Diffusion imaging markers of accelerated aging of the lower cingulum in subjective cognitive decline

IntroductionAlzheimer’s Disease (AD) typically starts in the medial temporal lobe, then develops into a neurodegenerative cascade which spreads to other brain regions. People with subjective cognitive decline (SCD) are more likely to develop dementia, especially in the presence of amyloid pathology. Thus, we were interested in the white matter microstructure of the medial temporal lobe in SCD, specifically the lower cingulum bundle that leads into the hippocampus. Diffusion tensor imaging (DTI) has been shown to differentiate SCD participants who will progress to mild cognitive impairment from those who will not. However, the biology underlying these DTI metrics is unclear, and results in the medial temporal lobe have been inconsistent.MethodsTo better characterize the microstructure of this region, we applied DTI to cognitively normal participants in the Cam-CAN database over the age of 55 with cognitive testing and diffusion MRI available (N = 325, 127 SCD). Diffusion MRI was processed to generate regional and voxel-wise diffusion tensor values in bilateral lower cingulum white matter, while T1-weighted MRI was processed to generate regional volume and cortical thickness in the medial temporal lobe white matter, entorhinal cortex, temporal pole, and hippocampus.ResultsSCD participants had thinner cortex in bilateral entorhinal cortex and right temporal pole. No between-group differences were noted for any of the microstructural metrics of the lower cingulum. However, correlations with delayed story recall were significant for all diffusion microstructure metrics in the right lower cingulum in SCD, but not in controls, with a significant interaction effect. Additionally, the SCD group showed an accelerated aging effect in bilateral lower cingulum with MD, AxD, and RD.DiscussionThe diffusion profiles observed in both interaction effects are suggestive of a mixed neuroinflammatory and neurodegenerative pathology. Left entorhinal cortical thinning correlated with decreased FA and increased RD, suggestive of demyelination. However, right entorhinal cortical thinning also correlated with increased AxD, suggestive of a mixed pathology. This may reflect combined pathologies implicated in early AD. DTI was more sensitive than cortical thickness to the associations between SCD, memory, and age. The combined effects of mixed pathology may increase the sensitivity of DTI metrics to variations with age and cognition

Medial and Lateral Entorhinal Cortex Differentially Excite Deep versus Superficial CA1 Pyramidal Neurons

Although hippocampal CA1 pyramidal neurons (PNs) were thought to comprise a uniform population, recent evidence supports two distinct sublayers along the radial axis, with deep neurons more likely to form place cells than superficial neurons. CA1 PNs also differ along the transverse axis with regard to direct inputs from entorhinal cortex (EC), with medial EC (MEC) providing spatial information to PNs toward CA2 (proximal CA1) and lateral EC (LEC) providing non-spatial information to PNs toward subiculum (distal CA1). We demonstrate that the two inputs differentially activate the radial sublayers and that this difference reverses along the transverse axis, with MEC preferentially targeting deep PNs in proximal CA1 and LEC preferentially exciting superficial PNs in distal CA1. This differential excitation reflects differences in dendritic spine numbers. Our results reveal a heterogeneity in EC-CA1 connectivity that may help explain differential roles of CA1 PNs in spatial and non-spatial learning and memory

Differential Axonal Projection of Mitral and Tufted Cells in the Mouse Main Olfactory System

In the past decade, much has been elucidated regarding the functional organization of the axonal connection of olfactory sensory neurons to olfactory bulb (OB) glomeruli. However, the manner in which projection neurons of the OB process odorant input and send this information to higher brain centers remains unclear. Here, we report long-range, large-scale tracing of the axonal projection patterns of OB neurons using two-photon microscopy. Tracer injection into a single glomerulus demonstrated widely distributed mitral/tufted cell axonal projections on the lateroventral surface of the mouse brain, including the anterior/posterior piriform cortex (PC) and olfactory tubercle (OT). We noted two distinct groups of labeled axons: PC-orienting axons and OT-orienting axons. Each group occupied distinct parts of the lateral olfactory tract. PC-orienting axons projected axon collaterals to a wide area of the PC but only a few collaterals to the OT. OT-orienting axons densely projected axon collaterals primarily to the anterolateral OT (alOT). Different colored dye injections into the superficial and deep portions of the OB external plexiform layer revealed that the PC-orienting axon populations originated in presumed mitral cells and the OT-orienting axons in presumed tufted cells. These data suggest that although mitral and tufted cells receive similar odor signals from a shared glomerulus, they process the odor information in different ways and send their output to different higher brain centers via the PC and alOT

Table_1_On gaps of clinical diagnosis of dementia subtypes: A study of Alzheimer’s disease and Lewy body disease.DOCX

IntroductionAlzheimer’s disease (AD) and Lewy body disease (LBD) are the two most common neurodegenerative dementias and can occur in combination (AD+LBD). Due to overlapping biomarkers and symptoms, clinical differentiation of these subtypes could be difficult. However, it is unclear how the magnitude of diagnostic uncertainty varies across dementia spectra and demographic variables. We aimed to compare clinical diagnosis and post-mortem autopsy-confirmed pathological results to assess the clinical subtype diagnosis quality across these factors.MethodsWe studied data of 1,920 participants recorded by the National Alzheimer’s Coordinating Center from 2005 to 2019. Selection criteria included autopsy-based neuropathological assessments for AD and LBD, and the initial visit with Clinical Dementia Rating (CDR) stage of normal, mild cognitive impairment, or mild dementia. Longitudinally, we analyzed the first visit at each subsequent CDR stage. This analysis included positive predictive values, specificity, sensitivity and false negative rates of clinical diagnosis, as well as disparities by sex, race, age, and education. If autopsy-confirmed AD and/or LBD was missed in the clinic, the alternative clinical diagnosis was analyzed.FindingsIn our findings, clinical diagnosis of AD+LBD had poor sensitivities. Over 61% of participants with autopsy-confirmed AD+LBD were diagnosed clinically as AD. Clinical diagnosis of AD had a low sensitivity at the early dementia stage and low specificities at all stages. Among participants diagnosed as AD in the clinic, over 32% had concurrent LBD neuropathology at autopsy. Among participants diagnosed as LBD, 32% to 54% revealed concurrent autopsy-confirmed AD pathology. When three subtypes were missed by clinicians, “No cognitive impairment” and “primary progressive aphasia or behavioral variant frontotemporal dementia” were the leading primary etiologic clinical diagnoses. With increasing dementia stages, the clinical diagnosis accuracy of black participants became significantly worse than other races, and diagnosis quality significantly improved for males but not females.DiscussionThese findings demonstrate that clinical diagnosis of AD, LBD, and AD+LBD are inaccurate and suffer from significant disparities on race and sex. They provide important implications for clinical management, anticipatory guidance, trial enrollment and applicability of potential therapies for AD, and promote research into better biomarker-based assessment of LBD pathology.</p

Intracranial artery stenosis is associated with cortical thinning in stroke-free individuals of two longitudinal cohorts

We examined the association between asymptomatic intracranial artery stenosis (aICAS) and cortical thickness using brain magnetic resonance morphometry in two cohorts. This cross-sectional study included stroke-free participants from the Northern Manhattan Study (NOMAS) and the National Alzheimer's Coordinating Center (NACC). We represented the predictor aICAS in NOMAS as a continuous global stenosis score reflecting an overall burden of stenosis (possible range 0–44) assessed by magnetic resonance angiography and in NACC as a dichotomous autopsy-determined Circle of Willis (CoW) atherosclerosis (none-mild vs moderate-severe). The primary outcome of interest was total cortical thickness. We analyzed each dataset separately using multivariable linear regression. The analysis included 1209 NOMAS (46% had any stenosis, 5% had ≥70% stenosis of at least one vessel; stenosis score range 0–11) and 392 NACC (36% moderate-severe CoW atherosclerosis) participants. We found an inverse relationship between stenosis score and total cortical thickness (β-estimate [95% confidence interval (CI)]: −2.98 [−5.85, −0.11]) in adjusted models. We replicated these results in NACC (β-estimate [95% CI]: −0.06 [−0.11, −0.003]). Post-hoc, we segregated stenosis scores by location and only posterior circulation stenosis score was associated with total cortical thickness (anterior β-estimate [95% CI]: −0.90 [−5.16, 3.36], posterior β-estimate [95% CI]: −7.25 [−14.30, −0.20]). We found both radiographically and neuropathologically determined aICAS to be associated with global cortical thinning. Interestingly, posterior circulation stenoses appeared to drive this association with global cortical thinning, raising the possibility of pathophysiologic mechanisms for cortical thinning other than impaired hemodynamics. •Asymptomatic intracranial artery stenosis is associated with cortical thinning.•This relationship was independent of vascular risk factors and Alzheimer's disease•Posterior circulation stenoses drove the finding, implying non-hemodynamic cause

Optical Imaging of Postsynaptic Odor Representation in the Glomerular Layer of the Mouse Olfactory Bulb

Olfactory glomeruli are the loci where the first odor-representation map emerges. The glomerular layer comprises exquisite local synaptic circuits for the processing of olfactory coding patterns immediately after their emergence. To understand how an odor map is transferred from afferent terminals to postsynaptic dendrites, it is essential to directly monitor the odor-evoked glomerular postsynaptic activity patterns. Here we report the use of a transgenic mouse expressing a Ca2+-sensitive green fluorescence protein (GCaMP2) under a Kv3.1 potassium-channel promoter. Immunostaining revealed that GCaMP2 was specifically expressed in mitral and tufted cells and a subpopulation of juxtaglomerular cells but not in olfactory nerve terminals. Both in vitro and in vivo imaging combined with glutamate receptor pharmacology confirmed that odor maps reported by GCaMP2 were of a postsynaptic origin. These mice thus provided an unprecedented opportunity to analyze the spatial activity pattern reflecting purely postsynaptic olfactory codes. The odor-evoked GCaMP2 signal had both focal and diffuse spatial components. The focalized hot spots corresponded to individually activated glomeruli. In GCaMP2-reported postsynaptic odor maps, different odorants activated distinct but overlapping sets of glomeruli. Increasing odor concentration increased both individual glomerular response amplitude and the total number of activated glomeruli. Furthermore, the GCaMP2 response displayed a fast time course that enabled us to analyze the temporal dynamics of odor maps over consecutive sniff cycles. In summary, with cell-specific targeting of a genetically encoded Ca2+ indicator, we have successfully isolated and characterized an intermediate level of odor representation between olfactory nerve input and principal mitral/tufted cell output

Associations of NREM Slow Wave Activity and Regional in‐vivo tau PET deposition in black and white community‐dwelling cognitively normal older‐adults with normal sleep

Abstract Background In this proof‐of‐concept study, we examined whether NREM slow wave activity (SWA) is associated with regional in‐vivo tau deposition; and whether race‐specific differences exist in this association, in clinically normal older adults with normal sleep, in the context of Aß. Method This was a cross‐sectional analysis of baseline data from 21 community‐dwelling cognitively normal older‐adults with normal sleep. Participants were matched on age, sex, BMI, and APOE4 carrier status in a 1:3 ratio, blacks: whites. Normal sleep was defined as 6‐9 h of total sleep time and absence of AHI4%>15 and AHI4%>5 with sleepiness. SWA was defined as power between 0.5‐4.0 Hz during NREM with NREM cycles characterized as stages NREM 2‐3 of = 15 min. terminated by rapid eye movement (REM) or wakefulness of = 5 min. Tau burden was assessed using 18F‐PI2620. Linear mixed‐effects models with random intercept and slope were used to assess associations between NREM SWA, and regional in‐vivo tau PET deposition, respectively, controlling for Aß, age, BMI, sex, APOE4‐status, education and other sleep variables. Result Of the 21 participants, 7 (33.3%) were black, 12 (57.1%) were women and 5 (24%) were APOE4 carriers. The mean (SD) age, and education were 69.1 (5.5), and 17.2 (3.8) years respectively. NREM SWA was associated with tau deposition in the entorhinal cortex, inferior and middle temporal ROIs, including gray matter neocortical ROIs i.e., anterior ventral striatum, orbitofrontal, precuneus, superior frontal, lateral temporal and posterior cingulate gyrus cortices (p <.01 for all). Racial differences existed in the entorhinal cortex, and inferior and middle temporal ROIs, including the lateral temporal, parietal, precuneus and posterior cingulate gyrus cortices (p <.02 for all), with black participants having lower tau levels relative to white participants. Divergent NREM SWA and tau associations were observed in the entorhinal cortex, precuneus, and inferior and middle temporal ROIs with NREM SWA negatively correlated with tau‐PET levels in whites and positively correlated in blacks. Conclusion Racial differences in physiological sleep features, uniquely associated with tau levels in the brain, may reflect one mechanism of how sociocultural factors, often through behavioral processes, become physiologically expressed as increased AD‐risk in blacks