Clusters of secretagogin-expressing neurons in the aged human olfactory tract lack terminal differentiation.

Expanding the repertoire of molecularly diverse neurons in the human nervous system is paramount to characterizing the neuronal networks that underpin sensory processing. Defining neuronal identities is particularly timely in the human olfactory system, whose structural differences from nonprimate macrosmatic species have recently gained momentum. Here, we identify clusters of bipolar neurons in a previously unknown outer "shell" domain of the human olfactory tract, which express secretagogin, a cytosolic Ca(2+) binding protein. These "shell" neurons are wired into the olfactory circuitry because they can receive mixed synaptic inputs. Unexpectedly, secretagogin is often coexpressed with polysialylated-neural cell adhesion molecule, ß-III-tubulin, and calretinin, suggesting that these neurons represent a cell pool that might have escaped terminal differentiation into the olfactory circuitry. We hypothesized that secretagogin-containing "shell" cells may be eliminated from the olfactory axis under neurodegenerative conditions. Indeed, the density, but not the morphological or neurochemical integrity, of secretagogin-positive neurons selectively decreases in the olfactory tract in Alzheimer's disease. In conclusion, secretagogin identifies a previously undescribed cell pool whose cytoarchitectonic arrangements and synaptic connectivity are poised to modulate olfactory processing in humans.

Neuropathological correlates of dopaminergic imaging in Alzheimer's disease and Lewy body dementias.

Investigation of dopaminergic transporter loss in vivo using (123)I-N-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane single photon emission computed tomography has been widely used as a diagnostic aid in Lewy body disease. However, it is not clear whether the pathological basis for the imaging changes observed reflects loss of dopaminergic transporter expressing neurons because of cell death or dysfunctional neurons due to possible nigral and/or striatal neurodegenerative pathology. We aimed to investigate the influence of nigral neuronal loss as well as nigral (α-synuclein, tau) and striatal (α-synuclein, tau, amyloid ß) pathology on striatal uptake in a cohort of autopsy-confirmed Alzheimer's disease (n = 4), dementia with Lewy bodies (n = 7) and Parkinson's disease dementia (n = 12) cases. Subjects underwent ante-mortem dopaminergic scanning and post-mortem assessments (mean interval 3.7 years). Striatal binding (caudate, anterior and posterior putamen) was estimated using region of interest procedures while quantitative neuropathological measurements of α-synuclein, tau and amyloid ß were carried out. Similarly, nigral neuronal density was assessed quantitatively. Stepwise linear regression was performed to identify significant pathological predictors of striatal binding. In all striatal regions, image uptake was associated with nigral dopaminergic neuronal density (P ≤ 0.04) but not α-synuclein (P ≥ 0.46), tau (P ≥ 0.18) or amyloid ß (P ≥ 0.22) burden. The results suggest that reduced uptake in vivo may be influenced considerably by neuronal loss rather than the presence of pathological lesions, in particular those related to Alzheimer's disease and Lewy body dementias. However, dysfunctional nigral neurons may have an additional effect on striatal uptake in vivo but their respective role remains to be elucidated.