Rationale in Imaging Neurodegenerative Diseases

In order to focus on problems of imaging neurodegen-erative diseases, it might be useful to start from some basic observations on such diseases, correlating pathology with diagnostic imaging.

Generally, neuropsychological impairment of neu-rodegenerative diseases is due to biochemical alterations, structural abnormalities and circuit impairment, which are interrelated. Biochemical changes occur earlier than histological and macroscopic alterations, preceding clinical symptoms. In AD, neuronal loss is more prominent in temporal and parietal lobes, particularly in entorhinal cortex, hippocampus and amygdala, withvolume reduction ofbrain and enlargement of cerebrospinal fluid spaces (CSF) [4]. Areas of neuronal loss vary according to the underlying disease: AD patients have significantly smaller left temporal lobes and parahippocampal gyri than those with dementia with Lewy bodies [5-7]. In addition, volume loss and cognitive impairment have been shown to be associted with genotype, particularly with APOE epsi-lon4 allele [8 -12]. Volume loss of hippocampal formation, which correlates with functional impairment, has been observed in preclinical AD patients, and volume loss rate is predictive of disease progression [13-18].

The volume of entorhinal cortex predicts development of AD [19-21]. In addition, and as a consequence of neuronal loss, there is a deafferentation with degeneration of white matter (WM) and reduction of connectivity between cerebral regions. Basal ganglia ferritin iron levels are increased in AD [22].

In clinical settings, a standard MR protocol in neu-rodegenerative disease includes T1, proton density (PD) and T2 weighted images in at least axial and coronal planes. Fast-fluid inversion recovery (fast FLAIR) sequences can replace PD images. Three-dimensional T1-weighted scans, as magnetization prepared gradient echo (MPRAGE) sequences, are essential for assessing brain atrophy.

Routine MR imaging investigates gross structural changes only, allowing the assessment of brain atrophy and differential diagnosis with other diseases causing dementia. MR is crucial for excluding tumours, infectious and inflammatory diseases, providing two items of information: whether chronic ischaemic damage is present, which is included in the differential diagnosis of dementia, and a qualitative appraisal of brain atrophy by visually assessing enlargement of perivascular and subarachnoid spaces (Fig. 17.1). Visual assessment has been proven to be specific in differential diagnosis between AD and other dementia, particularly if com bined with neuropsychological assessment [23]. However, in assessing single individuals, visual estimation ofbrain atrophy in the early stages maybe not sensitive and specific enough, because atrophy occurs when dementia signs are already present. In addition, in single patients, brain atrophy is not predictive of disease progression and does not provide an accurate quantification of potential response to therapy. Hypointense signal in basal ganglia is often present in gradient echo and PD-T2 images due to accumulation of calcium and iron. Subcortical hyperintense lesions in T2-weighted images can be present and should be considered as ischaemic damage, which is superimposed on brain atrophy, and are not associated with but contribute to cognitive impairment [24-26]. Periventricular hyper-intense areas in T2-weighted images should be considered as atrophic damage and are not associated with vascular risk and dementia [25, 27].

In summary, in single individuals conventional MR does not allow early and accurate diagnosis, prediction of disease progression or quantification of potential response to therapy. Based on such findings, indications for conventional MR imaging can be as follows:

1. To do differential diagnosis with other dementia.

2. To identify concurrent diseases that may induce dementia.

Fig. 17.1. Axial T2-weighted images obtained with a 3 T MR scanner at different levels showing moderate brain atrophy with enlargement of subarachnoid spaces and ventricles

3. To quantifybrain atrophy. This is performed in daily practice by subjective visual estimation but precise estimation can also be carried out using automated tools.

4. To perform early diagnosis of degenerative disease.

The latter aim is challenging because early changes in degenerative diseases are clinically silent and patients undergo MRI only if at least mild cognitive impairment (MCI) is present. On the other hand, conventional techniques have a low sensitivity for mild volume loss: only gross structural changes are assessed in routine practice. As a result, routine MR neuroimaging is unsuitable for the latter points.

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