Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease

Khan, Usman; Liu, Li; Provenzano, Frank A.; Berman, Diego E.; Profaci, Caterina P.; Sloan, Richard P.; Mayeux, Richard; Duff, Karen; Small, Scott A.

doi:10.1038/nn.3606

Cited by 501 publications

(512 citation statements)

References 57 publications

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“…Both blood flow and volume abnormalities were previously found in AD converters, 11,49 highlighting their mutual sensitivity to pathogenic mechanisms. However, rCBF may be more affected by early ADrelated pathological mechanisms than rCBV.…”

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confidence: 71%

Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients

Wirth

Binette

Brunecker

et al. 2016

J Cereb Blood Flow Metab

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Reductions of cerebral blood flow and gray matter structure have been implicated in early pathogenesis of Alzheimer's disease, potentially providing complementary information. The present study evaluated regional patterns of cerebral hypoperfusion and atrophy in patients with mild cognitive impairment and healthy older adults. In each participant, cerebral perfusion and gray matter structure were extracted within selected brain regions vulnerable to Alzheimer's disease using magnetic resonance imaging. Measures were compared between diagnostic groups with/without adjustment for covariates. In mild cognitive impairment patients, cerebral blood flow was significantly reduced in comparison with healthy controls in temporo-parietal regions and the basal ganglia in the absence of local gray matter atrophy. By contrast, gray matter structure was significantly reduced in the hippocampus in the absence of local hypoperfusion. Both, cerebral perfusion and gray matter structure were significantly reduced in the entorhinal and isthmus cingulate cortex in mild cognitive impairment patients compared with healthy older adults. Our results demonstrated partly divergent patterns of temporo-parietal hypoperfusion and medial-temporal atrophy in mild cognitive impairment patients, potentially indicating biomarker sensitivity to dissociable pathological mechanisms. The findings support applicability of cerebral perfusion and gray matter structure as complementary magnetic resonance imaging-based biomarkers in early Alzheimer's disease detection, a hypothesis to be further evaluated in longitudinal studies.

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mentioning

confidence: 71%

Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients

Wirth

Binette

Brunecker

et al. 2016

J Cereb Blood Flow Metab

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“…It is also conceivable that the asymmetry in long-term memory is explained either completely or in part because the left and right CA3 receive different information, akin to how the distinct functional contributions of dorsal and ventral hippocampus might arise through differences in first-and second-order inputs (37). One possible source of asymmetry before the hippocampus might be the lateral entorhinal cortex (LEC) input to dorsal hippocampus; the left LEC exhibits a higher metabolic demand than the right LEC (38), which may be indicative of distinct computational demands present in the neuronal circuitry. Asymmetry may even exist at the level of sensory inputs (30).…”

Section: Discussionmentioning

confidence: 99%

Left–right dissociation of hippocampal memory processes in mice

Shipton

El-Gaby

Apergis-Schoute

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

166

222

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Left-right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; however, little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere. Here we examined whether lateralized hippocampal memory processing is present in mice, where hemispheric asymmetry at the CA3-CA1 pyramidal neuron synapse has recently been demonstrated, with different spine morphology, glutamate receptor content, and synaptic plasticity, depending on whether afferents originate in the left or right CA3. To address this question, we used optogenetics to acutely silence CA3 pyramidal neurons in either the left or right dorsal hippocampus while mice performed hippocampus-dependent memory tasks. We found that unilateral silencing of either the left or right CA3 was sufficient to impair short-term memory. However, a striking asymmetry emerged in long-term memory, wherein only left CA3 silencing impaired performance on an associative spatial long-term memory task, whereas right CA3 silencing had no effect. To explore whether synaptic properties intrinsic to the hippocampus might contribute to this left-right behavioral asymmetry, we investigated the expression of hippocampal long-term potentiation. Following the induction of long-term potentiation by high-frequency electrical stimulation, synapses between CA3 and CA1 pyramidal neurons were strengthened only when presynaptic input originated in the left CA3, confirming an asymmetry in synaptic properties. The dissociation of hippocampal long-term memory function between hemispheres suggests that memory is routed via distinct left-right pathways within the mouse hippocampus, and provides a promising approach to help elucidate the synaptic basis of long-term memory. U nilateral specializations may facilitate greater processing power in bilateral brain structures by using the available neuronal circuitry more effectively. Nevertheless, the nature of the mechanisms that can act within the confines of duplicate neural structures to support different cognitive functions in each hemisphere remains elusive.The hippocampus is essential for certain forms of learning and memory, both in humans (1) and in rodents (2, 3), and also plays an important role in navigation (4). The left and right mammalian hippocampi comprise the same anatomical areas and directional connectivity, and yet in the human hippocampus, taskrelated activity may be localized to only one hemisphere (5). This lateralization may enable the left and right hippocampus to support complementary functions in human episodic memory, with left hippocampal activity associated with an egocentric, sequential representation of space but greater activity in the right hippocampus when an allocentric representation is used (6). It has been suggested that human hippocampal asymmetry is primarily dictated by external asymmetry-namely, the left hemispheric involvement in language processing and the stronger contribution of the right hemisphere to visuosp...

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“…Recent evidence suggests that, even in the preclinical stage of Alzheimer's disease, limbic structures are affected by tau pathology. There is also evidence that limbic dysfunction involves primarily the entorhinal cortex and then spreads to the parietal cortex (Khan et al, 2014) and inferior frontal areas, including the orbitofrontal cortex (Serrano-Pozo et al, 2011). This phenomenon is thought to be due to synaptic loss and trans-synaptic spread of pathological forms of tau through brain circuits involved in learning and memory formation (Spires-Jones and Hyman, 2014), which can explain the typical cognitive deficits seen in MCI due to AlzheimerЈs disease.…”

Section: Discussionmentioning

confidence: 99%

Network Disruption and Cerebrospinal Fluid Amyloid-Beta and Phospho-Tau Levels in Mild Cognitive Impairment

Canuet

Pusil

López

et al. 2015

Journal of Neuroscience

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Synaptic dysfunction is a core deficit in Alzheimer's disease, preceding hallmark pathological abnormalities. Resting-state magnetoencephalography (MEG) was used to assess whether functional connectivity patterns, as an index of synaptic dysfunction, are associated with CSF biomarkers [i.e., phospho-tau (p-tau) and amyloid beta (A␤42) levels]. We studied 12 human subjects diagnosed with mild cognitive impairment due to Alzheimer's disease, comparing those with normal and abnormal CSF levels of the biomarkers. We also evaluated the association between aberrant functional connections and structural connectivity abnormalities, measured with diffusion tensor imaging, as well as the convergent impact of cognitive deficits and CSF variables on network disorganization. One-third of the patients converted to Alzheimer's disease during a follow-up period of 2.5 years. Patients with abnomal CSF p-tau and A␤42 levels exhibited both reduced and increased functional connectivity affecting limbic structures such as the anterior/posterior cingulate cortex, orbitofrontal cortex, and medial temporal areas in different frequency bands. A reduction in posterior cingulate functional connectivity mediated by p-tau was associated with impaired axonal integrity of the hippocampal cingulum. We noted that several connectivity abnormalities were predicted by CSF biomarkers and cognitive scores. These preliminary results indicate that CSF markers of amyloid deposition and neuronal injury in early Alzheimer's disease associate with a dual pattern of cortical network disruption, affecting key regions of the default mode network and the temporal cortex. MEG is useful to detect early synaptic dysfunction associated with Alzheimer's disease brain pathology in terms of functional network organization.

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Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease

Cited by 501 publications

References 57 publications

Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients

Divergent regional patterns of cerebral hypoperfusion and gray matter atrophy in mild cognitive impairment patients

Left–right dissociation of hippocampal memory processes in mice

Network Disruption and Cerebrospinal Fluid Amyloid-Beta and Phospho-Tau Levels in Mild Cognitive Impairment

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