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1.  An Alzheimer’s Disease Genetic Risk Score Predicts Longitudinal Thinning of Hippocampal Complex Subregions in Healthy Older Adults 
eNeuro  2016;3(3):ENEURO.0098-16.2016.
Variants at 21 genetic loci have been associated with an increased risk for Alzheimer’s disease (AD). An important unresolved question is whether multiple genetic risk factors can be combined to increase the power to detect changes in neuroimaging biomarkers for AD. We acquired high-resolution structural images of the hippocampus in 66 healthy, older human subjects. For 45 of these subjects, longitudinal 2-year follow-up data were also available. We calculated an additive AD genetic risk score for each participant and contrasted this with a weighted risk score (WRS) approach. Each score included APOE (apolipoprotein E), CLU (clusterin), PICALM (phosphatidylinositol binding clathrin assembly protein), and family history of AD. Both unweighted risk score (URS) and WRS correlated strongly with the percentage change in thickness across the whole hippocampal complex (URS: r = −0.40; p = 0.003; WRS: r = −0.25, p = 0.048), driven by a strong relationship to entorhinal cortex thinning (URS: r = −0.35; p = 0.009; WRS: r = −0.35, p = 0.009). By contrast, at baseline the risk scores showed no relationship to thickness in any hippocampal complex subregion. These results provide compelling evidence that polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex. This work also supports the paradigm of studying genetic risk for disease in healthy volunteers. Together, these findings will inform clinical trial design by supporting the idea that genetic prescreening in healthy control subjects can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness.
PMCID: PMC4945997  PMID: 27482534
clinical trials; normal aging; polygenic risk score; preclinical Alzheimer's disease; structural MRI
2.  Corneal endothelial cells possess an elaborate multipolar shape to maximize the basolateral to apical membrane area 
Molecular Vision  2016;22:31-39.
The corneal endothelium is widely believed to consist of geometrically regular cells interconnected by junctional complexes. However, while en face visualization of the endothelial apical surface reveals characteristic polygonal borders, the overall form of the component cells has rarely been observed.
To visualize the shape of individual endothelial cells within the native monolayer, two independent Cre/LoxP-based cell labeling approaches were used. In the first, a P0-Cre mouse driver strain was bred to an R26-tdTomato reporter line to map neural crest–derived endothelial cells with cytosolic red fluorescent protein. In the second, HPRT-Cre induction of small numbers of green and red fluorescent protein–filled cells within a background of unlabeled cells was achieved using a dual-color reporter system, mosaic analysis with double markers (MADM). Selective imaging of the endothelial lateral membranes at different apicobasal levels was accomplished after staining with antibodies to ZO-1 and the neural cell adhesion molecule (NCAM).
When viewed in their entirety in whole-mount preparations, fluorescent protein–filled cells appear star-shaped, extending multiple dendritic processes that radiate outward in the plane of the monolayer. Examination of rare cases where cells expressing different fluorescent proteins lie directly adjacent to one another reveals that these long processes undergo extensive interdigitation. The resulting overlap allows individual cells to extend over a greater area than if the cell boundaries were mutually exclusive. Anti-NCAM staining of these interlocking peripheral cell extensions reveals an elaborate system of lateral membrane folds that, when viewed in optical sections, increase in complexity from the apical to the basal pole. This not only produces a substantial increase in the basolateral, relative to the apical, membrane but also greatly extends the paracellular pathway as a highly convoluted space.
Our analysis indicates that, far from being simple polygonal prisms, endothelial cells possess an elaborate multipolar shape. Their unusual geometry may be essential for the endothelium to carry out its role as the principal regulator of corneal extracellular fluid flux, and thus ultimately of tissue clarity.
PMCID: PMC4814271  PMID: 27081293
3.  A cortical pathway to olfactory naming: evidence from primary progressive aphasia 
Brain  2013;136(4):1245-1259.
It is notoriously difficult to name odours. Without the benefit of non-olfactory information, even common household smells elude our ability to name them. The neuroscientific basis for this olfactory language ‘deficit’ is poorly understood, and even basic models to explain how odour inputs gain access to transmodal representations required for naming have not been put forward. This study used patients with primary progressive aphasia, a clinical dementia syndrome characterized by primary deficits in language, to investigate the interactions between olfactory inputs and lexical access by assessing behavioural performance of olfactory knowledge and its relationship to brain atrophy. We specifically hypothesized that the temporal pole would play a key role in linking odour object representations to transmodal networks, given its anatomical proximity to olfactory and visual object processing areas. Behaviourally, patients with primary progressive aphasia with non-semantic subtypes were severely impaired on an odour naming task, in comparison with an age-matched control group. However, with the availability of picture cues or word cues, odour matching performance approached control levels, demonstrating an inability to retrieve but not to recognize the name and nature of the odorant. The magnitude of cortical thinning in the temporal pole was found to correlate with reductions in odour familiarity and odour matching to visual cues, whereas the inferior frontal gyrus correlated with both odour naming and matching. Volumetric changes in the mediodorsal thalamus correlated with the proportion of categorical mismatch errors, indicating a possible role of this region in error-signal monitoring to optimize recognition of associations linked to the odour. A complementary analysis of patients with the semantic subtype of primary progressive aphasia, which is associated with marked temporopolar atrophy, revealed much more pronounced impairments of odour naming and matching. In identifying the critical role of the temporal pole and inferior frontal gyrus in transmodal linking and verbalization of olfactory objects, our findings provide a new neurobiological foundation for understanding why even common odours are hard to name.
PMCID: PMC3613711  PMID: 23471695
olfaction; odour object knowledge; recognition; naming; language; semantics; temporal pole; inferior frontal gyrus; primary progressive aphasia; human brain; MRI
4.  Superior Memory and Higher Cortical Volumes in Unusually Successful Cognitive Aging 
It is “normal” for old age to be associated with gradual decline in memory and brain mass. However, there are anecdotal reports of individuals who seem immune to age-related memory impairment, but these individuals have not been studied systematically. This study sought to establish that such cognitive SuperAgers exist and to determine if they were also resistant to age-related loss of cortical brain volume. SuperAgers were defined as individuals over age 80 with episodic memory performance at least as good as normative values for 50- to 65-year-olds. Cortical morphometry of the SuperAgers was compared to two cognitively normal cohorts: age-matched elderly and 50- to 65-year-olds. The SuperAgers’ cerebral cortex was significantly thicker than their healthy age-matched peers and displayed no atrophy compared to the 50- to 65-year-old healthy group. Unexpectedly, a region of left anterior cingulate cortex was significantly thicker in the SuperAgers than in both elderly and middle-aged controls. Our findings identify cognitive and neuroanatomical features of a cohort that appears to resist average age-related changes of memory capacity and cortical volume. A better understanding of the underlying factors promoting this potential trajectory of unusually successful aging may provide insight for preventing age-related cognitive impairments or the more severe changes associated with Alzheimer’s disease. (JINS, 2012, 18, 1081–1085)
PMCID: PMC3547607  PMID: 23158231
Structural magnetic resonance imaging (MRI); Neuropsychology; Dementia; Freesurfer; Elderly; Neuroimaging
5.  APOE E4 is a susceptibility factor in amnestic but not aphasic dementias 
The goal of this study was to determine if the apolipoprotein ε (ApoE) gene, which is a well-established susceptibility factor for Alzheimer’s disease (AD) pathology in typical amnestic dementias, may also represent a risk factor in the language-based dementia, primary progressive aphasia (PPA). Apolipoprotein E genotyping was obtained from 149 patients with a clinical diagnosis of PPA, 330 cognitively healthy individuals (NC) and 179 patients with a clinical diagnosis of probable Alzheimer’s disease (PrAD). Allele frequencies were compared among the groups. Analyses were also completed by gender and in two subsets of PPA patients, one where patients were classified by subtype (logopenic, agrammatic and semantic) and another where pathologic data were available. The allele frequencies for the PPA group (ε2:5%, ε3:79.5%, and ε4:15.4%) showed a distribution similar to the NC group but significantly different from the PrAD group. The presence of an ε4 allele did not influence the age of symptom onset or aid in the prediction of AD pathology in PPA. These data show that the ε4 polymorphism, which is a well-known risk factor for AD pathology in typical amnestic dementias, has no similar relationship to the clinical syndrome of PPA or its association with AD pathology.
PMCID: PMC3100354  PMID: 21346518
6.  Anatomy of Language Impairments in Primary Progressive Aphasia 
Primary progressive aphasia (PPA) is a clinical dementia syndrome characterized by progressive decline in language function but relative sparing of other cognitive domains. There are three recognized PPA variants: agrammatic, semantic, and logopenic. Although each PPA subtype is characterized by the nature of the principal deficit, individual patients frequently display subtle impairments in additional language domains. The present study investigated the distribution of atrophy related to performance in specific language domains (i.e., grammatical processing, semantic processing, fluency, and sentence repetition) across PPA variants to better understand the anatomical substrates of language. Results showed regionally specific relationships, primarily in the left hemisphere, between atrophy and impairments in language performance. Most notable was the neuroanatomical distinction between fluency and grammatical processing. Poor fluency was associated with regions dorsal to the traditional boundaries of Broca’s area in the inferior frontal sulcus and the posterior middle frontal gyrus, whereas grammatical processing was associated with more widespread atrophy, including the inferior frontal gyrus and supramarginal gyrus. Repetition performance was correlated with atrophy in the posterior superior temporal gyrus. The correlation of atrophy with semantic processing impairment was localized to the anterior temporal poles. Atrophy patterns were more closely correlated with domain-specific performance than with subtype. These results show that PPA reflects a selective disruption of the language network as a whole, with no rigid boundaries between subtypes. Further, these atrophy patterns reveal anatomical correlates of language that could not have been surmised in patients with aphasia resulting from cerebrovascular lesions.
PMCID: PMC3112000  PMID: 21368046
7.  Accelerated turnover of taste bud cells in mice deficient for the cyclin-dependent kinase inhibitor p27Kip1 
BMC Neuroscience  2011;12:34.
Mammalian taste buds contain several specialized cell types that coordinately respond to tastants and communicate with sensory nerves. While it has long been appreciated that these cells undergo continual turnover, little is known concerning how adequate numbers of cells are generated and maintained. The cyclin-dependent kinase inhibitor p27Kip1 has been shown to influence cell number in several developing tissues, by coordinating cell cycle exit during cell differentiation. Here, we investigated its involvement in the control of taste cell replacement by examining adult mice with targeted ablation of the p27Kip1 gene.
Histological and morphometric analyses of fungiform and circumvallate taste buds reveal no structural differences between wild-type and p27Kip1-null mice. However, when examined in functional assays, mutants show substantial proliferative changes. In BrdU incorporation experiments, more S-phase-labeled precursors appear within circumvallate taste buds at 1 day post-injection, the earliest time point examined. After 1 week, twice as many labeled intragemmal cells are present, but numbers return to wild-type levels by 2 weeks. Mutant taste buds also contain more TUNEL-labeled cells and 50% more apoptotic bodies than wild-type controls. In normal mice, p27 Kip1 is evident in a subset of receptor and presynaptic taste cells beginning about 3 days post-injection, correlating with the onset of taste cell maturation. Loss of gene function, however, does not alter the proportions of distinct immunohistochemically-identified cell types.
p27Kip1 participates in taste cell replacement by regulating the number of precursor cells available for entry into taste buds. This is consistent with a role for the protein in timing cell cycle withdrawal in progenitor cells. The equivalence of mutant and wild-type taste buds with regard to cell number, cell types and general structure contrasts with the hyperplasia and tissue disruption seen in certain developing p27Kip1-null sensory organs, and may reflect a compensatory capability inherent in the regenerative taste system.
PMCID: PMC3110126  PMID: 21507264

Results 1-7 (7)