and another 78 (43.1%) only had a Braak Stage I or II. Only 8.9% of the sample had neuritic plaques. In the subgroup 50-54 years old (24.3%) we could not find any subject with moderate or high likelihood for pathologic AD. The youngest person with moderate likelihood for pathologic AD was 61 years old. Microinfacrts and small vessel disease were found in 15.9% and 24.7% of the sample, respectively. Lewy bodies were identified in only 2.7% of the sample. Age was not associated to non-AD neuropathologic indices. Conclusions: In a community based sample of persons 50-64 years old, intermediate or high likelihood neuropathologic AD is rare before the age of 60.