The retina: A window in which to view the pathogenesis of Alzheimer’s disease

Zhang, Jie; Shi, Lei; Shen, Yong

doi:10.1016/j.arr.2022.101590

Cited by 19 publications

(20 citation statements)

References 112 publications

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“…Taken together, this study extends previous findings of visuo-spatial alterations in mouse models of AD and other tauopathies [ 4 ] by demonstrating uniquely that the accumulation of a specific, pathogenic N-terminal-cleaved form of tau (i.e., NH 2 htau) in the V1 area of Tg2576 AD mice translates into functional impairments of their visual performance (i.e., reduced visual acuity) and that this diminution is significantly recovered by treatment with 12A12mAb.…”

Section: Resultssupporting

confidence: 90%

“…Multiple lines of evidence have shown that, in addition to the episodic memory and neuropsychiatric manifestations involving the hippocampal CA1 and temporal lobe neocortex, AD is a more globalized disorder encompassing sensory impairments in olfaction, hearing and especially vision [ 1 ]. In particular, deficits in visual system function have been described in experimental AD animal models [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ] and in affected patients [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ] consistent with the extensive neuropathology of Aβ plaques and tau neurofibrillary tangles (NFT) in their visual primary and association cortices and sensory system, including the optic nerves and retina themselves. More importantly, in both human beings and in vivo model systems, visuo-spatial complaints and retinal functional deficits are reported to manifest in concomitance [ 23 , 24 , 25 , 26 ] or, sometimes, even precede [ 27 , 28 , 29 , 30 , 31 , 32 ], the occurrence of the signs of memory/learning deterioration traditionally associated with the clinical symptomatology of AD.…”

Section: Introductionmentioning

confidence: 99%

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Immunotherapy with Cleavage-Specific 12A12mAb Reduces the Tau Cleavage in Visual Cortex and Improves Visuo-Spatial Recognition Memory in Tg2576 AD Mouse Model

et al. 2023

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Tau-targeted immunotherapy is a promising approach for treatment of Alzheimer’s disease (AD). Beyond cognitive decline, AD features visual deficits consistent with the manifestation of Amyloid β-protein (Aβ) plaques and neurofibrillary tangles (NFT) in the eyes and higher visual centers, both in animal models and affected subjects. We reported that 12A12—a monoclonal cleavage-specific antibody (mAb) which in vivo neutralizes the neurotoxic, N-terminal 20–22 kDa tau fragment(s)–significantly reduces the retinal accumulation in Tg(HuAPP695Swe)2576 mice of both tau and APP/Aβ pathologies correlated with local inflammation and synaptic deterioration. Here, we report the occurrence of N-terminal tau cleavage in the primary visual cortex (V1 area) and the beneficial effect of 12A12mAb treatment on phenotype-associated visuo-spatial deficits in this AD animal model. We found out that non-invasive administration of 12 A12mAb markedly reduced the pathological accumulation of both truncated tau and Aβ in the V1 area, correlated to significant improvement in visual recognition memory performance along with local increase in two direct readouts of cortical synaptic plasticity, including the dendritic spine density and the expression level of activity-regulated cytoskeleton protein Arc/Arg3.1. Translation of these findings to clinical therapeutic interventions could offer an innovative tau-directed opportunity to delay or halt the visual impairments occurring during AD progression

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Immunotherapy with Cleavage-Specific 12A12mAb Reduces the Tau Cleavage in Visual Cortex and Improves Visuo-Spatial Recognition Memory in Tg2576 AD Mouse Model

et al. 2023

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“…Thinner macular thickness indicates a reduced number of retinal neurons in the entire layer of the macula in Alzheimer’s disease ( Cheung et al, 2019 ). Retinal neural degeneration has been discovered in AD patients and transgenic mice ( Zhang et al, 2022 ). Interestingly, a longitudinal multimodal in vivo study showed a positive correlation between total retinal thickness and visual cortex gray matter volume in a mouse model of AD ( Chiquita et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…They are considered as part of the central nervous system ( Patton et al, 2005 ; London et al, 2013 ). There is increasing evidence that the brain and retina are affected in patients with AD ( Zhang et al, 2022 ). Additionally, pathological AD hallmarks have been observed in the retina, including neuron loss caused by hyperphosphorylation of tau protein (p-tau), Aβ plaques, and neurofibrillary tangles ( Ho et al, 2012 ; Cabrera DeBuc et al, 2017 ; Golzan et al, 2017 ; Koronyo et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

The correlation of retinal neurodegeneration and brain degeneration in patients with Alzheimer’s disease using optical coherence tomography angiography and MRI

Zhao

Yan

et al. 2023

Front. Aging Neurosci.

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IntroductionPathological changes in Alzheimer’s disease can cause retina and optic nerve degeneration. The retinal changes are correlated with cognitive function. This study aimed to explore the relationship of retinal differences with neuroimaging in patients with Alzheimer’s disease, analyze the association of cognitive function with retinal structure and vascular density, and identify potential additional biomarkers for early diagnosis of Alzheimer’s disease.MethodWe performed magnetic resonance imaging (MRI) scans and neuropsychological assessments in 28 patients with mild Alzheimer’s disease and 28 healthy controls. Retinal structure and vascular density were evaluated by optical coherence tomography angiography (OCTA). Furthermore, we analyzed the correlation between neuroimaging and OCTA parameters in patients with mild Alzheimer’s disease with adjustment for age, gender, years of education, and hypertension.ResultsIn patients with mild Alzheimer’s disease, OCTA-detected retinal parameters were not significantly correlated with MRI-detected neuroimaging parameters after Bonferroni correction for multiple testing. Under multivariable analysis controlled for age, gender, years of education, and hypertension, the S-Hemi (0–3) sector of macular thickness was significantly associated with Mini-cog (β = 0.583, P = 0.002) with Bonferroni-corrected threshold at P < 0.003.ConclusionOur findings suggested decreased macular thickness might be associated with cognitive function in mild AD patients. However, the differences in retinal parameters didn’t correspond to MRI-detected parameters in this study. Whether OCTA can be used as a new detection method mirroring MRI for evaluating the effect of neuronal degeneration in patients with mild Alzheimer’s disease still needs to be investigated by more rigorous and larger studies in the future.

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“…The retina shares similar neurobiology of neuronal cells and microvasculature with those in central nervous system (CNS), thus, changes in retina structure and function may serve as a window to access the changes in CNS (Liao et al, 2021;Zhang et al, 2022). In recent years, a number of clinical studies have shown that AD patients have functional visual defects and anatomical changes in retinal structure.…”

Section: Introductionmentioning

confidence: 99%

Correlation between retinal structure and brain multimodal magnetic resonance imaging in patients with Alzheimer’s disease

Hao

Zhang²,

Jiao³

et al. 2023

Front. Aging Neurosci.

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BackgroundThe retina imaging and brain magnetic resonance imaging (MRI) can both reflect early changes in Alzheimer’s disease (AD) and may serve as potential biomarker for early diagnosis, but their correlation and the internal mechanism of retinal structural changes remain unclear. This study aimed to explore the possible correlation between retinal structure and visual pathway, brain structure, intrinsic activity changes in AD patients, as well as to build a classification model to identify AD patients.MethodsIn the study, 49 AD patients and 48 healthy controls (HCs) were enrolled. Retinal images were obtained by optical coherence tomography (OCT). Multimodal MRI sequences of all subjects were collected. Spearman correlation analysis and multiple linear regression models were used to assess the correlation between OCT parameters and multimodal MRI findings. The diagnostic value of combination of retinal imaging and brain multimodal MRI was assessed by performing a receiver operating characteristic (ROC) curve.ResultsCompared with HCs, retinal thickness and multimodal MRI findings of AD patients were significantly altered (p < 0.05). Significant correlations were presented between the fractional anisotropy (FA) value of optic tract and mean retinal thickness, macular volume, macular ganglion cell layer (GCL) thickness, inner plexiform layer (IPL) thickness in AD patients (p < 0.01). The fractional amplitude of low frequency fluctuations (fALFF) value of primary visual cortex (V1) was correlated with temporal quadrant peripapillary retinal nerve fiber layer (pRNFL) thickness (p < 0.05). The model combining thickness of GCL and temporal quadrant pRNFL, volume of hippocampus and lateral geniculate nucleus, and age showed the best performance to identify AD patients [area under the curve (AUC) = 0.936, sensitivity = 89.1%, specificity = 87.0%].ConclusionOur study demonstrated that retinal structure change was related to the loss of integrity of white matter fiber tracts in the visual pathway and the decreased LGN volume and functional metabolism of V1 in AD patients. Trans-synaptic axonal retrograde lesions may be the underlying mechanism. Combining retinal imaging and multimodal MRI may provide new insight into the mechanism of retinal structural changes in AD and may serve as new target for early auxiliary diagnosis of AD.

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The retina: A window in which to view the pathogenesis of Alzheimer’s disease

Cited by 19 publications

References 112 publications

Immunotherapy with Cleavage-Specific 12A12mAb Reduces the Tau Cleavage in Visual Cortex and Improves Visuo-Spatial Recognition Memory in Tg2576 AD Mouse Model

Immunotherapy with Cleavage-Specific 12A12mAb Reduces the Tau Cleavage in Visual Cortex and Improves Visuo-Spatial Recognition Memory in Tg2576 AD Mouse Model

The correlation of retinal neurodegeneration and brain degeneration in patients with Alzheimer’s disease using optical coherence tomography angiography and MRI

Correlation between retinal structure and brain multimodal magnetic resonance imaging in patients with Alzheimer’s disease

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