D010 Evaluating amyloid-beta peptides as CSF biomarkers of cognitive status in Huntington's disease

<h3>Background</h3> Recent evidence indicates that beyond the accumulation of mutant Huntingtin protein (mHTT), tau and other proteinopathies are associated with the clinical phenotypes of Huntington9s disease (HD). Postmortem studies have suggested the presence of amyloid-beta and phosphorylated tau co-pathology in the HD brains,¹ but reports based on CSF quantification have shown conflicting data regarding the levels of AB42, AB40^{2 3} and amyloid precursor protein (APP).⁴ Notably, no studies have focused on the possible association between AB pathology and cognitive status in HD. <h3>Aims</h3> To investigate the utility of CSF amyloid-beta peptides as biomarkers of cognitive status in HD. <h3>Methods</h3> A descriptive cross-sectional study was conducted in genetically confirmed HD patients and age-matched healthy controls. CSF levels of AB42, AB40, AB42/AB40 ratio, neurofilament (NfL), total tau (t-Tau), and phosphorylated tau (pTau231) were quantified using the Simoa platform. Clinical and motor assessments were performed to evaluate disease severity. A comprehensive neuropsychological assessment was conducted focusing on global cognition using the Parkinson’s Disease-Cognitive Rating Scale (PD-CRS) and on standardized assessments covering episodic memory, language, executive function and attention, processing speed, and visuoperceptive/visuospatial processes. <h3>Results</h3> Seventy-nine individuals were included: 51 HD patients (27 premanifest, 24 manifest) and 28 controls [table 1]. While no differences were observed in AB42 or AB40 levels between groups. A statistically significant difference was found in the AB42/AB40 ratio (p=0,012) [table 2]. None of the patients exhibited pathological levels of AB42 or the AB42/AB40 ratio. The AB42/AB40 ratio and AB42 CSF levels showed no association with cognitive status. Conversely, NfL, t-Tau, and p231Tau CSF levels were negatively associated with cognition in several tests [table 3]. <h3>Conclusions</h3> Our findings suggest that, contrarily to NfL and Tau, CSF measurement of amyloid-beta peptides may not serve as a useful biomarker of cognitive status in HD. <h3>References</h3> Davis MY, Keene CD, Jayadev S, Bird T. The co-occurrence of Alzheimer’s disease and Huntington’s disease: a neuropathological study of 15 elderly Huntington9s disease subjects. <i>J Huntingtons Dis</i>. 2014;<b>3</b>(2):209–17. doi: 10.3233/JHD-140111. Ye LQ, Li XY, Zhang YB, Cheng HR, Ma Y, Chen DF, Tao QQ, Li HL, Wu ZY. The discriminative capacity of CSF AB-amyloid 42 and Tau in neurodegenerative diseases in the Chinese population. <i>J Neurol Sci.</i> 2020 May 15;<b>412</b>:116756. doi: 10.1016/j.jns.2020.116756. Korpela S, Sundblom J, Zetterberg H, Constantinescu R, Svenningsson P, Paucar M, Niemelä V. Cerebrospinal fluid glial fibrillary acidic protein, in contrast to amyloid beta protein, is associated with disease symptoms in Huntington9s disease. <i>J Neurol Sci</i>. 2024 Apr 15;<b>459</b>:122979. doi: 10.1016/j.jns.2024.122979. Lowe AJ, Sjödin S, Rodrigues FB, Byrne LM, Blennow K, Tortelli R, <i>et al</i>. Cerebrospinal fluid endo-lysosomal proteins as potential biomarkers for Huntington9s disease. <i>PLoS ONE</i>. 2020;<b>15</b>(8):e0233820. doi: 10.1371/journal.pone.0233820.