The matter of white matter in Alzheimer's disease. -On white matter disease from neuropathology and neuroimaging to clinical presentation

Sammanfattning: Alzheimer's disease (AD) is the most prevalent type of dementing disorder. The cortical pathology of AD has been recognized for almost a century. In later years, an associated pathological feature of AD has been identified which affects the white matter. This white matter disease (WMD), defined in the microscope, consists of a subtotal tissue loss of the white matter structural components. WMD is observed in more than 50 % of AD cases upon neuropathological investigation, but it has been more difficult to diagnose in the living patient. The mild but widespread pathology that constitutes WMD could be difficult to discriminate with computerised tomoraphy and magnetic resonance imaging (MRI). The new MRI technique diffusion tensor imaging (DTI) was thought to be suitable for the detection of WMD, both post-mortem and in-vivo. However, studies which evaluate the potential of DTI to detect true white matter pathology are lacking. The overall aim of the thesis was to find methods to translate the knowledge gained by microscopic analysis of WMD to a clinical setting to ascertain potential clinical outcome in the dementia profile of AD. This was done using neuropathology (study I, II, III and IV), post-mortem DTI (study V) and clinical DTI and symptomatology (study VI). In neuropathological study I, WMD in AD cases was shown to correspond to a significant reduction of oligodendrocytes and an increase of astrocytes compared to control cases. In neuropathological study II, it was demonstrated that increasing severity of WMD in AD cases was associated with a statistically significant reduction in myelin density. In neuropathological study III, increasing degrees of WMD in AD cases were found to correspond to gradually decreasing numbers of small vessels in the white matter. In neuropathological study IV, the regional distribution of WMD in AD was studied. WMD was found to be most pronounced in the frontal white matter followed by parietal-, frontoparietal-, temporal- and finally the occipital white matter. In the correlative neuropathological/post-mortem DTI study V, true white matter pathology verified by microscopic assessment was shown to correspond to findings on DTI. In the clinical study VI, frontal white matter changes detected by DTI, but not by conventional MRI, were found to correlate with reduced performance on tests of executive function in both AD and healthy age-matched control cases. The overall result from the neuropathological studies demonstrates that it is possible to quantitate the structural components that constitute WMD in AD with the use of neuropathological morphological methods. Specifically, WMD in AD corresponds to a quantifiable reduction of oligodendrocytes, myelin and small vessels. WMD is distributed in large regions of the brain, with accentuation in the frontal lobes. The findings of reduced numbers of small vessels that parallel increasing severity of WMD support the hypothesis of an alleged ischemic origin for WMD in AD. The correlative neuropathological/post-mortem DTI study demonstrates that DTI has the potential to detect true white matter pathology. The clinical study reveals that DTI seems to be a suitable method for detection of white matter changes which correspond to measures of cognitive dysfunction. Frontal white matter changes seem to have influence on the clinical presentation, both in AD and in healthy aging. In summary, this thesis explores WMD in AD from neuropathology via post-mortem and clinical imaging to clinical presentation.