Cardiovascular risk factors and carotid stenosis predict cerebral haemodynamic impairment in Alzheimer’s Disease

Abstract: Alzheimer’s Disease (AD) is the most common form of progressive dementia among internistic patients. Many hypotheses have been postulated for AD pathogenesis, and there is a growing but conflicting evidence about a vascular theory (1,3). Recently, we found a significant correlation between extracranial carotid atherosclerosis, intracranial vascular reactivity and mini-mental state examination (MMSE) impairment over a 12-months observation in a cohort of 442 AD patients (2). Aims: Aim of this study was to evaluate the correlation between intracranial vascular reactivity index (breath-holding index, BHI), extracranial carotid atherosclerotic involvement and classical cardiovascular risk factors, as demographic characteristics, smoking, hypertension, diabetes and dyslipidemia in a cohort of patients affected by clinically defined AD. Patients and Methods: We enrolled 745 consecutive patients followed by the dementia ward of our University Hospital (A.O.U. Ospedali Riuniti, Ancona). Each patient underwent a standardized interview about clinical history, neuropsycological evaluation, extracranial echo-color Doppler ultrasound and transcranial doppler (TCD), testing BHI for each side. We synthesized each classical risk factor and sex into a dichotomous variable; the number of risk factors affecting a single patient were collected into an ordinal variable (ranging from 0 risk factors to 4 risk factors); extracranial echo-color Doppler result was expressed into an ordinal variable, ranging from ‘‘no stenosis’’ to ‘‘bilateral haemodynamic stenosis’’. Only hemodynamically significant ([60% of the internal carotid lumen) stenoses were considered. MMSE scores, corrected for age and sex, were collected as continuous variables. Breath-holding index, calculated by dividing the percent increase in mean flow velocity occurring during breath-holding by the length of time (in seconds) subjects hold their breath after a normal inspiration, was synthesized both as a dichotomous variable (\0.69, pathologic, [0.69, normal) (3) and as an ordinal variable (normal, monolateral pathologic and bilateral pathologic). Statistical analysis was conducted with two ordinal regression models, one considering BHI as dichotomous, the other considering BHI as ordinal. Both models included the classical risk factors, the synthetic variable for the number of risk factors and the ordinal variable for extracranial echo-color Doppler results. Results have been weighted by MMSE, age and sex. Ordinal regression was calculated with SPSS 13.0 for Windows systems. Probability of each event was calculated as 1/[1 + (ea-bx)], being a the level threshold and bx the factor level. Results: The probability of a normal BHI in AD patients decreased proportionally with the increase of the number of vascular risk factors, from 95% in patients with no risk factor to 21% of patients with four risk factors (Fig. 1, p\0.05). Extracranial echo-color Doppler ultrasound could also predict a pathological BHI: the probability of a normal BHI decreased from 73% among patients without hemodynamically significant stenosis to 21% in patients with bilateral stenosis (Fig. 2, p\0.05). Each vascular risk factor was also associated with an increase of the risk of developing a pathological (monolateral or bilateral) BHI (p\0.05). Discussion: AD is a complex disease, and its pathogenesis, still uncleared, could be related to microvascular alterations in a favourable genetic background. Hypertension, diabetes, smoking and dyslipidemia have already been associated to AD and its progression (1). Both BHI and extracranial vessels involvement can predict a worse outcome at 12 months in MMSE, independently from specific treatment and risk factors presence (2). BHI is a suitable index for cerebral hemodynamics status, and its alteration could express the final pathway of vascular derangement in AD. Classical risk factors and extracranial haemodynamic impairment could act on intracranial circulation initiating and maintaining the cascade of events responsible of AD progression.