Test-retest reliability and longitudinal analysis of automated hippocampal subregion volumes in healthy ageing and Alzheimer's disease populations

The hippocampal formation is a complex brain structure that is important in cognitive processes such as memory, mood, reward processing and other executive functions. Histological and neuroimaging studies have implicated the hippocampal region in neuropsychiatric disorders as well as in neurodegenerative diseases. This highly plastic limbic region is made up of several subregions that are believed to have different functional roles. Therefore, there is a growing interest in imaging the subregions of the hippocampal formation rather than modelling the hippocampus as a homogenous structure, driving the development of new automated analysis tools. Consequently, there is a pressing need to understand the stability of the measures derived from these new techniques. In this study, an automated hippocampal subregion segmentation pipeline, released as a developmental version of Freesurfer (v6.0), was applied to T1-weighted magnetic resonance imaging (MRI) scans of 22 healthy older participants, scanned on 3 separate occasions and a separate longitudinal dataset of 40 Alzheimer's disease (AD) patients. Test-retest reliability of hippocampal subregion volumes was assessed using the intra-class correlation coefficient (ICC), percentage volume difference and percentage volume overlap (Dice). Sensitivity of the regional estimates to longitudinal change was estimated using linear mixed effects (LME) modelling. The results show that out of the 24 hippocampal subregions, 20 had ICC scores of 0.9 or higher in both samples; these regions include the molecular layer, granule cell layer of the dentate gyrus, CA1, CA3 and the subiculum (ICC > 0.9), whilst the hippocampal fissure and fimbria had lower ICC scores (0.73-0.88). Furthermore, LME analysis of the independent AD dataset demonstrated sensitivity to group and individual differences in the rate of volume change over time in several hippocampal subregions (CA1, molecular layer, CA3, hippocampal tail, fissure and presubiculum). These results indicate that this automated segmentation method provides a robust method with which to measure hippocampal subregions, and may be useful in tracking disease progression and measuring the effects of pharmacological intervention

A protocol for manual segmentation of medial temporal lobe subregions in 7 Tesla MRI

Recent advances in MRI and increasing knowledge on the characterization and anatomical variability of medial temporal lobe (MTL) anatomy have paved the way for more specific subdivisions of the MTL in humans. In addition, recent studies suggest that early changes in many neurodegenerative and neuropsychiatric diseases are better detected in smaller subregions of the MTL rather than with whole structure analyses. Here, we developed a new protocol using 7 Tesla (T) MRI incorporating novel anatomical findings for the manual segmentation of entorhinal cortex (ErC), perirhinal cortex (PrC; divided into area 35 and 36), parahippocampal cortex (PhC), and hippocampus; which includes the subfields subiculum (Sub), CA1, CA2, as well as CA3 and dentate gyrus (DG) which are separated by the endfolial pathway covering most of the long axis of the hippocampus. We provide detailed instructions alongside slice-by-slice segmentations to ease learning for the untrained but also more experienced raters. Twenty-two subjects were scanned (19–32 yrs, mean age = 26 years, 12 females) with a turbo spin echo (TSE) T2-weighted MRI sequence with high-resolution oblique coronal slices oriented orthogonal to the long axis of the hippocampus (in-plane resolution 0.44 × 0.44 mm2) and 1.0 mm slice thickness. The scans were manually delineated by two experienced raters, to assess intra- and inter-rater reliability. The Dice Similarity Index (DSI) was above 0.78 for all regions and the Intraclass Correlation Coefficients (ICC) were between 0.76 to 0.99 both for intra- and inter-rater reliability. In conclusion, this study presents a fine-grained and comprehensive segmentation protocol for MTL structures at 7 T MRI that closely follows recent knowledge from anatomical studies. More specific subdivisions (e.g. area 35 and 36 in PrC, and the separation of DG and CA3) may pave the way for more precise delineations thereby enabling the detection of early volumetric changes in dementia and neuropsychiatric diseases

Segmenting subregions of the human hippocampus on structural magnetic resonance image scans: An illustrated tutorial

BACKGROUND: The hippocampus plays a central role in cognition, and understanding the specific contributions of its subregions will likely be key to explaining its wide-ranging functions. However, delineating substructures within the human hippocampus in vivo from magnetic resonance image scans is fraught with difficulties. To our knowledge, the extant literature contains only brief descriptions of segmentation procedures used to delineate hippocampal subregions in magnetic resonance imaging/functional magnetic resonance imaging studies. // METHODS: Consequently, here we provide a clear, step-by-step and fully illustrated guide to segmenting hippocampal subregions along the entire length of the human hippocampus on 3T magnetic resonance images. // RESULTS: We give a detailed description of how to segment the hippocampus into the following six subregions: dentate gyrus/Cornu Ammonis 4, CA3/2, CA1, subiculum, pre/parasubiculum and the uncus. Importantly, this in-depth protocol incorporates the most recent cyto- and chemo-architectural evidence and includes a series of comprehensive figures which compare slices of histologically stained tissue with equivalent 3T images. // CONCLUSION: As hippocampal subregion segmentation is an evolving field of research, we do not suggest this protocol is definitive or final. Rather, we present a fully explained and expedient method of manual segmentation which remains faithful to our current understanding of human hippocampal neuroanatomy. We hope that this 'tutorial'-style guide, which can be followed by experts and non-experts alike, will be a practical resource for clinical and research scientists with an interest in the human hippocampus

J Magn Reson Imaging

PurposeChronic hypoxemia is the prime cause of fetal brain injury and long-term sequelae such as neurodevelopmental compromise, seizures and cerebral palsy. This study aims to investigate the impact of chronic hypoxemia on neonatal brains, and follow developmental alterations and adaptations non-invasively in a guinea pig model.Materials and MethodsThirty guinea pigs underwent either normoxic and hypoxemic conditions during the critical stage of brain development (0.7 gestation) and studied prenatally (n=16) or perinatally (n=14). Fourteen newborns (7 hypoxia and 7 normoxia group) were scanned longitudinally to characterize physiological and morphological alterations, and axonal myelination and injury using in vivo DTI, T2 mapping, and T2-weighted MRI. Sixteen fetuses (8 hypoxia and 8 normoxia) were studied ex vivo to assess hypoxia-induced neuronal injury/loss using Nissl staining and quantitative reverse transcriptase Polymerase Chain Reaction methods.ResultsDevelopmental brains in the hypoxia group showed lower fractional anisotropy in the corpus callosum (\ue2\u2c6\u201912%, p=0.02) and lower T2 values in the hippocampus (\ue2\u2c6\u201916%, p=0.003) compared with the normoxia group with no differences in the cortex (p>0.07), indicating vulnerability of the hippocampus and cerebral white matter during early development. Fetal guinea pig brains with chronic hypoxia demonstrated an over-tenfold increase in expression levels of hypoxia index genes such as erythropoietin and HIF-1\uce\ub1, and an over 40% reduction in neuronal density, confirming prenatal brain damage.ConclusionIn vivo MRI measurement, such as DTI and T2 mapping, provides quantitative parameters to characterize neuro-developmental abnormalities and to monitor the impact of prenatal insult on the postnatal brain maturation of guinea pigs.DP00187-5/DP/NCCDPHP CDC HHS/United StatesP30 AG035982/AG/NIA NIH HHS/United StatesP30 AG035982/AG/NIA NIH HHS/United StatesP30 HD002528/HD/NICHD NIH HHS/United StatesP30 HD002528/HD/NICHD NIH HHS/United StatesR01 HL049041/HL/NHLBI NIH HHS/United StatesR01 HL049041-13/HL/NHLBI NIH HHS/United StatesR03 HD062734/HD/NICHD NIH HHS/United StatesR03 HD062734/HD/NICHD NIH HHS/United StatesS10 RR029577/RR/NCRR NIH HHS/United StatesS10 RR29577/RR/NCRR NIH HHS/United StatesUL1 RR033179/RR/NCRR NIH HHS/United StatesUL1RR033179/RR/NCRR NIH HHS/United States2016-09-01T00:00:00Z25504885PMC446805

Multi-modal characterization of rapid anterior hippocampal volume increase associated with aerobic exercise.

The hippocampus has been shown to demonstrate a remarkable degree of plasticity in response to a variety of tasks and experiences. For example, the size of the human hippocampus has been shown to increase in response to aerobic exercise. However, it is currently unknown what underlies these changes. Here we scanned sedentary, young to middle-aged human adults before and after a six-week exercise intervention using nine different neuroimaging measures of brain structure, vasculature, and diffusion. We then tested two different hypotheses regarding the nature of the underlying changes in the tissue. Surprisingly, we found no evidence of a vascular change as has been previously reported. Rather, the pattern of changes is better explained by an increase in myelination. Finally, we show hippocampal volume increase is temporary, returning to baseline after an additional six weeks without aerobic exercise. This is the first demonstration of a change in hippocampal volume in early to middle adulthood suggesting that hippocampal volume is modulated by aerobic exercise throughout the lifespan rather than only in the presence of age related atrophy. It is also the first demonstration of hippocampal volume change over a period of only six weeks, suggesting gross morphometric hippocampal plasticity occurs faster than previously thought

Radiological-pathological correlation in Alzheimer's disease : systematic review of antemortem MRI findings

Background: The standard method of ascertaining Alzheimer’s disease (AD) remains postmortem assessment of amyloid plaques and neurofibrillary degeneration. Vascular pathology, Lewy bodies, TDP-43, and hippocampal sclerosis are frequent comorbidities. There is therefore a need for biomarkers that can assess these aetiologies and provide a diagnosis in vivo. Objective: We conducted a systematic review of published radiological-pathological correlation studies to determine the relationship between antemortem magnetic resonance imaging (MRI) and neuropathological findings in AD. Methods: We explored PubMed in June-July 2015 using “Alzheimer’s disease” and combinations of radiological and pathological terms. After exclusion following screening and full-text assessment of the 552 extracted manuscripts, three others were added from their reference list. In fine, we report results based on 27 articles. Results: Independently of normal age-related brain atrophy, AD pathology is associated with whole-brain and hippocampal atrophy and ventricular expansion as observed on T1-weighted images. Moreover, cerebral amyloid angiopathy and cortical microinfarcts are also related to brain volume loss in AD. Hippocampal sclerosis and TDP-43 are respectively associated with hippocampal and medial temporal lobe atrophy. Brain volume loss correlates more strongly with tangles than with any other pathological finding. White matter hyperintensities observed on proton density, T2-weighted and FLAIR images are strongly related to vascular pathologies, but are also associated with other histological changes such as gliosis or demyelination. Discussion: Cerebral atrophy and white matter changes in the living brain reflect underlying neuropathology and may be detectable using antemortem MRI. In vivo MRI may therefore be an avenue for AD pathological staging

Glutamate Imaging of Mouse Models of Neurodegeneration

Malfunctions in the glutamatergic system of the central nervous system have been implicated in neurodegenerative diseases such as Alzheimer’s disease (AD), tauopathies, and Parkinson’s disease (PD). A non-invasive measurement of glutamate would enhance our understanding of neurodegenerative processes and potentially facilitate early diagnosis. The current method for measuring glutamate in vivo is proton magnetic resonance spectroscopy (1HMRS) although it has poor spatial resolution and weak sensitivity to glutamate changes. The primary objective of this thesis was to measure pathology induced changes in glutamate levels in mouse models of neurodegeneration using a novel magnetic resonance imaging technique, glutamate chemical exchange saturation transfer (GluCEST) imaging. Several studies were performed in three mouse models of neurodegeneration: the APP-PS1 transgenic model of amyloid-beta pathology of AD, the PS19 transgenic model of tau pathology, and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model of PD. Glutamate levels derived from GluCEST imaging were correlated with results from 1HMRS and immunohistochemistry (IHC). The primary IHC antibodies that were investigated include markers of phosphorylated tau protein, synapse density, neuron density, glial cell reactivity, a glutamate transporter, and an NMDA receptor. GluCEST contrast correlated with 1HMRS-derived glutamate levels in the striatum of APP-PS1 mice (R2=0.91) and the thalamus of PS19 mice (R2=0.64). However, GluCEST detected deficits in PS19 mice four months earlier than 1HMRS, highlighting the method’s enhanced sensitivity to glutamate. Demonstrating the advantage of high spatial resolution, GluCEST imaging measured sub-hippocampal dynamics in glutamate levels in the aging PS19 mouse. A gradient in glutamate levels along the mouse hippocampus was also measured in vivo using GluCEST. While hippocampal glutamate levels were significantly decreased in early stages of PS19 tauopathy, glutamate levels in the dentate gyrus (DG) and cornu ammonis (CA1) increased at 9-13 months. Decreased GluCEST was concurrent with synapse loss and occurred before structural volume loss. Elevated GluCEST was associated with glial fibrillary acidic protein (GFAP) immunostaining in late stages of the PS19 tauopathy model and in the striatum of the MPTP PD model. Results of this work demonstrate the use of GluCEST imaging to study regional and temporal variations in glutamate in different pathologies associated with neurodegeneration