Whether hippocampal neurogenesis persists throughout life in the human brain is not fully resolved. Here, we demonstrate that hippocampal neurogenesis is persistent through the tenth decade of life and is detectable in patients with mild cognitive impairments and Alzheimer's disease. In a cohort of 18 participants with a mean age of 90.6 years, Nestin + Sox2 + neural progenitor cells (NPCs) and DCX + neuroblasts and immature neurons were detected, but their numbers greatly varied between participants. Nestin + cells localize in the anterior hippocampus, and NPCs, neuroblasts, and immature neurons are evenly distributed along the anterior to posterior axis. The number of DCX + PCNA + cells is reduced in mild cognitive impairments, and higher numbers of neuroblasts are associated with better cognitive status. The number of DCX + PCNA + cells correlates with functional interactions between presynaptic SNARE proteins. Our results suggest that hippocampal neurogenesis persists in the aged and diseased human brain and that it is possibly associated with cognition.

For research purposes, postmortem MRI of the human brain offers an advantage over in vivo imaging in that a postmortem sample can be sliced for histological examination immediately after the MRI scan (1-13), or otherwise tested in ways that are not appropriate for living subjects (14). However, postmortem imaging of the brain also presents new challenges that have not been dealt with for in vivo imaging. In particular, the MRI properties of postmortem tissue can change rapidly as a result of decomposition and chemical fixation. These largely uncharacterized changes in the tissue properties of the postmortem brain can lead to errors in the interpretation of MR findings, and can pose complications in the selection of appropriate data acquisition parameters. The purpose of this work was to investigate the MR-related changes that occur in a human brain hemisphere during formaldehyde fixation.The goal of chemical fixation is to preserve postmortem tissue in a state similar to that found in vivo (15). This can be accomplished by immersing the brain in a solution that contains a fixative agent such as formaldehyde. Over time, the fixative agent diffuses inward from the surface of the brain, slowing or stopping tissue decomposition. However, until complete fixation occurs, postmortem tissue remains vulnerable to bacterial degradation and autolysis (15). Formaldehyde fixation of the tissue promotes protein cross-linking (16 -18) and immobilization of water molecules and may lead to a reduction of the T 2 relaxation time (19). Conversely, decomposition of the tissue may lead to increased water content or increased water mobility which may increase T 2 values. Thus, T 2 relaxation can potentially provide important information about the changes that occur in brain tissue during fixation.Postmortem brain MRI studies have demonstrated that T 2 values are lower in a fixed postmortem brain than in vivo, for both white and gray matter (20 -23). One investigation indicated that T 2 values at locations near the surface of the brain decreased sharply within the first 7 days of formaldehyde fixation, reaching a plateau after that (up to 5 weeks postmortem) (20). In another study, three fixed brains were each scanned up to 21 times over the course of 3 weeks, and it was shown that T 2 values of tissue located within 1.4 cm of the brain surface decreased sharply and reached a plateau within approximately 5 days postmortem (21). In an 11-week-long study, the T 2 values of frontal gray matter in formaldehyde-fixed brains were observed to decrease sharply in the first 10 h postmortem (22). None of the aforementioned studies explicitly reported on T 2 changes in deep brain tissue, nor have prior studies examined fixed tissue over a period of more than 3 months.Sustained T 2 increases in any kind of fixed postmortem tissue have seldom been reported (14,16). In the most recent study to report such a T 2 increase, a small sample of bovine nasal cartilage was immersed for 9 weeks in 0.1% formalin (ϳ0.04% formaldehyde) solution (16). During th...

The volume of the hippocampus measured with structural magnetic resonance imaging (MRI) is increasingly used as a biomarker for Alzheimer's disease (AD). However, the neuropathologic basis of structural MRI changes in the hippocampus in the elderly has not been directly assessed. Postmortem MRI of the aging human brain, combined with histopathology, could be an important tool to address this issue. Therefore, this study combined postmortem MRI and histopathology in 100 elderly subjects from the Rush Memory and Aging Project and the Religious Orders Study. First, to validate the information contained in postmortem MRI data, we tested the hypothesis that postmortem hippocampal volume is smaller in subjects with clinically diagnosed Alzheimer's disease compared to subjects with mild or no cognitive impairment, as observed in antemortem imaging studies. Subsequently, the relations of postmortem hippocampal volume to AD pathology, Lewy bodies, amyloid angiopathy, gross infarcts, microscopic infarcts, and hippocampal sclerosis were examined. It was demonstrated that hippocampal volume was smaller in persons with a clinical diagnosis of AD compared to those with no cognitive impairment (P = 2.6×10−7) or mild cognitive impairment (P = 9.6×10−7). Additionally, hippocampal volume was related to multiple cognitive abilities assessed proximate to death, with its strongest association with episodic memory. Among all pathologies investigated, the most significant factors related to lower hippocampal volume were shown to be AD pathology (P = 0.0018) and hippocampal sclerosis (P = 4.2×10−7). Shape analysis allowed for visualization of the hippocampal regions most associated with volume loss for each of these two pathologies. Overall, this investigation confirmed the relation of hippocampal volume measured postmortem to clinical diagnosis of AD and measures of cognition, and concluded that both AD pathology and hippocampal sclerosis affect hippocampal volume in old age, though the impacts of each pathology on the shape of the hippocampus may differ.

IntroductionThe molecular underpinnings of the dissociation of cognitive performance and neuropathological burden are poorly understood, and there are currently no known genetic or epigenetic determinants of the dissociation.Methods and findings“Residual cognition” was quantified by regressing out the effects of cerebral pathologies and demographic characteristics on global cognitive performance proximate to death. To identify genes influencing residual cognition, we leveraged neuropathological, genetic, epigenetic, and transcriptional data available for deceased participants of the Religious Orders Study (n = 492) and the Rush Memory and Aging Project (n = 487). Given that our sample size was underpowered to detect genome-wide significance, we applied a multistep approach to identify genes influencing residual cognition, based on our prior observation that independent genetic and epigenetic risk factors can converge on the same locus. In the first step (n = 979), we performed a genome-wide association study with a predefined suggestive p < 10−5, and nine independent loci met this threshold in eight distinct chromosomal regions. Three of the six genes within 100 kb of the lead SNP are expressed in the dorsolateral prefrontal cortex (DLPFC): UNC5C, ENC1, and TMEM106B. In the second step, in the subset of participants with DLPFC DNA methylation data (n = 648), we found that residual cognition was related to differential DNA methylation of UNC5C and ENC1 (false discovery rate < 0.05). In the third step, in the subset of participants with DLPFC RNA sequencing data (n = 469), brain transcription levels of UNC5C and ENC1 were evaluated for their association with residual cognition: RNA levels of both UNC5C (estimated effect = −0.40, 95% CI −0.69 to −0.10, p = 0.0089) and ENC1 (estimated effect = 0.0064, 95% CI 0.0033 to 0.0096, p = 5.7 × 10−5) were associated with residual cognition. In secondary analyses, we explored the mechanism of these associations and found that ENC1 may be related to the previously documented effect of depression on cognitive decline, while UNC5C may alter the composition of presynaptic terminals. Of note, the TMEM106B allele identified in the first step as being associated with better residual cognition is in strong linkage disequilibrium with rs1990622A (r2 = 0.66), a previously identified protective allele for TDP-43 proteinopathy. Limitations include the small sample size for the genetic analysis, which was underpowered to detect genome-wide significance, the evaluation being limited to a single cortical region for epigenetic and transcriptomic data, and the use of categorical measures for certain non-amyloid-plaque, non-neurofibrillary-tangle neuropathologies.ConclusionsThrough a multistep analysis of cognitive, neuropathological, genomic, epigenomic, and transcriptomic data, we identified ENC1 and UNC5C as genes with convergent genetic, epigenetic, and transcriptomic evidence supporting a potential role in the dissociation of cognition and neuropathology in an aging population, and we expa...

Development of a diffusion tensor (DT) template that is representative of the micro-architecture of the human brain is crucial for comparisons of neuronal structural integrity and brain connectivity across populations, as well as for the generation of a detailed white matter atlas. Furthermore, a DT template in ICBM space may simplify consolidation of information from DT, anatomical and functional MRI studies. The previously developed “IIT DT brain template” was produced in ICBM-152 space, based on a large number of subjects from a limited age-range, using data with minimal image artifacts, and non-linear registration. That template was characterized by higher image sharpness, provided the ability to distinguish smaller white matter fiber structures, and contained fewer image artifacts, than several previously published DT templates. However, low-dimensional registration was used in the development of that template, which led to a mismatch of DT information across subjects, eventually manifested as loss of local diffusion information and errors in the final tensors. Also, low-dimensional registration led to a mismatch of the anatomy in the IIT and ICBM-152 templates. In this work, a significantly improved DT brain template in ICBM-152 space was developed, using high-dimensional non-linear registration and the raw data collected for the purposes of the IIT template. The accuracy of inter-subject DT matching was significantly increased compared to that achieved for the development of the IIT template. Consequently, the new template contained DT information that was more representative of single-subject human brain data, and was characterized by higher image sharpness than the IIT template. Furthermore, a bootstrap approach demonstrated that the variance of tensor characteristics was lower in the new template. Additionally, compared to the IIT template, brain anatomy in the new template more accurately matched ICBM-152 space. Finally, spatial normalization of a number of DT datasets through registration to the new and existing IIT templates was improved when using the new template.

The aging brain is vulnerable to a wide array of neuropathologies. Prior work estimated that the three most studied of these, Alzheimer’s disease (AD), infarcts, and Lewy bodies, account for about 40% of the variation in late life cognitive decline. However, that estimate did not incorporate many other diseases that are now recognized as potent drivers of cognitive decline (e.g. limbic predominant age-related TDP-43 encephalopathy [LATE-NC], hippocampal sclerosis, other cerebrovascular conditions). We examined the degree to which person-specific cognitive decline in old age is driven by a wide array of neuropathologies. 1,164 deceased participants from two longitudinal clinical-pathologic studies, the Rush Memory and Aging Project and Religious Orders Study, completed up to 24 annual evaluations including 17 cognitive performance tests and underwent brain autopsy. Neuropathologic examinations provided 11 pathologic indices, including markers of AD, non-AD neurodegenerative diseases (i.e. LATE-NC, hippocampal sclerosis, Lewy bodies), and cerebrovascular conditions (i.e. macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis). Mixed effects models examined the linear relation of pathologic indices with global cognitive decline, and random change point models examined the relation of the pathologic indices with the onset of terminal decline and rates of preterminal and terminal decline. Cognition declined an average of about 0.10 unit per year (estimate = -0.101, SE = 0.003, p &lt; 0.001) with considerable heterogeneity in rates of decline (variance estimate for the person-specific slope of decline was 0.0094, p &lt; 0.001). When considered separately, 10 of the 11 pathologic indices were associated with faster decline and accounted for between 2 and 34% of the variation in decline, respectively. When considered simultaneously, the 11 pathologic indices together accounted for a total of 43% of the variation in decline; AD-related indices accounted for 30–36% of the variation, non-AD neurodegenerative indices 4–10%, and cerebrovascular indices 3–8%. Finally, the 11 pathologic indices combined accounted for less than a third of the variation in the onset of terminal decline (28%) and rates of preterminal (32%) and terminal decline (19%). Although age-related neuropathologies account for a large proportion of the variation in late life cognitive decline, considerable variation remains unexplained even after considering a wide array of neuropathologies. These findings highlight the complexity of cognitive aging and have important implications for the ongoing effort to develop effective therapeutics and identify novel treatment targets.

ObjectiveTo examine the associations of physical activity, Alzheimer disease (AD), and other brain pathologies and cognition in older adults.MethodsWe studied 454 brain autopsies from decedents in a clinical-pathologic cohort study. Nineteen cognitive tests were summarized in a global cognitive score. Total daily physical activity summarized continuous multiday recordings of activity during everyday living in the community setting. A global motor ability score summarized 10 supervised motor performance tests. A series of regression analyses were used to examine associations of physical activity, AD, and other brain pathologies with global cognition proximate to death controlling for age, sex, education, and motor abilities.ResultsHigher levels of total daily activity (estimate 0.148, 95% confidence interval 0.053–0.244, SE 0.049, p = 0.003) and better motor abilities (estimate 0.283, 95% confidence interval, 0.175–0.390, SE 0.055, p < 0.001) were independently associated with better cognition. These independent associations remained significant when terms for AD and other pathologies were added as well as in sensitivity analyses excluding cases with poor cognition or dementia. Adding interaction terms, the associations of total daily activity and motor abilities with cognition did not vary in individuals with and without dementia. The associations of AD and other pathologies with cognition did not vary with the levels of total daily activity or motor abilities.ConclusionsPhysical activity in older adults may provide cognitive reserve to maintain function independent of the accumulation of diverse brain pathologies. Further studies are needed to identify the molecular mechanisms underlying this potential reserve and to ensure the causal effects of physical activity.

The development of a brain template for diffusion tensor imaging (DTI) is crucial for comparisons of neuronal structural integrity and brain connectivity across populations, as well as for the development of a white matter atlas. Previous efforts to produce a DTI brain template have been compromised by factors related to image quality, the effectiveness of the image registration approach, the appropriateness of subject inclusion criteria, the completeness and accuracy of the information summarized in the final template. The purpose of this work was to develop a DTI human brain template using techniques that address the shortcomings of previous efforts. Therefore, data containing minimal artifacts were first obtained on 67 healthy human subjects selected from an age-group with relatively similar diffusion characteristics (20–40 years of age), using an appropriate DTI acquisition protocol. Non-linear image registration based on mean diffusion-weighted and fractional anisotropy images was employed. DTI brain templates containing median and mean tensors were produced in ICBM-152 space and made publicly available. The resulting set of DTI templates is characterized by higher image sharpness, provides the ability to distinguish smaller white matter fiber structures, contains fewer image artifacts, than previously developed templates, and to our knowledge, is one of only two templates produced based on a relatively large number of subjects. Furthermore, median tensors were shown to better preserve the diffusion characteristics at the group level than mean tensors. Finally, white matter fiber tractography was applied on the template and several fiber-bundles were traced.