Parkinsonism
In the case of PD, the two major diagnostic considerations are either conditions that produce tremor but are not associated with dopamine deficiency (i.e. essential tremor or dystonic tremor) or other conditions that result in an akinetic-rigid syndrome, such as multiple system atrophy (MSA) or progressive supranuclear palsy (PSP). Imaging with radiotracers that assess presynaptic dopamine function such as single photon emission computed tomography (SPECT) using the dopamine transporter (DAT) ligand [
123I]FP-CIT (DaTscan) will reliably differentiate between PD and ET [
2]. Several studies in which imaging was conducted as an outcome measure in patients thought to have early PD found that dopamine function (assessed using DAT SPECT or [
18F]F-dopa PET) was preserved in approximately 15% of patients [
3,
4]. This phenomenon, which has become known as Scans Without Evidence of Dopamine Deficiency (SWEDD) is now thought to mostly correlate with dystonic tremor [
5]. Such subjects do not show evidence of disease progression on serial DAT studies [
6], are not dependent upon dopaminergic medication [
7] and careful examination reveals the clinical features to be distinct from PD [
8,
9].
The more challenging diagnostic consideration is the separation of PD from other akinetic-rigid syndromes. While PD shows a characteristic pattern of impaired dopaminergic function that is asymmetric and affects the posterior more than the anterior striatum [
10], this pattern may also be seen in MSA [
11] and is therefore insufficient on its own to reliably differentiate between the two conditions. However, MSA is typically associated with loss of dopamine receptors, which are preserved in PD. Thus the combination of pre- and post-synaptic abnormalities of dopamine transmission may help differentiate PD from the Parkinson-plus syndromes [
11,
12]. Two other radiotracer approaches are worth considering for the differentiation of PD from other akinetic-rigid syndromes. PD is associated with a characteristic pattern of increased glucose metabolism in basal ganglia and cerebellum with concurrent reductions in multiple cortical regions, the so-called PD Related Pattern (PDRP)[
13]. This pattern is not seen in MSA, PSP or other akinetic-rigid conditions such as corticobasal syndrome and the pattern of glucose metabolism can be used for diagnostic classification with a high degree of specificity [
14,
15]. Finally, PD is frequently associated with autonomic dysfunction reflecting degeneration of sympathetic ganglia, whereas in MSA, the degeneration is predominantly central. Thus cardiac sympathetic imaging using [
123I]MIBG (SPECT), or [
11C]
m- hydroxyephedrine or [
18F]fluorodopamine (PET) is typically abnormal in PD, but preserved MSA and PSP [
16‐
18], although the differentiation may not be entirely reliable [
19].
Traditional MRI changes of MSA (increased iron deposition in globus pallidus, rim of putaminal hyperintensity, "hot cross bun sign")[
20] and PSP ("hummingbird sign")[
21] may not be entirely reliable, particularly in early disease. However, diffusion MRI may allow diagnostic differentiation [
22‐
24], and PSP may be identified by detailed measurements of the midbrain and superior cerebellar peduncles [
25]. Multimodal MR techniques assessing diffusivity (microstructural damage), fractional anisotropy (white matter tract integrity) and iron appear to separate PD from controls with a high degree of sensitivity and specificity [
26] but have not yet been routinely applied to differential diagnosis.
Dementia
MRI may clearly be of help in differentiating between Alzheimer disease (AD) and multi-infarct dementia. Amongst the other degenerative causes of dementia, dementia with Lewy bodies (DLB) and frontotemporal dementias are the most important. Structural MRI shows atrophy of the hippocampus and entorhinal cortex in AD [
27], as well as involvement of the lateral parietal, posterior superior temporal and medial posterior cingulate cortices. This is in contrast to FTD, where atrophy is more prominent in frontal or temporal poles. However, while the pattern of atrophy may help differentiate some variants of FTD, there is considerable overlap between Pick complex and AD [
28]. Newer techniques such as diffusion tensor imaging may be of greater help in the differential diagnosis of degenerative dementias. DTI has demonstrated abnormal white matter in the parietal lobes of patients with DLB compared to AD [
29].
Functional studies may be more sensitive in detecting abnormalities that differentiate various forms of dementia. Thus fMRI studies reveal reduced frontal but increased cerebellar activation during performance of a working memory task in FTD compared to AD [
30]. In recent years, there has been increasing interest in networks of connectivity that are present during rest. Activity in the so-called default mode network, which includes precuneus, posterior cingulate cortex, orbitofrontal, medial prefrontal and ventral anterior cingulate cortex, as well as inferior parietal, left dorsolateral prefrontal and left parahippocampal gyrus, is suppressed during performance of a cognitive task [
31]. Resting state or task-free fMRI identifies networks whose activity is correlated over time. Default mode network activity is reduced in AD compared to controls [
32]. In contrast, behavioural variant FTD is associated with increased activity in the default mode network but reduced activity in the so-called salience network, which encompasses fronto-insular, cingulate, striatal, thalamic and brainstem nodes [
33]. A detailed discussion of functional network disruption in degenerative dementias has recently appeared [
34].
[
18F]fluorodeoxyglucose (FDG) PET shows reduced glucose metabolism in parietotemporal cortex in AD. FDG PET has a small positive influence on sensitivity and a modest influence on specificity compared with initial clinical evaluation in AD. Positive and negative predictive values for FDG PET compared to the gold standard of pathological diagnosis are both approximately 0.8 and PET significantly enhances the diagnostic accuracy of clinical evaluation [
35]. Dementia with Lewy bodies results in a greater degree of occipital hypometabolism than AD and FDG PET may thus assist in the differentiation of the two disorders, as verified at autopsy [
36]. Similarly, FDG PET may help improve diagnostic accuracy for FTD versus AD, as the former typically affects frontal lobes, anterior temporal and anterior cingulate cortex [
37]. Dementia with Lewy bodies can also be differentiated from AD based on imaging evidence of dopamine deficiency using dopamine transporter SPECT [
38] or [
18F]F-dopa PET [
39].
While patterns of glucose hypometabolism may be helpful in distinguishing between AD and control state, as well as between AD and other dementing disorders, in recent years interest has focused on the use of agents that label amyloid. The best known of these is [
11C] labeled Pittsburgh Compound B (PiB), a thioflavin derivative that appears to be specific for β-amyloid deposition [
40]. A number of other [
18F]-labeled agents have been developed and these may prove useful, particularly for centres at some distance from a cyclotron, given the longer of half-life of [
18F] (approximately 2 hours) compared with that of [
11C] (approximately 20 minutes). PiB binding is increased in widespread cortical and subcortical regions in AD. This may clearly be helpful for the differentiation of AD from frontotemporal dementia, although a sizeable minority of FTD patients demonstrate increased PiB uptake and it is not clear whether this may represent concurrent AD pathology [
41]. PiB binding may also be present in patients with DLB or PD-dementia, but this appears to reflect binding to β-amyloid rather than to α-synuclein [
42‐
44].