Cognitive impairment as a complication of type diabetes: identification of new biomarkers

• Autores: Andrea Ciudin
• Directores de la Tesis: Cristina Hernández Pascual (dir. tes.), Rafael Simó Canonge (dir. tes.)
• Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2017
• Idioma: español
• Tribunal Calificador de la Tesis: José Álvarez Sabin (presid.), Albert Lecube Torelló (secret.), Mircea Balasa (voc.)
• Programa de doctorado: Programa de Doctorado en Medicina por la Universidad Autónoma de Barcelona
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• Resumen

  • Evidence is accumulating that type 2 diabetes (T2D) is associated with cognitive impairment and dementia, and numerous epidemiological studies have demonstrated that T2D patients have a significantly higher risk of developing dementia, in particular Alzheimer’s disease (AD). Mild cognitive impairment (MCI) is a clinically heterogeneous syndrome associated with an elevated dementia conversion rate, in particular the Alzheimer´s disease. It has been reported that diabetes is a risk factor for MCI but there is unclear if the rate of dementia conversion in MCI patients is higher in T2D patients. The aim of first part of the thesis was to explore whether T2D is a risk factor for dementia conversion in MCI patients. Therefore, we designed a longitudinal nested case-control study, including: 101 T2D patients older than 60 years with MCI matched by age and gender with 101 non-diabetic patients with MCI. The risk factors independently associated to dementia conversion from MCI, after adjusting by age, presence of diabetes, hypertension, hypercholesterolemia and time of follow-up were T2D (OR: 2.09; CI 95%: 1.15-3.79) and the presence of APOE ε4 allele (OR: 2.56; CI: 1.32-4.96). In the T2D patients group, at the first neuropsychological evaluation, the converters had a significantly higher risk score of dementia (DSDRS) than the non-converters (7,621,88 versus 6,352,62 respectively, p=0,032), for similar age (76,765,35 versus 74,656,35 years, p=0,084), as well as significantly higher prevalence of diabetic retinopathy and severe hypoglycemia.

    At present, there are no markers able to identify the T2D at risk for developing AD. As the retina shares many anatomical and physiological features with the brain, including embryological origin, it has been suggested that it may provide an easily accessible and non-invasive way of examining the pathology in the brain. The multifocal electroretinogram (mfERG) is considered the gold standard procedure in the evaluation of the retinal function, but due to its complexity is reserved only to the research. The retinal microperimetry is a simple, non-invasive surogate of the mfERG and can be easly employed in the daily clinic. On this basis, the aim of the second part of the thesis was to identify T2D patients at risk for developing AD based on the assessment of retinal neurodegeneration by means of retinal microperimetry. We have evaluated 35 T2D patients with AD matched by age, gender, hypertension and dislipidemia with 35 T2D patients with MCI. Retinal function was assessed by standard microperimetry (MAIA microperimeter 3rd generation). Brain neurodegeneration was evaluated by MRI and 18-FDG-PET. The group of T2D with AD had significantly lower retinal sensitivity than the MCI patients (17,79±6,71dB vs 21,58±4,3, p<0,001). Retinal sensitivity assessed by microperimetry correlated with parameters of brain imaging (MRI) and function (18FDG-PET), commonly included in the diagnostic procedures of patients with cognitive impairment, as well as with Alzheimer's Disease Assessment Scale-cognition sub-scale (ADAS-Cog).

    The conclusions derived from the thesis are that T2D is an independent risk factor for conversion to dementia in MCI patients, being the presence of diabetic retinopathy and hypoglycaemia important determinants of the cognitive decline in T2D with MCI. Furthermore, retinal sensitivity assessed by microperimetry discriminates between T2D patients with MCI and AD. On these bases, a holistic and integrative approach taking into account clinical factors (retinal neurodegeneration assessment by microperimetry, hypoglycaemia, diabetic retinopathy) will permit us to model a phenotype and to create a score that will permit us to better identify those T2D patients at risk of AD.

    To the best of our knowledge this approach has never been used in this setting and could be a very useful tool for identifying T2D patients at risk of developing AD.