White matter pathology in normal pressure hydrocephalus and subcortical arteriosclerotic encephalopathy. Clinical, CSF and MRI aspects

Abstract: Normal pressure hydrocephalus (NPH) and subcortical arteriosclerotic encephalopathy (SAE) are common causes of gait disturbance, cognitive impairment and urinary incontinence in the elderly. In spite of a primarily different pathogenesis with a potentially reversible CSF dynamic disturbance in NPH and an irreversible microangiopathy in SAE, patients with NPH and SAE can present with similar symptoms and exhibit white matter changes that are difficult to distinguish, constituting a diagnostic and therapeutic challenge.The aim of this thesis was to evaluate the diagnostic, predictive and pathophysiological significance of white matter pathology in NPH and SAE by analysis of MR images and biochemical CSF markers reflecting white matter alterations. We analysed CSF markers reflecting demyelination, axonal degeneration, gliosis and neurotransmission. MR images were analysed by two separate methods; 1) A novel visual rating protocol registering the location, the extension and the shape of periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH), the number of subcortical and cortical infarctions, the flow void sign and the width of the ventricular system; 2) An objective, rule-based, semiautomatic segmentation method for quantification of PVH and DWMH. Neurological signs and symptoms and psychometric test score were quantified in all patients and in the NPH patients also three months after shunt surgery. Clinical variables were standardised and used for calculating the outcome of treatment. We included 124 patients with NPH and 19 patients with SAE. Eighty-three percent of the NPH patients improved after shunt surgery. In spite of the refined quantification of white matter changes, only minor differences were found between NPH and SAE patients. They also shared the major part of the quantified symptoms. CSF Sulfatide, a demyelination marker, was increased in all SAE patients, distinguishing between SAE and NPH patients with a sensitivity of 74% and a specificity of 94%, making it a potential diagnostic marker. Abundant PVH and DWMH preoperatively correlated with clinical improvement after shunt surgery, as did postoperative reduction in PVH, supporting the prognostic value of MRI in NPH. High CSF levels of neurofilament protein (NFL), a marker of neuronal degeneration, correlated with the severity of symptoms and with a favourable outcome after surgery which may imply that the symptoms in NPH are related to periventricular white matter changes. CSF sulfatide correlated with the amount of DWMH and NFL with both PVH and DWMH, suggesting that DWMH might relate to demyelination and PVH to neuronal axonal dysfunction. Our results of similarities in symptomatology and white matter MRI changes in NPH and SAE consequently indicate some common pathophysiological mechanism. The difference in sulfatide levels, however, suggests abundant demyelination in SAE but not in NPH. Thus, NPH and SAE, probably initiated by different pathogenic mechanisms, may in later stages comprise a common pathophysiological pathway of white matter degeneration that could further enhance the subcortical white matter pathology. The results of this study will probably improve the medical care