Retinal thickness in Alzheimer's disease: A systematic review and meta-analysis

Introduction Retinal characteristics are increasingly recognized as biomarkers for neurodegenerative diseases. Retinal thickness measured by optical coherence tomography may reflect the presence of Alzheimer's disease (AD). We performed a meta-analysis on retinal thickness in AD and mild cognitive impairment (MCI) patients and healthy controls (HCs). Methods We selected 25 studies with measurements of retinal thickness including 887 AD patients, 216 MCI patients, and 864 HCs that measured retinal thickness. Outcomes were peripapillary retinal nerve fiber layer (RNFL) and macular thickness. The main outcome was the standardized mean differences (SMDs). We used STATA to perform the meta-analysis (StataCorp, Texas; version 14.0). Results Relative to HCs, AD and MCI patients had lower peripapillary RNFL (SMD 0.98 [CI −1.30, −0.66, P < .0001] and SMD 0.71 [CI −1.24, −0.19, P = .008]). Total macular thickness was decreased in AD patients (SMD 0.88 [CI −1.12, −0.65, P = .000]). Discussion Retinal thickness is decreased in AD and MCI patients compared to HC. This confirms that neurodegenerative diseases may be reflected by retinal changes

Different curcumin forms selectively bind fibrillar amyloid beta in post mortem Alzheimer's disease brains: Implications for in-vivo diagnostics

The combined fluorescent and Aβ-binding properties of the dietary spice curcumin could yield diagnostic purpose in the search for a non-invasive Aβ-biomarker for Alzheimer's disease (AD). However, evidence on the binding properties of curcumin, its conjugates and clinically used bio-available formulations to AD neuropathological hallmarks is scarce. We therefore assessed the binding properties of different curcumin forms to different neuropathological deposits in post-mortem brain tissue of cases with AD, other neurodegenerative diseases, and controls. Post mortem brain tissue was histochemically assessed for the binding of curcumin, its isoforms, conjugates and bio-available forms and compared to routinely used staining methods. For this study we included brains of early onset AD, late onset AD, primary age-related tauopathy (PART), cerebral amyloid angiopathy (CAA), frontotemporal lobar degeneration (FTLD) with tau or TAR DNA-binding protein 43 (TDP-43) inclusions, dementia with Lewy bodies (DLB), Parkinson's disease (PD) and control cases without brain pathology. We found that curcumin binds to fibrillar amyloid beta (Aβ) in plaques and CAA. It does not specifically bind to inclusions of protein aggregates in FTLD-tau cases, TDP-43, or Lewy bodies. Curcumin isoforms, conjugates and bio-available forms show affinity for the same Aβ structures. Curcumin staining overlaps with immunohistochemical detection of Aβ in fibrillar plaques and CAA, and to a lesser extent cored plaques. A weak staining of neurofibrillary tangles was observed, while other structures immunopositive for phosphorylated tau remained negative. In conclusion, curcumin, its isoforms, conjugates and bio-available forms selectively bind fibrillar Aβ in plaques and CAA in post mortem AD brain tissue. Curcumin, being a food additive with fluorescent properties, is therefore an interesting candidate for in-vivo diagnostics in AD, for example in retinal fluorescent imaging

Retinal thickness correlates with parietal cortical atrophy in early-onset Alzheimer's disease and controls

The retina may reflect Alzheimer's disease (AD) neuropathological changes and is easily visualized with optical coherence tomography (OCT). Retinal thickness decrease has been correlated to AD, however, without information on amyloid status. We correlated retinal (layer) thickness to AD biomarkers in amyloid-positive early-onset AD (EOAD) patients and amyloid-negative controls. We measured macular thickness and peripapillary retinal nerve fiber layer thickness with OCT in 15 EOAD patients and 15 controls and correlated retinal thickness to visual rating scores for atrophy on magnetic resonance imaging. Total macular thickness correlated to parietal cortical atrophy in both groups (Spearman ρ -0.603, P = .001). Macular and peripapillary retinal nerve fiber layer thicknesses were not significantly decreased in EOAD compared to controls. Retinal thickness does not discriminate EOAD from controls but is correlated to parietal cortical atrophy in both groups. These findings may suggest reflection of cerebral cortical changes in the retina, independent of amyloi

Detection of tomato spotted wilt virus using monoclonal antibodies and riboprobes.

The immunoreactivity of a panel of monoclonal antibodies raised to tomato spotted wilt virus (TSWV) was examined in enzyme-linked immunosorbent assays (ELISA) and dot immunobinding assays (DIBA) procedures. MAbs 6.12.15 and 2.9 were specific for the nucleocapsid protein of TSWV. The sensitivity of the two immunoassays was compared with that of a dot-blot hybridization technique using riboprobes (RNA transcripts) to TSWV M RNA. Using deproteinized plant extracts or purified virus preparations, as little as 1 pg RNA could be detected. Although an ELISA using MAb 6.12.15, a DIBA procedure using MAb 3.22.6 and the dot-blot hybridization, detected several TSWV isolates in different host species equally well, the ELISA was most precise and most suitable for routine diagnosis in the field

Is retinal vasculature a biomarker in amyloid proven Alzheimer's disease?

Introduction: The retina is a potential source of noninvasive vascular biomarkers for Alzheimer's disease (AD). We assessed retinal microvasculature in well-characterized AD cases, taking ophthalmological confounders into account. Methods: We included 48 amyloid-positive AD patients and 38 amyloid-negative cognitively normal control subjects. All participants underwent ophthalmological screening to exclude interfering ocular disease. Using a multimodal approach, we measured retinal vascular parameters, choroidal thickness, macular vascular density, and foveal avascular zone size. Results: We found no disease effects on retinal vascular measures (all β′s .2), adjusted for confounders. Venular tortuosity was inversely associated with Fazekas score in control subjects (β −0.56, P < .01), while vessel density in the outer ring of the macula was inversely associated with Fazekas score in AD cases (β −0.64, P < .01). Discussion: In conclusion, retinal vasculature did not discriminate patients with AD from control subjects, despite evident changes on clinical, neuroimaging, and cerebrospinal fluid biomarkers, challenging the use of retinal vasculature measurements as AD biomarker

Amyloid-beta and phosphorylated tau in post-mortem Alzheimer’s disease retinas

Abstract In-vivo labeling of retinal amyloid-beta(Aβ) and tau has potential as non-invasive biomarker for Alzheimer’s disease (AD). However, literature on the presence of Aβ and phosphorylated tau (pTau) in AD retinas is inconclusive. We therefore assessed the presence of Aβ and pTau in post-mortem retinas in 6 AD and 6 control cases who donated brains and eyes to the Netherlands Brain Bank. Neuropathological diagnosis of AD was made according to NIA-AA criteria. Formalin fixed retinas were dissected in quadrants and cross-sections of medial and superior retinas were made. Immuno-histochemical stainings were performed for Aβ, amyloid precursor protein (APP) and pTau. To assess translation to an in-vivo set up using curcumin as labelling fluorophore, co-stainings with curcumin were performed. No typical Aβ-plaques and neurofibrillary tangles, like in the cerebral cortex, were observed in AD retinas. A diffuse immunoreactive signal for pTau was increased in the inner and outer plexiform layers of the retina in AD cases compared to control cases with absence of cerebral amyloid pathology. Immunostaining with anti-Aβ and anti-APP antibodies yielded signal in ganglion cells, amacrine cells, horizontal cells and Müller cells in both control and AD cases. We observed small extracellular deposits positive for anti-Aβ antibodies 12F4 and 6E10 and negative for 4G8 and curcumin. A subset of these deposits could be characterized as corpora amylacea. In conclusion we found that retinal manifestations of AD pathology appear to be different compared to cerebral AD pathology. Using a qualitative cross-sectional approach, we did not find Aβ/APP related differences in the retina between AD and control subjects. In contrast, tau related changes were found to be present in cases with cerebral AD pathology, suggesting retinal tau as a potential biomarker for AD

Retinal thickness as a potential biomarker in patients with amyloid-proven early- and late-onset Alzheimer's disease

Introduction: Retinal thickness measured with optical coherence tomography has been proposed as a noninvasive biomarker for Alzheimer's disease (AD). We therefore measured retinal thickness in well-characterized AD and control participants, considering ophthalmological confounders. Methods: We included 57 amyloid-proven AD cases and 85 cognitively normal, amyloid-negative controls. All subjects underwent retinal thickness measurements with spectral domain optical coherence tomography and an ophthalmological assessment to exclude ocular disease. Results: Retinal thickness did not discriminate cases from controls, including stratified analyses for early- versus late-onset AD. We found significant associations between macular thickness and global cortical atrophy [β −0.358; P =.01] and parietal cortical atrophy on magnetic resonance imaging [β −0.371; P <.01] in AD cases. Discussion: In this study, representing the largest optical coherence tomography cohort with amyloid-proven AD cases, we show that retinal thickness does not discriminate AD from controls, despite evident changes on clinical, neuroimaging, and CSF measures, querying the use of retinal thickness measurements as an AD biomarker

Retinal changes in Alzheimer\u27s disease— integrated prospects of imaging, functional and molecular advances

Alzheimer's Disease (AD) is a devastating neurodegenerative disorder of the brain, clinically characterised by cognitive deficits that gradually worsen over time. There is, at present, no established cure, or disease-modifying treatments for AD. As life expectancy increases globally, the number of individuals suffering from the disease is projected to increase substantially. Cumulative evidence indicates that AD neuropathological process is initiated several years, if not decades, before clinical signs are evident in patients, and diagnosis made. While several imaging, cognitive, CSF and blood-based biomarkers have been proposed for the early detection of AD; their sensitivity and specificity in the symptomatic stages is highly variable and it is difficult to justify their use in even earlier, pre-clinical stages of the disease. Research has identified potentially measurable functional, structural, metabolic and vascular changes in the retina during early stages of AD. Retina offers a distinctively accessible insight into brain pathology and current and developing ophthalmic technologies have provided us with the possibility of detecting and characterising subtle, disease-related changes. Recent human and animal model studies have further provided mechanistic insights into the biochemical pathways that are altered in the retina in disease, including amyloid and tau deposition. This information coupled with advances in molecular imaging has allowed attempts to monitor biochemical changes and protein aggregation pathology in the retina in AD. This review summarises the existing knowledge that informs our understanding of the impact of AD on the retina and highlights some of the gaps that need to be addressed. Future research will integrate molecular imaging innovation with functional and structural changes to enhance our knowledge of the AD pathophysiological mechanisms and establish the utility of monitoring retinal changes as a potential biomarker for AD