Hippocampal Diffusion Research Articles

Identification of diffusion, kurtosis, and propagator MRI markers of Alzheimer’s disease pathology in post-mortem human tissue

Abstract Alzheimer’s disease (AD) is an irreversible degenerative brain disease affecting 6.7 million Americans and while the hallmark AD pathologies of plaques and tangles follow a stereotyped progression during the course of the disease, clinical markers for early diagnosis are lacking and approximately 20% of all AD cases are ultimately misdiagnosed. Conventional clinical MRI is capable of reporting severe brain atrophy, but fails to recognize earlier biomarkers associated with more subtle cellular and molecular changes. Microstructural Magnetic Resonance Imaging (MRI) techniques are promising to address this challenge and may sensitively detect and distinguish tissue degeneration, tauopathies, and beta amyloid plaques to improve accuracy of diagnosis and enable early detection. The objective of this study was to identify and compare the most promising microstructural markers of AD pathology over a range of diffusion and relaxometry-based MRI techniques from conventional to advanced. To accomplish this, we performed MRI microscopy of post-mortem human temporal lobe specimens (n = 14) at high resolution and image quality and evaluated the relative influence of metrics across multiple microstructural MRI frameworks using principal component analysis (PCA). We performed additional correlation analysis between metrics identified by PCA and clinical neuropathology scores of Braak stage and plaque and tangle load. Hippocampal diffusion and restriction metrics contributed most to the first principal component, and the correlation with Braak score was positive for diffusivity and negative for restriction metrics. Additionally, the MAP-MRI propagator anisotropy (PA) metric of microscale anisotropy was strongly and negatively correlated with AD pathology while the conventional fractional anisotropy (FA) metric showed little or no correspondence and there was not a strong association between FA and PA by PCA. Entorhinal cortex findings were minimal except for reported increases in restriction due to plaque content. Taken together, our findings suggest that microstructural MRI metrics of restriction and diffusion are most prominent and may reflect degenerative processes in AD brain tissue and that microscale anisotropy may be more advantageous than conventional FA for the detection of subtle and earlier cellular changes in AD.

Transient global amnesia and hippocampal diffusion restriction: an overlooked radiological finding.

Transient global amnesia (TGA) is characterized by isolated sudden anterograde amnesia. Diffusion restriction can be observed in the hippocampus on DWI-MRI at varying rates in TGA patients. This study analyzes the prevalence and characteristics of the hippocampal diffusion restriction (HDR), its relationship with vascular risk factors, and the prevalence of lesions overlooked in routine reports. 91 patients diagnosed with TGA at a tertiary hospital between 2011 and 2022 were evaluated retrospectively. The mean age was 64.8 ± 7.3years, and 63.7% of patients were female. 75.8% of the patients had at least one vascular risk factor. Focal diffusion restriction was detected in 17 patients (18.5%) on DWI-MRI, with only one being extra-hippocampal. 81.2% of HDR was detected when DWI-MRI scan was performed between 12 and 96h after the onset of symptoms. HDR was detected most when the imaging was performed in 24 to 48h (p = 0.03). There was no correlation between the duration of symptoms and the detection rates of HDR (p = 0.55). In 9 patients (53% of 17) diffusion restriction was not specified in routine radiology reports. Although focal ischemia, venous flow abnormalities, migraine and epileptic phenomena have been suggested in its etiology, TGA is a clinical condition of which pathophysiology has not been determined clearly. Signal changes observed in DWI-MRI has led to discussions that cerebrovascular etiology may play a role, yet more comprehensive studies are required to prevent and manage TGA. HDRs can be overlooked in routine reports. Therefore, the DWI-MRI images of patients with TGA should be examined vigilantly.

Imaging Biomarker for Early-Stage Alzheimer Disease: Utility of Hippocampal Histogram Analysis of Diffusion Metrics.

Biomarkers have been required for diagnosing early Alzheimer disease. We assessed the utility of hippocampal diffusion parameters for diagnosing Alzheimer disease pathology in mild cognitive impairment. Sixty-nine patients with mild cognitive impairment underwent both CSF measurement and multi-shell diffusion imaging at 3T. Based on the CSF biomarker level, patients were classified according to the presence (Alzheimer disease group, n = 35) or absence (non-Alzheimer disease group, n = 34) of Alzheimer disease pathology. Neurite orientation dispersion and density imaging and diffusion tensor imaging parametric maps were generated. Two observers independently created the hippocampal region of interest for calculating histogram features. Interobserver correlations were calculated. The statistical significance of intergroup differences was tested by using the Mann-Whitney U test. Logistic regression analyses, using both the clinical scale and the image data, were used to predict intergroup differences, after which group discriminations were performed. Most intraclass correlation coefficient values were between 0.59 and 0.91. In the regions of interest of both observers, there were statistically significant intergroup differences for the left-side neurite orientation dispersion and density imaging-derived intracellular volume fraction, right-side diffusion tensor imaging-derived mean diffusivity, left-side diffusion tensor imaging-derived mean diffusivity, axial diffusivity, and radial diffusivity (P < .05). Logistic regression models revealed that diffusion parameters contributed the most to discriminating between the groups. The areas under the receiver operating characteristic curve for the regions of interest of observers A/B were 0.69/0.68, 0.69/0.68, 0.73/0.68, 0.71/0.68, and 0.68/0.68 for the left-side intracellular volume fraction (mean), right-side mean diffusivity (mean), left-side mean diffusivity (10th percentile), axial diffusivity (10th percentile), and radial diffusivity (mean). Hippocampal diffusion parameters might be useful for the early diagnosis of Alzheimer disease.

Hippocampal microstructure, but not macrostructure, mediates age differences in episodic memory.

Separate unimodal magnetic resonance imaging (MRI) literatures have shown that hippocampal gray matter macrostructure (volume) and microstructure (diffusion) decline with age and relate to episodic memory performance, with multimodal MRI studies reporting that episodic memory may be better explained by a combination of these metrics. However, these effects are often assessed independent of age or only within older adults and therefore do not address whether these distinct modalities explain variance in (i.e, mediate) the effect of age on episodic memory. Here, we simultaneously examined the unique and joint contribution of hippocampal volume and diffusion to age-related differences in episodic memory in 83 younger and 61 older adults who underwent a T1- and diffusion-weighted MRI and completed the Rey Auditory Verbal Learning Test. As expected, older age was significantly related to smaller volume and higher diffusion (intracellular, dispersion, and free) in bilateral hippocampus and to worse episodic memory performance (immediate and delayed free recall, recognition). Structural equation modelling revealed that the age-memory relationship was significantly mediated by hippocampal diffusion, but not volume. A non-significant influential indirect effect further revealed that the structural metrics did not jointly mediate the age-memory relationship. Together, these findings indicate that hippocampal microstructure uniquely contributes to age-related differences in episodic memory and suggest that volume and diffusion capture distinct neurobiological properties of hippocampal gray matter.

Long period changes of hippocampal diffusion kurtosis imaging and its correlation with cognitive dysfunction after incomplete cerebral ischemia-reperfusion in rats.

This study aims to summarize the changes of functional diffusion kurtosis imaging (DKI) parameters in the bilateral hippocampal CA1 region of the hemorrhagic shock reperfusion (HSR) model of rats and their correlation with cognitive dysfunction. Adult male Sprague-Dawley rats (9-10weeks of age, weighing 350-400g) were randomized into the HSR group (n = 30) and the sham-operated group (Sham) (n = 30). Rats in the HSR group and the Sham group were subdivided into five time points (1, 2, 4, 8, and 12weeks) for examination. Diffusion kurtosis imaging (DKI) was performed. Cognitive dysfunction was analyzed by the Morris Water Maze. The correlation between the DKI parameters and cognitive dysfunction was analyzed by the Spearman correlation. In the HSR group, the values of axial kurtosis (Ka), radial kurtosis (Kr), and mean kurtosis (MK) in the bilateral hippocampal CA1 of rats at 1, 2, 4, 8 and 12weeks after the surgery were significantly higher. The rats in the HSR group had significantly longer escape latency than in the Sham group. The rats in the HSR group had significantly shorter time and shorter distance in target quadrant than those in the Sham group. The escape latency had positive correlation with MK, Ka, and Kr. The distance and the time in target quadrant had negative correlation with MK, Ka, and Kr. The parameters get from the DKI could accurately evaluate the abnormal blood perfusion and microstructure changes in hippocampal CA1 area of the incomplete cerebral ischemia reperfusion rats induced by HSR. MK, Ka, and Kr values could reflect the decreased learning and memory ability in HSR rat model.

Recurrent Transient Global Amnesia with Contralateral Hippocampal Restricted Diffusion MRI Changes: A Case Report (P4-4.001)

<h3>Objective:</h3> To describe a case of recurrent transient global amnesia (TGA) with temporally spaced bilateral hippocampal restricted diffusion on MRI. <h3>Background:</h3> TGA is defined as a sudden onset of anterograde and retrograde amnesia that lasts 24 hours, and can recur over time. Multiple mechanisms have been proposed to explain this condition, including cortical spreading depression, venous congestion, hypoxic-ischemic events, epileptic phenomena, and ineffective connectivity in bilateral hippocampal structures (subiculum-fimbria, entorhinal cortex-CA4) due to vascular impairment. Bilateral hippocampal involvement has been described in the setting of TGA with focal mesial hippocampal diffusion restriction in diffusion-weighted imaging (DWI). Herein we postulate that recurrent TGA results from neuroanatomical network and vascular supply impairment. <h3>Design/Methods:</h3> Retrospectively chart review of a patient with recurrent TGA. <h3>Results:</h3> A 59-year woman with history of head injury in her 30s, migraine, B12 deficiency, benign paroxysmal positional vertigo, degenerative spine disease, post-traumatic stress disorder, and tobacco use, presented with typical symptoms of TGA. Brain MRI demonstrated punctate restricted diffusion in the right hippocampus. A repeat MRI sixteen months after showed complete resolution in DWI. The patient presented with a second similar episode twelve months later; MRI demonstrated punctate lesions in DWI in the left hippocampus. The patient had a negative evaluation for stroke and epilepsy. Of note the patient did report a migraine during each episode. <h3>Conclusions:</h3> To our knowledge, this is the first reported case of recurrent TGA in which there is temporally spaced bilateral hippocampal restricted diffusion on MRI. Our case report aligns with recent theories that recurrent TGA might be related to neuroanatomical network and vascular supply impairment rather than an isolated lesional defect. <b>Disclosure:</b> Dr. Mora Munoz has nothing to disclose. Dr. McKee has nothing to disclose. Dr. Buletko has nothing to disclose. Dr. Mays has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dynamed Plus (EBSCO Industries, Inc.). Dr. Mays has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for CoolTech Medical. Dr. Mays has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biodelivery Science International. Dr. Mays has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen. Dr. Mays has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Abbvie. Dr. Mays has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for DynaMed Plus .

Teaching Neuro Images : Hippocampal foci of restricted diffusion in transient global amnesia

A 71-year-old man presented with a sudden onset of anterograde amnesia and repetitive questioning. Symptoms lasted 12 hours. MRI performed 48 hours after onset showed right hippocampal restricted diffusion foci (figure, A and B).

Higher hippocampal diffusivity values in welders are associated with greater R2* in the red nucleus and lower psychomotor performance

IntroductionChronic excessive welding exposure may be related to higher metal accumulation and structural differences in different subcortical structures. We examined how welding affected brain structures and their associations with metal exposure and neurobehavioral consequences. MethodsStudy includes 42 welders and 31 controls without a welding history. Welding-related structural differences were assessed by volume and diffusion tensor imaging (DTI) metrics in basal ganglia, red nucleus (RN), and hippocampus. Metal exposure was estimated by both exposure questionnaires and whole blood metal levels. Brain metal accumulations were estimated by R1 (for Mn) and R2* (for Fe). Neurobehavioral status was assessed by standard neuropsychological tests. ResultsCompared to controls, welders displayed higher hippocampal mean (MD), axial (AD), and radial diffusivity (RD) (p’s < 0.036), but similar DTI or volume in other ROIs (p’s > 0.117). Welders had higher blood metal levels (p’s < 0.004), higher caudate and RN R2* (p’s < 0.014), and lower performance on processing/psychomotor speed, executive function, and visuospatial processing tasks (p’s < 0.046). Higher caudate and RN R2* were associated with higher blood Fe and Pb (p’s < 0.043), respectively. RN R2* was a significant predictor of all hippocampal diffusivity metrics (p’s < 0.006). Higher hippocampal MD and RD values were associated with lower Trail Making Test-A scores (p’s < 0.025). A mediation analysis of both groups revealed blood Pb indirectly affected hippocampal diffusivity via RN R2* (p’s < 0.041). DiscussionWelding-related higher hippocampal diffusivity metrics may be associated with higher RN R2* and lower psychomotor speed performance. Future studies are warranted to test the role of Pb exposure in these findings.

Hippocampal Metabolic Alterations in Amyotrophic Lateral Sclerosis: A Magnetic Resonance Spectroscopy Study

Magnetic resonance spectroscopy (MRS) in amyotrophic lateral sclerosis (ALS) has been overwhelmingly applied to motor regions to date and our understanding of frontotemporal metabolic signatures is relatively limited. The association between metabolic alterations and cognitive performance in also poorly characterised. In a multimodal, prospective pilot study, the structural, metabolic, and diffusivity profile of the hippocampus was systematically evaluated in patients with ALS. Patients underwent careful clinical and neurocognitive assessments. All patients were non-demented and exhibited normal memory performance. 1H-MRS spectra of the right and left hippocampi were acquired at 3.0T to determine the concentration of a panel of metabolites. The imaging protocol also included high-resolution T1-weighted structural imaging for subsequent hippocampal grey matter (GM) analyses and diffusion tensor imaging (DTI) for the tractographic evaluation of the integrity of the hippocampal perforant pathway zone (PPZ). ALS patients exhibited higher hippocampal tNAA, tNAA/tCr and tCho bilaterally, despite the absence of volumetric and PPZ diffusivity differences between the two groups. Furthermore, superior memory performance was associated with higher hippocampal tNAA/tCr bilaterally. Both longer symptom duration and greater functional disability correlated with higher tCho levels. Hippocampal 1H-MRS may not only contribute to a better academic understanding of extra-motor disease burden in ALS, but given its sensitive correlations with validated clinical metrics, it may serve as practical biomarker for future clinical and clinical trial applications. Neuroimaging protocols in ALS should incorporate MRS in addition to standard structural, functional, and diffusion sequences.

Longitudinal hippocampal diffusion-weighted imaging and T2 relaxometry demonstrate regional abnormalities which are stable and predict subfield pathology intemporallobeepilepsy.

High-resolution (1 mm isotropic) diffusion tensor imaging (DTI) of the hippocampus in temporal lobe epilepsy (TLE) patients has shown patterns of hippocampal subfield diffusion abnormalities, which were consistent with hippocampal sclerosis (HS) subtype on surgical histology. The objectives of this longitudinal imaging study were to determine the stability of focal hippocampus diffusion changes over time in TLE patients, compare diffusion and quantitative T2 abnormalities of the sclerotic hippocampus, and correlate presurgical mean diffusivity (MD) and T2 maps with postsurgical histology. Nineteen TLE patients and 19 controls underwent two high-resolution (1 mm isotropic) DTI and 1.1 × 1.1 × 1 mm3 T2 relaxometry scans (in a subset of 16 TLE patients and 9 controls) of the hippocampus at 3T, with a 2.6 ± 0.8 year inter-scan interval. Within-participant hippocampal volume, MD and T2 were compared between the scans. Contralateral hippocampal changes 2.3 ± 1.0 years after surgery and ipsilateral preoperative MD maps versus postoperative subfield histopathology were evaluated in eight patients who underwent surgical resection of the hippocampus. Reduced volume and elevated MD and T2 of sclerotic hippocampi remained unchanged between longitudinal scans. Focal regions of elevated MD and T2 in bilateral hippocampi of HS TLE were detected consistently at both scans. Regions of high MD and T2 correlated and remained consistent over time. Volume, MD, and T2 remained unchanged in postoperative contralateral hippocampus. Regional elevations of MD identified subfield neuron loss on postsurgical histology with 88% sensitivity and 88% specificity. Focal T2 elevations identified subfield neuron loss with 75% sensitivity and 88% specificity. Diffusion and T2 abnormalities in ipsilateral and contralateral hippocampi remained unchanged between the scans suggesting permanent microstructural alterations. MD and T2 demonstrated good sensitivity and specificity to detect hippocampal subfield neuron loss on postsurgical histology, supporting the potential that high-resolution hippocampal DTI and T2 could be used to diagnose HS subtype before surgery.

Acute neurological disease as a trigger or co-occurrence of transient global amnesia: a case series and systematic review.

Transient global amnesia (TGA) represents a benign neurological syndrome of unknown pathophysiology, often accompanied by vanishing hippocampal punctate lesions on diffusion-weighted imaging (hippocampal punctate diffusion lesion, HPDL). The recent literature suggests that TGA may be triggered by acute neurological conditions. To study patients with TGA triggered by an acute neurological disease. We retrospectively reviewed patients from two neurology centres with TGA (with or without HPDL) in whom an acute neurological condition could be identified as trigger. We also performed a systematic review of the literature of this situation using predefined search terms. We identified 38 patients (median age 62years, 55.3% female): 6 from our centres and 32 from the literature. Acute neurovascular diseases that preceded or were associated with TGA included ischemic and haemorrhagic strokes, convexity subarachnoid haemorrhage, and reversible cerebral vasoconstriction syndrome. As non-vascular acute neurological diseases, we identified migraine and peripheral-origin vertigo. The clinical manifestation of the neurological trigger showed a variable temporal relation with TGA onset; in some cases preceding and in others co-occurring with TGA manifestation. In some cases, presumed neurological triggers were asymptomatic and diagnosed from the neuroimaging done for the TGA. Acute vascular and non-vascular neurological events may trigger TGAs or may occur simultaneously. In the first case, such an acute neurological disease may activate direct pathways within the nervous systems leading to TGA, or alternatively elicit a bodily sympathetic overactivity cascade. In the second case, both neurological events may be the result of a common external stressor.

Associations of plasma neurofilament light protein levels with cognitive functions and brain structure parameters

AbstractBackgroundNeurofilament light (NfL) protein level is considered a non‐specific marker of neurodegeneration. NfL levels have been associated with established, non‐blood based neurodegenerative markers, including cognitive performance and reduced brain volume. However, most studies were small (N&lt;300), and compared levels in patients (MCI, Alzheimer’s disease) with those in healthy controls. We investigated to what extent NfL levels are associated with cognitive performance and MRI measures of brain volume and microstructure, in a large non‐demented population‐based sample.MethodThe analyses were based on 4,578 participants (30‐95 years) of the Rhineland Study, a community‐based cohort study in Bonn, Germany. Plasma NfL levels were measured on the SIMOA platform. We assessed cognitive performance with tests for memory, processing speed, executive function and crystallized intelligence and an eye movement (EM) test battery. 3,206 persons underwent structural and diffusion weighted MR imaging. Imaging outcomes included volumetric measures (total brain, grey matter, white matter, hippocampus); diffusion tensor measures (fractional anisotropy; mean, radial, and axial diffusivity); and neurite orientation dispersion and density imaging (NODDI) measures. We used multivariable regression models to assess the relation between NfL levels and cognitive performance and MRI measures with adjustment for possible confounders.ResultAcross all participants, we found only negligibly small associations between NfL levels and cognitive performance, brain volumetric and diffusion tensor measures. However, age‐stratified analyses revealed that in age 40‐49 and from age 60 onwards higher NfL levels were associated with lower orientation dispersion index (ODI). In the 70‐ to 79‐year‐olds, higher NfL levels were additionally associated with higher prosaccade accuracy, higher mean, axial and radial diffusivity, higher extracellular and lower intracellular volume fraction and a lower neurite density index. In the 80+‐year‐olds, NfL levels were negatively associated with hippocampal and white matter volume and positively associated with fractional anisotropy and radial diffusivity.ConclusionHigher NfL levels were associated with smaller hippocampal volume and diffusion tensor and NODDI measures in older subjects. In younger persons (up to age 70 years), NfL levels were only associated with ODI. This suggests that NfL level is a sensitive marker of subtle changes in brain microstructure, especially in old age.

Reader Response: Amnestic Syndrome and Bilateral Hippocampal Diffusion Abnormalities From Opioid Use.

Reports of opioid-associated amnestic syndrome1 have increased with the rising use of opioids, particularly among young men.2 At our institution in British Columbia, which has one of the highest rates of opioid-related hospitalizations in Canada,3 we have observed at least 3 such cases in the last 4 years with similar initial imaging. All were positive for fentanyl on urine toxicology. One of these was associated with a delayed leukoencephalopathy causing akinetic mutism, which developed roughly 3 weeks after initial presentation with isolated anterograde amnesia. Diffuse delayed leukoencephalopathy was recently reported as an unexpected outcome of acute opioid-associated amnestic syndrome.4 It would be interesting to know the eventual outcome in this case, and if any follow-up was provided. Monitoring for a delayed leukoencephalopathy should be considered by neurologists caring for these vulnerable patients. Prognosis should be deferred until these patients have been stable for at least 1 month after presentation.

Author Response: Amnestic Syndrome and Bilateral Hippocampal Diffusion Abnormalities From Opioid Use.

We thank Drs. Randhawa and Chen for their comments on our article.1 We appreciate their insightful comments regarding the possibility of delayed leukoencephalopathy in patients with acute opioid-associated amnestic syndrome.2 Our patient1 did indeed have interval follow-up at 1, 3, and 34 months after the index hospitalization. By 1 month, the patient returned to his previous cognitive baseline with no reported memory deficits. Since his hospitalization, he has not experienced any new neurologic symptoms, including headaches, vision changes, weakness, sensory changes, tremor, bradykinesia, or gait changes. No further brain imaging was indicated. We agree that patients with opioid-associated amnestic syndrome warrant close follow-up given the possibility of unforeseen neurologic sequelae. Going forward, it will be important to understand the risk factors predisposing to opioid-associated delayed leukoencephalopathy and the latent period range after opioid exposure.

Correlations between hippocampal functional connectivity, structural changes, and clinical data in patients with relapsing-remitting multiple sclerosis: a case-control study using multimodal magnetic resonance imaging.

Multiple sclerosis is associated with structural and functional brain alterations leading to cognitive impairments across multiple domains including attention, memory, and the speed of information processing. The hippocampus, which is a brain important structure involved in memory, undergoes microstructural changes in the early stage of multiple sclerosis. In this study, we analyzed hippocampal function and structure in patients with relapsing-remitting multiple sclerosis and explored correlations between the functional connectivity of the hippocampus to the whole brain, changes in local brain function and microstructure, and cognitive function at rest. We retrospectively analyzed data from 20 relapsing-remitting multiple sclerosis patients admitted to the Department of Neurology at the China-Japan Union Hospital of Jilin University, China, from April 2015 to November 2019. Sixteen healthy volunteers were recruited as the healthy control group. All participants were evaluated using a scale of extended disability status and the Montreal cognitive assessment within 1 week before and after head diffusion tensor imaging and functional magnetic resonance imaging. Compared with the healthy control group, the patients with relapsing-remitting multiple sclerosis had lower Montreal cognitive assessment scores and regions of simultaneously enhanced and attenuated whole-brain functional connectivity and local functional connectivity in the bilateral hippocampus. Hippocampal diffusion tensor imaging data showed that, compared with the healthy control group, patients with relapsing-remitting multiple sclerosis had lower hippocampal fractional anisotropy values and higher mean diffusivity values, suggesting abnormal hippocampal structure. The left hippocampus whole-brain functional connectivity was negatively correlated with the Montreal cognitive assessment score (r = -0.698, P = 0.025), and whole-brain functional connectivity of the right hippocampus was negatively correlated with extended disability status scale score (r = -0.649, P = 0.042). The mean diffusivity value of the left hippocampus was negatively correlated with the Montreal cognitive assessment score (r = -0.729, P = 0.017) and positively correlated with the extended disability status scale score (r = 0.653, P = 0.041). The right hippocampal mean diffusivity value was positively correlated with the extended disability status scale score (r = 0.684, P = 0.029). These data suggest that the functional connectivity and presence of structural abnormalities in the hippocampus in patients with relapse-remission multiple sclerosis are correlated with the degree of cognitive function and extent of disability. This study was approved by the Ethics Committee of China-Japan Union Hospital of Jilin University, China (approval No. 201702202) on February 22, 2017.

Neuroimaging measures of iron and gliosis explain memory performance in aging.

Evidence from animal and histological studies has indicated that accumulation of iron in the brain results in reactive gliosis that contributes to cognitive deficits. The current study extends these findings to human cognitive aging and suggests that magnetic resonance imaging (MRI) techniques like quantitative relaxometry can be used to study iron and its effects in vivo. The effects of iron on microstructure and memory performance were examined using a combination of quantitative relaxometry and multicompartment diffusion imaging in 35 young (21.06 ± 2.18 years) and 28 older (72.58 ± 6.47 years) adults, who also completed a memory task. Replicating past work, results revealed age‐related increases in iron content (R2*) and diffusion, and decreases in memory performance. Independent of age group, iron content was significantly related to restricted (intracellular) diffusion in regions with low‐moderate iron (hippocampus, caudate) and to all diffusion metrics in regions with moderate‐high iron (putamen, globus pallidus). This pattern is consistent with different stages of iron‐related gliosis, ranging from astrogliosis that may influence intracellular diffusion to microglial proliferation and increased vascular permeability that may influence all sources of diffusion. Further, hippocampal restricted diffusion was significantly related to memory performance, with a third of this effect related to iron content; consistent with the hypothesis that higher iron‐related astrogliosis in the hippocampus is associated with poorer memory performance. These results demonstrate the sensitivity of MRI to iron‐related gliosis and extend our understanding of its impact on cognition by showing that this relationship also explains individual differences in memory performance.

Structural and functional hippocampal alterations in Multiple sclerosis and neuromyelitis optica spectrum disorder

Background: Hippocampal involvement may differ between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Objective: To investigate the morphometric, diffusion and functional alterations in hippocampus in MS and NMOSD and the clinical significance. Methods: A total of 752 participants including 236 MS, 236 NMOSD and 280 healthy controls (HC) were included in this retrospective multi-center study. The hippocampus and subfield volumes, fractional anisotropy (FA) and mean diffusivity (MD), amplitude of low frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and their associations with clinical variables were investigated. Results: The hippocampus showed significantly lower volume, FA and greater MD in MS compared to NMOSD and HC (p < 0.05), while no abnormal ALFF or DC was identified in any group. Hippocampal subfields were affected in both diseases, though subiculum, presubiculum and fimbria showed significantly lower volume only in MS (p < 0.05). Significant correlations between diffusion alterations, several subfield volumes and clinical variables were observed in both diseases, especially in MS (R = −0.444 to 0.498, p < 0.05). FA and MD showed fair discriminative power between MS and HC, NMOSD and HC (AUC > 0.7). Conclusions: Hippocampal atrophy and diffusion abnormalities were identified in MS and NMOSD, partly explaining how clinical disability and cognitive impairment are differentially affected.

Toward individualized prediction of seizure recurrence: Hippocampal neuroimaging features in a cohort of patients from a first seizure clinic

PurposeWe performed an exploratory analysis of electroencephalography (EEG) and neuroimaging data from a cohort of 51 patients with first seizure (FS) and new-onset epilepsy (NOE) to identify variables, or combinations of variables, that might discriminate between clinical trajectories over a one-year period and yield potential biomarkers of epileptogenesis. MethodsPatients underwent EEG, hippocampal and whole brain structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS) within six weeks of the index seizure, and repeat neuroimaging one year later. We classified patients with FS as having had a single seizure (FS-SS) or having converted to epilepsy (FS-CON) after one year and performed logistic regression to identify combinations of variables that might discriminate between FS-SS and FS-CON, and between FS-SS and the combined group FS-CON + NOE. We performed paired t-tests to assess changes in quantitative variables over time. ResultsSeveral combinations of variables derived from hippocampal structural MRI, DTI, and MRS provided excellent discrimination between FS-SS and FS-CON in our sample, with areas under the receiver operating curve (AUROC) ranging from 0.924 to 1. They also provided excellent discrimination between FS-SS and the combined group FS-CON + NOE in our sample, with AUROC ranging from 0.902 to 1. After one year, hippocampal fractional anisotropy (FA) increased bilaterally, hippocampal radial diffusivity (RD) decreased on the side with the larger initial measurement, and whole brain axial diffusivity (AD) increased in patients with FS-SS; hippocampal volume decreased on the side with the larger initial measurement, hippocampal FA increased bilaterally, hippocampal RD decreased bilaterally and whole brain AD, FA and mean diffusivity increased in the combined group FS-CON + NOE (corrected threshold for significance, q = 0.017). ConclusionWe propose a prospective, multicenter study to develop and test models for the prediction of seizure recurrence in patients after a first seizure, based on hippocampal neuroimaging. Further longitudinal neuroimaging studies in patients with a first seizure and new-onset epilepsy may provide clues to the microstructural changes occurring at the earliest stages of epilepsy and yield biomarkers of epileptogenesis.

Microstructural Plasticity in the Hippocampus of Healthy Older Adults after Acute Exercise.

The hippocampus experiences structural and functional decline with age and is a critical region for memory and many cognitive processes. Exercise is beneficial for the aging brain and shows preferential benefits for hippocampal volume, activation, and memory-related cognitive processes. However, research thus far has primarily focused on the effects of exercise on long-term volumetric changes in the hippocampus using structural magnetic resonance imaging. Critically, microstructural alterations within the hippocampus over short time intervals are associated with neuroplasticity and cognitive changes that do not alter its volume but are still functionally relevant. However, it is not yet known if microstructural neuroplasticity occurs in the hippocampus in response to a single session of exercise. We used a within-subject design to determine if a 30-min bout of moderate-intensity aerobic exercise altered bilateral hippocampal diffusion tensor imaging measures in healthy older adults (n = 30) compared with a seated rest control condition. Significantly lower fractional anisotropy and higher mean diffusivity were found after exercise relative to seated rest within the bilateral hippocampus, and this effect was driven by higher radial diffusivity. No significant differences in axial diffusivity were observed. These findings suggest that a single exercise session can lead to microstructural alterations in the hippocampus of healthy older adults. These differences may be associated with changes in the extracellular space and glial, synaptic, and dendritic processes within the hippocampus. Repeated microstructural alterations resulting from acute bouts of exercise may accumulate and precede larger volumetric and functional improvements in the hippocampus.

Dairy-Derived Emulsifiers in Infant Formula Show Marginal Effects on the Plasma Lipid Profile and Brain Structure in Preterm Piglets Relative to Soy Lecithin.

Breastfed infants have higher intestinal lipid absorption and neurodevelopmental outcomes compared to formula-fed infants, which may relate to a different surface layer structure of fat globules in infant formula. This study investigated if dairy-derived emulsifiers increased lipid absorption and neurodevelopment relative to soy lecithin in newborn preterm piglets. Piglets received a formula diet containing soy lecithin (SL) or whey protein concentrate enriched in extracellular vesicles (WPC-A-EV) or phospholipids (WPC-PL) for 19 days. Both WPC-A-EV and WPC-PL emulsions, but not the intact diets, increased in vitro lipolysis compared to SL. The main differences of plasma lipidomics analysis were increased levels of some sphingolipids, and lipid molecules with odd-chain (17:1, 19:1, 19:3) as well as mono- and polyunsaturated fatty acyl chains (16:1, 20:1, 20:3) in the WPC-A-EV and WPC-PL groups and increased 18:2 fatty acyls in the SL group. Indirect monitoring of intestinal triacylglycerol absorption showed no differences between groups. Diffusor tensor imaging measurements of mean diffusivity in the hippocampus were lower for WPC-A-EV and WPC-PL groups compared to SL indicating improved hippocampal maturation. No differences in hippocampal lipid composition or short-term memory were observed between groups. In conclusion, emulsification of fat globules in infant formula with dairy-derived emulsifiers altered the plasma lipid profile and hippocampal tissue diffusivity but had limited effects on other absorptive and learning abilities relative to SL in preterm piglets.