Exercise moderates age-related atrophy of the medial temporal lobe

ABSTRACTA better understanding of early brain changes that precede loss of independence in diseases like Alzheimer’s disease (AD) is critical for development of disease-modifying therapies. Quantitative MRI, such as T2 relaxometry, can identify microstructural changes relevant to early stages of pathology. Recent evidence suggests heterogeneity of T2 may be a more informative measure of early pathology than absolute T2. Here we test whether T2 markers of brain integrity precede the volume changes we know are present in established AD and whether such changes are most marked in medial temporal lobe (MTL) subfields known to be most affected early in AD. We show that T2 heterogeneity was greater in people with mild cognitive impairment (MCI; n=49) compared to healthy older controls (n=99) in all MTL subfields, but this increase was greatest in MTL cortices, and smallest in dentate gyrus. This reflects the spatio-temporal progression of neurodegeneration in AD. T2 heterogeneity in the entorhinal cortex also predicted cognitive decline over a year in people with MCI, where measures of volume or T2 in any other subfield or whole hippocampus could not. Increases in T2 heterogeneity in MTL cortices may reflect localised pathological change and may present as one of the earliest detectible brain changes prior to atrophy. Finally, we describe a mechanism by which memory, as measured by accuracy and reaction time on a paired associate learning task, deteriorates with age. Age-related memory deficits were explained in part by lower subfield volumes, which in turn were directly associated with greater T2 heterogeneity. We propose that tissue with high T2 heterogeneity represents extant tissue at risk of permanent damage but with the potential for therapeutic rescue. This has implications for early detection of neurodegenerative disease.

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Pentyl-4-yn-valproic acid enhances both spatial and avoidance learning and attenuates age-related NCAM-mediated neuroplastic decline within the rat medial temporal lobe

Journal of Neurochemistry ◽

10.1046/j.1471-4159.2001.00411.x ◽

2001 ◽

Vol 78 (4) ◽

pp. 704-714 ◽

Cited By ~ 31

Author(s):

Keith J. Murphy ◽

Gerard B. Fox ◽

Andrew G. Foley ◽

Helen C. Gallagher ◽

Alan O'Connell ◽

...

Keyword(s):

Valproic Acid ◽

Temporal Lobe ◽

Avoidance Learning ◽

Medial Temporal Lobe ◽

Age Related

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Magnetic resonance imaging brain atrophy assessment in primary age-related tauopathy (PART)

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0842-z ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 4

Author(s):

Miguel Quintas-Neves ◽

Merilee A. Teylan ◽

Lilah Besser ◽

João Soares-Fernandes ◽

Charles N. Mock ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Semantic Memory ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Resonance Imaging ◽

Medial Temporal Lobe Atrophy ◽

Braak Staging ◽

Age Related ◽

Lobe Atrophy

AbstractAlzheimer disease (AD) is a neurodegenerative disorder characterized pathologically by the accumulation of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFTs). Recently, primary age-related tauopathy (PART) has been described as a new anatomopathological disorder where NFTs are the main feature in the absence of neuritic plaques. However, since PART has mainly been studied in post-mortem patient brains, not much is known about the clinical or neuroimaging characteristics of PART. Here, we studied the clinical brain imaging characteristics of PART focusing on neuroanatomical vulnerability by applying a previously validated multiregion visual atrophy scale. We analysed 26 cases with confirmed PART with paired clinical magnetic resonance imaging (MRI) acquisitions. In this selected cohort we found that upon correcting for the effect of age, there is increased atrophy in the medial temporal region with increasing Braak staging (r = 0.3937, p = 0.0466). Upon controlling for Braak staging effect, predominantly two regions, anterior temporal (r = 0.3638, p = 0.0677) and medial temporal (r = 0.3836, p = 0.053), show a trend for increased atrophy with increasing age. Moreover, anterior temporal lobe atrophy was associated with decreased semantic memory/language (r = − 0.5823, p = 0.0056; and r = − 0.6371, p = 0.0019, respectively), as was medial temporal lobe atrophy (r = − 0.4445, p = 0.0435). Overall, these findings support that PART is associated with medial temporal lobe atrophy and predominantly affects semantic memory/language. These findings highlight that other factors associated with aging and beyond NFTs could be involved in PART pathophysiology.

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Age-related alterations in prelimbic cortical neuron Arc expression vary by behavioral state and cortical layer

10.1101/2020.08.11.247262 ◽

2020 ◽

Author(s):

Abbi R. Hernandez ◽

Leah M. Truckenbrod ◽

Maya E. Barrett ◽

Katelyn N. Lubke ◽

Benjamin J. Clark ◽

...

Keyword(s):

Prefrontal Cortex ◽

Cortical Neuron ◽

Long Range ◽

Temporal Lobe ◽

Cortical Neurons ◽

Medial Temporal Lobe ◽

Perirhinal Cortex ◽

Early Gene ◽

Projection Neurons ◽

Age Related

AbstractPrefrontal cortical and medial temporal lobe connectivity is critical for higher cognitive functions that decline in older adults. Likewise, these cortical areas are among the first to show anatomical, functional, and biochemical alterations in advanced age. The prelimbic subregion of the prefrontal cortex and the perirhinal cortex of the medial temporal lobe are densely reciprocally connected and well-characterized as undergoing age-related neurobiological changes that correlate with behavioral impairment. Despite this fact, it remains to be determined how changes within these brain regions manifest as alterations in their functional connectivity. In our previous work, we observed an increased probability of age-related dysfunction for perirhinal cortical neurons that projected to the prefrontal cortex in old rats compared to neurons that were not identified as projection neurons. The current study was designed to investigate the extent to which aged prelimbic cortical neurons also had altered patterns of Arc expression during behavior, and if this was more evident in those cells that had long-range projections to the perirhinal cortex. The expression patterns of the immediate-early gene Arc were quantified in behaviorally characterized rats that also received the retrograde tracer cholera toxin B (CTB) in the perirhinal cortex to identify projection neurons to this region. As in our previous work, the current study found that CTB+ cells were more active than those that did not have the tracer. Moreover, there were age-related reductions in prelimbic cortical neuron Arc expression that correlated with a reduced ability of aged rats to multitask. Unlike the perirhinal cortex, however, the age-related reduction in Arc expression was equally likely in CTB+ and CTB− negative cells. Thus, the selective vulnerability of neurons with long-range projections to dysfunction in old age may be a unique feature of the perirhinal cortex. Together, these observations identify a mechanism involving prelimbic-perirhinal cortical circuit disruption in cognitive aging.

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Medial Temporal Lobe Subregional Atrophy in Aging and Alzheimer's Disease: A Longitudinal Study

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.750154 ◽

2021 ◽

Vol 13 ◽

Author(s):

Léa Chauveau ◽

Elizabeth Kuhn ◽

Cassandre Palix ◽

Francesca Felisatti ◽

Valentin Ourry ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Adult Lifespan ◽

Parahippocampal Cortex ◽

Age Related ◽

Preclinical Ad ◽

Brodmann Areas ◽

Over Time

Medial temporal lobe (MTL) atrophy is a key feature of Alzheimer's disease (AD), however, it also occurs in typical aging. To enhance the clinical utility of this biomarker, we need to better understand the differential effects of age and AD by encompassing the full AD-continuum from cognitively unimpaired (CU) to dementia, including all MTL subregions with up-to-date approaches and using longitudinal designs to assess atrophy more sensitively. Age-related trajectories were estimated using the best-fitted polynomials in 209 CU adults (aged 19–85). Changes related to AD were investigated among amyloid-negative (Aβ−) (n = 46) and amyloid-positive (Aβ+) (n = 14) CU, Aβ+ patients with mild cognitive impairment (MCI) (n = 33) and AD (n = 31). Nineteen MCI-to-AD converters were also compared with 34 non-converters. Relationships with cognitive functioning were evaluated in 63 Aβ+ MCI and AD patients. All participants were followed up to 47 months. MTL subregions, namely, the anterior and posterior hippocampus (aHPC/pHPC), entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36 [as perirhinal cortex (PRC) substructures], and parahippocampal cortex (PHC), were segmented from a T1-weighted MRI using a new longitudinal pipeline (LASHiS). Statistical analyses were performed using mixed models. Adult lifespan models highlighted both linear (PRC, BA35, BA36, PHC) and nonlinear (HPC, aHPC, pHPC, ERC) trajectories. Group comparisons showed reduced baseline volumes and steeper volume declines over time for most of the MTL subregions in Aβ+ MCI and AD patients compared to Aβ− CU, but no differences between Aβ− and Aβ+ CU or between Aβ+ MCI and AD patients (except in ERC). Over time, MCI-to-AD converters exhibited a greater volume decline than non-converters in HPC, aHPC, and pHPC. Most of the MTL subregions were related to episodic memory performances but not to executive functioning or speed processing. Overall, these results emphasize the benefits of studying MTL subregions to distinguish age-related changes from AD. Interestingly, MTL subregions are unequally vulnerable to aging, and those displaying non-linear age-trajectories, while not damaged in preclinical AD (Aβ+ CU), were particularly affected from the prodromal stage (Aβ+ MCI). This volume decline in hippocampal substructures might also provide information regarding the conversion from MCI to AD-dementia. All together, these findings provide new insights into MTL alterations, which are crucial for AD-biomarkers definition.

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Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01225-3 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

L. E. M. Wisse ◽

S. Ravikumar ◽

R. Ittyerah ◽

S. Lim ◽

J. Lane ◽

...

Keyword(s):

Temporal Lobe ◽

Medial Temporal Lobe ◽

Strong Association ◽

Amyloid Β ◽

Stratum Radiatum ◽

Post Mortem ◽

Age Related ◽

Important Region ◽

Cornu Ammonis ◽

Mri Scans

AbstractThe medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-β and α-synuclein pathology were rated on a scale of 0 (absent)—3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman’s rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r = − 0.27 to r = − 0.46), and (2) tau with BA35 (r = − 0.31) and SRLM thickness (r = − 0.33). In amyloid-β and TDP-43 negative cases, we found strong significant associations of tau with ERC (r = − 0.40), BA35 (r = − 0.55), subiculum (r = − 0.42) and CA1 thickness (r = − 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-β suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

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Age-related differences in medial temporal lobe involvement during conceptual fluency

Brain Research ◽

10.1016/j.brainres.2014.09.061 ◽

2015 ◽

Vol 1612 ◽

pp. 48-58 ◽

Cited By ~ 11

Author(s):

Wei-Chun Wang ◽

Ilana T.Z. Dew ◽

Roberto Cabeza

Keyword(s):

Temporal Lobe ◽

Medial Temporal Lobe ◽

Conceptual Fluency ◽

Age Related

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F44. Age-Related Changes in Reversal Learning and Medial Temporal Lobe Circuitry in Children

Biological Psychiatry ◽

10.1016/j.biopsych.2018.02.657 ◽

2018 ◽

Vol 83 (9) ◽

pp. S254-S255

Author(s):

Xhenis Brahimi ◽

Hilary Marusak ◽

Christine Rabinak

Keyword(s):

Temporal Lobe ◽

Reversal Learning ◽

Medial Temporal Lobe ◽

Age Related ◽

Age Related Changes

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Worth the Wait: Delayed Recall after 1 Week Predicts Cognitive and Medial Temporal Lobe Trajectories in Older Adults

Journal of the International Neuropsychological Society ◽

10.1017/s1355617720001009 ◽

2020 ◽

pp. 1-7

Author(s):

Cutter A. Lindbergh ◽

Nicole Walker ◽

Renaud La Joie ◽

Sophia Weiner-Light ◽

Adam M. Staffaroni ◽

...

Keyword(s):

Older Adults ◽

Executive Functioning ◽

Temporal Lobe ◽

Gray Matter ◽

Medial Temporal Lobe ◽

Neuropsychological Testing ◽

Occipital Lobe ◽

Delayed Recall ◽

Age Related ◽

Gray Matter Volumes

Abstract Objective: We evaluated whether memory recall following an extended (1 week) delay predicts cognitive and brain structural trajectories in older adults. Method: Clinically normal older adults (52–92 years old) were followed longitudinally for up to 8 years after completing a memory paradigm at baseline [Story Recall Test (SRT)] that assessed delayed recall at 30 min and 1 week. Subsets of the cohort underwent neuroimaging (N = 134, mean age = 75) and neuropsychological testing (N = 178–207, mean ages = 74–76) at annual study visits occurring approximately 15–18 months apart. Mixed-effects regression models evaluated if baseline SRT performance predicted longitudinal changes in gray matter volumes and cognitive composite scores, controlling for demographics. Results: Worse SRT 1-week recall was associated with more precipitous rates of longitudinal decline in medial temporal lobe volumes (p = .037), episodic memory (p = .003), and executive functioning (p = .011), but not occipital lobe or total gray matter volumes (demonstrating neuroanatomical specificity; p > .58). By contrast, SRT 30-min recall was only associated with longitudinal decline in executive functioning (p = .044). Conclusions: Memory paradigms that capture longer-term recall may be particularly sensitive to age-related medial temporal lobe changes and neurodegenerative disease trajectories.

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