Neuropsychological Markers of Medial Perirhinal and Entorhinal Cortex Functioning are Impaired Twelve Years Preceding Diagnosis of Alzheimer’s Dementia

Hirni, Daniela I.; Kivisaari, Sasa L.; Krumm, Sabine; Monsch, Andreas U.; Berres, Manfred; Oeksuez, Fatma; Reinhardt, Julia; Ulmer, Stephan; Kressig, Reto W.; Stippich, Christoph; Taylor, Kirsten I.

doi:10.3233/jad-150158

Cited by 29 publications

(23 citation statements)

References 43 publications

(55 reference statements)

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“…Specifically, effect sizes for age differences in incorrect trials required to learn similar object discriminations in Experiment 1 (Cohen's d 5 1.34, 95% confidence interval (CI) 5 -22 to 20) and performance on Lure 2 (d 5 2.30, CI 5 -.56 to 5.16) and Lure 3 trials (d 5 1.98, CI 5 -.79 to 4.75) in Experiment 2 are greater than that observed for the age difference in performance on high-similarity spatial discriminations in our previously published study (d 5 .99, CI 5 .95-1.03) (Johnson et al, 2016). Critically, these findings are consistent with knowledge that lateral entorhinal and perirhinal cortices, which are more likely to contribute to visual and object discriminations, show earlier evidence of neuropathology with advanced age and progression to Alzheimer's disease (Braak & Braak, 1991;Braak, Braak, & Bohl, 1993;Hirni et al, 2016;Krumm et al, 2016;Khan et al, 2014).…”

Section: Domain-general Discrimination Deficits With Aging As They supporting

confidence: 86%

Rodent age‐related impairments in discriminating perceptually similar objects parallel those observed in humans

et al. 2017

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The ability to accurately remember distinct episodes is supported by high-level sensory discrimination. Performance on mnemonic similarity tasks, which test high-level discrimination, declines with advancing age in humans and these deficits have been linked to altered activity in hippocampal CA3 and dentate gyrus. Lesion studies in animal models, however, point to the perirhinal cortex as a brain region critical for sensory discriminations that serve memory. Reconciliation of the contributions of different regions within the cortical-hippocampal circuit requires the development of a discrimination paradigm comparable to the human mnemonic similarity task that can be used in rodents. In the present experiments, young and aged rats were cross-characterized on a spatial water maze task and two variants of an object discrimination task: one in which rats incrementally learned which object of a pair was rewarded and different pairs varied in their similarity (Experiment 1), and a second in which rats were tested on their ability to discriminate a learned target object from multiple lure objects with an increasing degree of feature overlap (Experiment 2). In Experiment 1, aged rats required more training than young to correctly discriminate between similar objects. Comparably, in Experiment 2, aged rats were impaired in discriminating a target object from lures when the pair shared more features. Discrimination deficits across experiments were correlated within individual aged rats, though, for the cohort tested, aged rats were not impaired overall in spatial learning and memory. This could suggest discrimination deficits emerging with age precede declines in spatial or episodic memory, an observation that has been made in humans. Findings of robust impairments in object discrimination abilities in the aged rats parallel results from human studies, supporting use of the developed tasks for mechanistic investigation of cortical-hippocampal circuit dysfunction in aging and disease.

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Section: Domain-general Discrimination Deficits With Aging As They supporting

confidence: 86%

Rodent age‐related impairments in discriminating perceptually similar objects parallel those observed in humans

et al. 2017

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“…Given prior findings of PRC dysfunction in animal models of aging (Burke et al, 2011(Burke et al, , 2014Ryan et al, 2012) and AD-related pathology in the region (Braak, Braak, and Bohl, 1993;Braak and Braak, 1995;Hirni et al, 2016;Jack et al, 1997), it is interesting and perhaps surprising that we found no evidence for age-related PRC dysfunction. One possibility is that mnemonic discrimination more uniquely drives age-related differences in alEC than PRC in the context of our task.…”

Section: Discussionmentioning

confidence: 44%

“…Moreover, it will be important to distinguish simple agerelated changes from those that indicate a disease state. The entorhinal cortex (EC) is among the first and most profoundly affected regions in age-related pathologies, such as Alzheimer's disease (AD) (Braak, Braak, and Bohl, 1993;Braak and Braak, 1995;Hirni et al, 2016;Jack et al, 1997). In particular, the EC, undergoes structural and functional alterations relating to AD (Burke et al, 2011(Burke et al, , 2014Ryan et al, 2012;Stranahan and Mattson, 2010), even in older preclinical humans (Khan et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Functional Imbalance of Anterolateral Entorhinal Cortex and Hippocampal Dentate/CA3 Underlies Age-Related Object Pattern Separation Deficits

et al. 2018

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The entorhinal cortex (EC) is among the earliest brain areas to deteriorate in Alzheimer's disease (AD). However, the extent to which functional properties of the EC are altered in the aging brain, even in the absence of clinical symptoms, is not understood. Recent human fMRI studies have identified a functional dissociation within the EC, similar to what is found in rodents. Here, we used high-resolution fMRI to identify a specific hypoactivity in the anterolateral EC (alEC) commensurate with major behavioral deficits on an object pattern separation task in asymptomatic older adults. Only subtle deficits were found in a comparable spatial condition, with no associated differences in posteromedial EC between young and older adults. We additionally linked this condition to dentate/CA3 hyperactivity, and the ratio of activity between the regions was associated with object mnemonic discrimination impairment. These results provide novel evidence of alEC-dentate/CA3 circuit dysfunction in cognitively normal aged humans. eTOC BlurbReagh et al. identify a novel mechanistic pathway for the decline in pattern separation of object stimuli observed with aging -a network dysregulation characterized by hypoactivity in the anterolateral entorhinal cortex and hyperactivity in the dentate and CA3 subregions of the hippocampus. This novel biomarker yields a potential tool for assessing the neural basis of agerelated memory decline. †

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“…The neurofibrillary pathology affects these regions early in the course of Alzheimer's disease 32 and neurofibrillary pathology associated with cognitive decline 47 . Indeed, semantic memory impairments putatively reflecting pathology in these regions have previously been shown to be apparent well-before a clinical diagnosis of neurodegenerative disease 48 . Thus, future studies should consider the sensitivity of the primacy progression score as an early cognitive-biomarker of Alzheimer's disease.…”

Section: Discussionmentioning

confidence: 99%

Serial position effects reflect the integrity of distinct brain regions in Major and Minor Neurocognitive Disorder

et al. 2019

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Serial Position Effects (SPE) in wordlist learning provide a rich set of metrics of cognitive functioning. In this study, we systematically mapped the neuroanatomical correlates of SPEs across delays in Major and Minor Neurocognitive disorders. Primacy, middle, and recency SPE scores of the California Verbal Learning Test at Learning, Short delay, and Long delay in healthy controls and patients with neurodegenerative disease were correlated with MRI gray matter signal intensities (voxel-based morphometry, VBM). The VBM analyses revealed distinct patterns of brain-behavioral correlations depending on both the SPE and the time-point. Unlike patients, the healthy controls' performance incrementally improved recall of primacy items from Learning to Short and to Long delay, i.e., primacy progression. Moreover, the proportion of correct primacy items recalled at long delay compared to Learning correlated with bilateral medial temporal lobe regions, which commonly bear the brunt of pathology of Alzheimer's disease. The results implicate the primacy progression score as an accessible and sensitive measure for disease detection, progression, and therapeutic response in Major and Minor Neurocognitive disorders. 2/123/12 10/12

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Neuropsychological Markers of Medial Perirhinal and Entorhinal Cortex Functioning are Impaired Twelve Years Preceding Diagnosis of Alzheimer’s Dementia

Cited by 29 publications

References 43 publications

Rodent age‐related impairments in discriminating perceptually similar objects parallel those observed in humans

Rodent age‐related impairments in discriminating perceptually similar objects parallel those observed in humans

Functional Imbalance of Anterolateral Entorhinal Cortex and Hippocampal Dentate/CA3 Underlies Age-Related Object Pattern Separation Deficits

Serial position effects reflect the integrity of distinct brain regions in Major and Minor Neurocognitive Disorder

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