Danielle Ledoux

Neuroimaging Findings in Patients With Down Syndrome and Nystagmus.

To the Editors: Children with Down syndrome reportedly have a high prevalence of nystagmus.1-3 The etiology of nystagmus in Down syndrome has been presumed to be idiopathic, although evidence for this is limited. Whether cerebellar hypoplasia, a common magnetic resonance imaging (MRI) finding in Down syndrome, contributes to nystagmus has been investigated recently because of the role of the cerebellum on gaze-holding mechanisms within the brain.4 We sought to report the prevalence of nystagmus in a large cohort of patients with Down syndrome and to determine whether underlying progressive neurologic disease contributes to nystagmus. We performed a retrospective chart review of all patients with Down syndrome seen in the Ophthalmology Department at Boston Children’s Hospital from 2000 to 2010 who were diagnosed as having nystagmus on clinical examination. Patients with manifest nystagmus, latent nystagmus, and manifest latent nystagmus were included. Neuroimaging results for computed tomography (CT) and MRI were recorded when performed, and the primary indications for neuroimaging were reviewed. A total of 806 patients with Down syndrome were identified. The prevalence of nystagmus was 17% (138 of 806), and nystagmus was binocular in all but one case (137 of 138). Manifest nystagmus occurred in 59% (81 of 138), latent nystagmus in 9% (12 of 138), and manifest latent nystagmus in 32% (45 of 138) of patients with Down syndrome. Neuroimaging was performed specifically for the indication of nystagmus in 5% (7 of 138) of patients. Results were completely normal in 4 patients. In 2 patients, unrelated, benign findings of choroid plexus cysts and asymmetric enlargement of the lateral ventricles were described. In 1 patient, dysmorphic cerebellar hemispheres were noted. With the exception of the cerebellar findings, no other results were potentially related to the etiology of the nystagmus. Neuroimaging was performed in 19 additional patients with Down syndrome for other neurologic indications, including but not limited to a history of infantile spasms, headache, vertigo, and developmental delay. In total, 19% (26 of 138) of patients with Down syndrome with a clinical diagnosis of nystagmus had neuroimaging, and in no case was a progressive neurologic process found to explain the presence of nystagmus. Three of these children were noted to have cerebellar hypoplasia. Other studies have shown rates of nystagmus in patients with Down syndrome similar to our study’s prevalence of 17%. For example, da Cunha and Moreira5 demonstrated 18% prevalence in a cohort of 152 children with Down syndrome, and Stephen et al.6 described 16% prevalence in a cohort of 72 patients. To date, we report the prevalence of nystagmus in the largest cohort of pediatric patients with Down syndrome of which we are aware. Nystagmus in pediatric patients with Down syndrome can prompt the question as to whether or not imaging is warranted. Neuroimaging is not entirely without risk in this population. There are risks related to sedation, side effects of dye used to enhance imaging, and potential exposure to radiation with CT. In our cohort, neuroimaging did not reveal any underlying progressive neurologic process as the basis for nystagmus. In the absence of other focal neurologic signs or indications, neuroimaging to exclude progressive neurologic disease as a cause of nystagmus may be of low yield in the population with Down syndrome.

IN VIVO ASSESSMENT OF MOLECULAR AGING BY QUASI-ELASTIC LIGHT SCATTERING IN HUMAN LENS

lipidated and quickly catabolized (2) APOE4 particles are themselves toxic. During the disease progression Ab exists as monomer, soluble Ab oligomers and fibrillar Ab. There is increasing evidence that Ab oligomers are the most toxic species, contributing to AD related cognitive decline, synaptic dysfunction and inhibition of long-term potentiation. We hypothesize that APOE4 interaction with Ab diminishes the formation of toxic oligomeric species and alleviates its deleterious effects. Methods: Electron microscopy and western and dot blotting were used to characterize complexes, resulting from co-incubating monomeric Ab with APOE3 or APOE4 at oligomer forming conditions. Utilizing primary mouse neuronal cultures we determined the effect of Ab oligomers +/APOE particles on transcriptome profiles. We also examined the impact of these co-incubations on synaptic markers and structure utilizing Sholl analysis. Lastly, we infused Ab oligomers +/APOE particles into the hippocampi of WT mice and examined their impact on cognitive performance utilizing novel object recognition and fear conditioning. Results:We demonstrate that ApoE3 and ApoE4 particles decrease Ab oligomer formation. Furthermore, treatment of neurons with APOE-Ab complexes significantly impacts the transcriptome and neuronal structurewhen compared to Ab oligomers alone. Hippocampal infusion of Ab oligomers significantly decreased cognitive performance in WT mice in two memory paradigms. Lastly, APOE3 and APOE4 when used at equal concentrations are equally protective against deleterious effects of Ab oligomers on cognitive function. Conclusions: This study demonstrates the importance of oligomeric Ab in AD related cognitive decline and the ability of APOE to influence oligomeric Ab toxicity. Moreover, this study provides further support of APOE as a potential therapeutic target for AD.

Monitoring Molecular Aging of Lens Proteins using Noninvasive Quasi-Elastic Light Scattering

Post-translational modifications of lens proteins during aging can be monitored with quasi-elastic light scattering. Here, we show the ability of the technique to detect these changes both ;in vitro and ;in vivo.

Noninvasive detection of Alzheimer's disease lens pathology in down syndrome by quasi-elastic light scattering

In Down syndrome there is increased deposition of Alzheimer’s disease-related Amyloid-β protein in the brain and lens. Here we use quasi-elastic light scattering to noninvasively detect Alzheimer’s disease lens pathology in subjects with Down syndrome.

Optic Nerve Appearance in Patients With Down Syndrome

To the Editors: Children with Down syndrome (DS) are commonly seen by pediatric ophthalmologists because signifi cant ocular conditions are associated with the disorder.1 The presence of optic nerve anomalies has been noted in various small case series on children with DS.2,3 We sought to determine the prevalence and character of optic nerve abnormalities among patients with DS in a large pediatric cohort and to ascertain whether patients with DS and optic nerve fi ndings suggestive of an intracranial process (nerve elevation or pallor) had corresponding central nervous system pathology. A retrospective review of the charts of all patients with DS (10-year study period) seen by the ophthalmology service at Boston Children’s Hospital was performed to identify those with optic nerve anomalies. One hundred sixteen patients with DS and optic nerve abnormalities were identifi ed (116 of 806, 14% of patients with DS). The most frequently identifi ed abnormality was a myopic appearance and/or peripapillary atrophy of the optic nerve head. Other anomalies included peripapillary pigmentation, scleral crescent, optic nerve pallor, and non-myopic peripapillary atrophy (Figure 1). Seventeen patients had elevated optic nerve heads (17 of 806, 2%), eight of whom underwent neuroimaging. No imaged patient was found to have pathology compatible with optic nerve swelling. B-scan ultrasonography was performed on fi ve patients, either after neuroimaging or as a primary diagnostic measure. Optic nerve head drusen were found in all of these children. Four patients with DS in the cohort had pale optic nerves. Optic nerve head anomalies were not attributable to an undiagnosed intracranial lesion in any case. Among the optic nerve anomalies identifi ed in our cohort, we focused particularly on those that could be associated with a vision-threatening or life-threatening process: optic nerve head elevation and optic nerve pallor. In previous small case series, optic nerve head elevation was noted in 3% to 5% of patients with DS.2-4 In this investigation, none of those with elevated or pale nerves had undiagnosed life or vision-threatening pathology either clinically or by neuroimaging. This is consistent with prior research on CNS lesions in the DS population because solid intracranial tumors appear to be extremely rare in these patients.5 Based on our fi ndings in this study, we recommend a systematic approach to evaluating children with DS who have elevated-appearing optic nerves. B-scan ultrasonography may be employed as a fi rstline diagnostic modality in these patients. It is inexpensive, non-invasive, and sensitive for optic disc drusen. A positive scan obviates the need for costly and invasive testing because drusen can be monitored ophthalmoscopically and with visual fi eld testing. In the case of a negative scan, further measures should be considered, including neurologic consultation, neuroimaging, and lumbar puncture. Patients who demonstrate nerve pallor of unknown etiology may prompt neuroimaging in addition to neurologic and/or neuroophthalmic consultation.

Noninvasive detection of Alzheimer's disease Aβ pathology in the lenses of human subjects with Down syndrome

we have been manually counting diffuse Aß plaques (DPs), neuritic Aß plaques (NPs), and neurofibrillary tangles (NFTs) in multiple brain sections for every patient in our neuropathologic database for over 20 years. Such counting, however, is time consuming and involves technical challenges. To minimize these sources of experimental bias and to standardize our database, we wanted to develop computer based algorithms that exploit the advantages of digital pathology and advanced image analysis software. Methods: We examined cases from the UK-ADC database including brains with AD pathological severity ranging from normal controls to end-stage AD. In our initial sample we analyzed a total of 54 cases, from which portions of superior and middle temporal gyri (SMTG) were selected and stained with both Aß and PHF-1 antibodies. The slides were then scanned using the Aperio ScanScope XT at a 40x magnification. For amyloid quantitation, two parameters were calculated: a DP density and an overall amyloid burden, using modified algorithms from the Aperio Image Analysis Toolbox , respectively. To quantitate NPs and NFTs, we first utilized the Genie Histology Pattern Recognition software to ‘teach’ the computer to identify these structures.We then used a modified positive pixel count to calculate NP burden and a modified nuclear algorithm to calculate NFT density. Results: We found good correlation between our recorded manual counts and the amyloid burden, DP density, and NFT density. We also found good correlation between NP burden and our manual counts, however such studies were somewhat confounded by the differences between the modified Bielschowsky silver stain and the PHF-1 immunohistochemical stain. Conclusions: Image analysis, using our modified algorithms, offers a more efficient and replicable, and less-biased method, relative to manual counting.