Clinical and imaging study of cerebellar hemorrhages in cerebral amyloid angiopathy: Summary of the doctoral thesis in medical sciences: 321.05 - Clinical neurology

Abstract

Intracerebral hemorrhage is the second most common form of stroke, after ischemic stroke. Frequent causes of spontaneous intracerebral hemorrhage include arterial hypertension, cerebral amyloid angiopathy, aneurysmal hemorrhages, and hemorrhages resulting from vascular malformations [1]. Non-traumatic intracerebral hemorrhages account for 9–27% of all strokes worldwide [2], [3]. Overall, the incidence of intracerebral hemorrhage ranges from 12 to 31 cases per 100,000 individuals [4], [5], [6]. The incidence increases with advancing age, doubling every 10 years after the age of 35 [7]. The major risk factors for intracerebral hemorrhage remain arterial hypertension, cerebral amyloid angiopathy (CAA), advanced age, and the use of anticoagulant medications. Cerebral amyloid angiopathy (CAA), a pathology characterized by the deposition of betaamyloid peptide in small and medium-sized vessels of the brain and leptomeninges, is typically the cause of primary lobar intracerebral hemorrhages. It may occur sporadically, sometimes in association with Alzheimer’s disease (AD), or as part of a familial syndrome [8], [9], [10]. Although CAA overlaps clinically with Alzheimer’s disease, CAA represents a form of vascular dementia, whereas AD is a non-vascular dementia [11]. These two clinically distinct conditions share several pathophysiological and pathological features, including beta-amyloid (Aβ) deposition. Considering that neurodegenerative diseases exhibit characteristics of cerebrovascular pathology involving disruption of the blood–brain barrier, and cerebrovascular diseases display features of neurodegeneration, such as neuronal loss and demyelination [12], there appears to be a common link between neurodegenerative and cerebrovascular diseases that requires further elucidation and documentation [13], [14]. CAA is an increasingly important health concern as the population ages, with its prevalence rising with age and being observed in more than half of elderly individuals [15]. The disease is characterized by the progressive deposition of Aβ in the walls of cortical and leptomeningeal vessels. Other features of CAA include intracerebral hemorrhage and progressive dementia, particularly in older adults [16], [17]. Unfortunately, despite its high prevalence in the elderly, there are no therapies capable of modifying the course of the disease. Understanding the mechanisms underlying its pathology and progression remains crucial, especially as the prevalence of age-related diseases continues to increase, contributing significantly to global disability. The most important risk factor associated with CAA is advanced age, which encompasses both genetic and non-genetic risk determinants. Primary lobar intracerebral hemorrhage (ICH) is the hallmark clinical manifestation of cerebral amyloid angiopathy [18]. However, the clinical presentation may vary, and some patients may present with only subacute cognitive decline, focal neurological deficits, headache, or seizures [16]. Neuroimaging is the main component in the diagnosis and monitoring of CAA. Topographical localization of hemorrhagic lesions is based on magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) with amyloid tracers [19], [20], [21], [22], [23]. The widespread use of T2*-weighted MRI sequences over the past 15 years has led to an increased detection of cerebral microbleeds (CMBs)—small, well-defined hypointense lesions not visible on conventional MRI [24]. Histopathological studies show that CMBs correspond to focal hemosiderin deposits adjacent to small vessels affected by hypertensive angiopathy or CAA [25], [26]. The Boston criteria for the diagnosis of CAA were introduced in 1995 and incorporate imaging and histopathological markers [27]. Although these criteria represent the most widely used diagnostic tool, definitive diagnosis can only be made post-mortem, which remains a major limitation. Cerebellar involvement in CAA is a controversial and insufficiently clarified topic. Spontaneous cerebellar hemorrhages are usually associated with changes secondary to arterial hypertension [28]. However, it is hypothesized that a subgroup of cerebellar hemorrhages— whether isolated or combined with supratentorial hemorrhages—may be associated with amyloid deposition. The scientific novelty of this study lies in its original and in-depth exploration of cerebellar involvement in CAA—an area rarely addressed in the literature, which predominantly focuses on supratentorial cortico-subcortical pathology. The study proposes a comparative clinicoimaging analysis between patients with CAA with and without cerebellar involvement, highlighting the topographical relevance of cerebellar hemorrhages as a potential marker for the etiopathogenic mechanism (amyloid versus hypertensive). At the same time, the research attempts to integrate the concept of the cerebellar affectivecognitive syndrome into the spectrum of cognitive manifestations associated with CAA, suggesting that cerebellar injury may influence cognitive processing. Research Aim To investigate the role of cerebellar involvement in cerebral amyloid angiopathy (CAA), with the objective of characterizing its impact on clinico-imaging manifestations, cognitive function, and diagnostic and clinical management strategies. Objectives • To identify imaging and clinical differences between CAA patients with and without cerebellar involvement, in order to improve differential diagnosis. • To investigate the relationship between cerebellar involvement and cognitive status using standardized scores (e.g., MMSE) to highlight potential functional consequences. • To analyze the implications of cerebellar involvement for the application of the revised Boston criteria and for establishing clinical management strategies, including imaging monitoring and treatment adjustment. Methodology The study included patients diagnosed with spontaneous cerebral hemorrhages on initial CT imaging, evaluated through a retrospective–prospective cohort analysis conducted between 2009 and 2019. The study was approved by the Ethics Committee of the “Nicolae Testemițanu” State University of Medicine and Pharmacy (protocol no. 60 from 21.05.2018), as well as by the Institutional Review Board (IRB) of the Hadassah–Hebrew University Medical Center (approval HMO 1.0 20-0437-20 from 10.06.2020). Neurological deficit severity in symptomatic hemorrhages was assessed using the National Institutes of Health Stroke Scale (NIHSS), while functional disability was evaluated using the Modified Rankin Scale (mRS). Cognitive status was assessed using the Mini-Mental State Examination (MMSE). Expected Results The expected outcomes include identifying the imaging and clinical characteristics of patients with CAA, correlating these with the severity of neurological manifestations, and defining clinico-radiological profiles that may contribute to optimizing diagnosis and treatment.