Imaging Markers in Dementia

It is increasingly recognized that both structural and functional imaging may help the clinician in the diagnosis of dementia disorders by providing specific markers for the disease process.

The clinical definition of dementia applies to several neurodegenerative disorders as well as cognitive dysfunction due to cerebrovascular disease. Although specific clinical criteria for the different dementia disorders exist, these have limited sensitivity and specificity.

Diagnostic guidelines suggest that at least one structural scan, i.e. computerized tomography (CT) or magnetic resonance imaging (MRI) should be performed in the evaluation of a dementia patient to identify space-occupying or vascular lesions (ref. 1, ref. 2).

Functional scans, i.e. single photon emission tomography (SPECT) and positron emission tomography (PET) scans, are considered optional investigations in case of diagnostic uncertainty.

However, it is increasingly recognized that both structural and functional imaging may help the clinician in the diagnosis and differential diagnosis of dementia disorders by providing specific markers for the disease process.

Imaging markers should be relevant to the disease process, and reflect the disease severity, they must perform as "surrogate markers" for the disease. In the following, surrogate markers for neurodegeneration obtained with neuroimaging, especially in Alzheimer’s disease (AD), will be reviewed.

FUNCTIONAL IMAGING MARKERS

Functional imaging in dementia include studies of unspecific markers of brain function such as cerebral blood flow (CBF) and brain glucose metabolism (CMRglc) as well as studies of neurotransmitter systems and specific disease processes in the brain, such as beta-amyloid deposition in AD.

Neuronal synaptic activity

Both CBF and CMRglc correlate to neuronal synaptic activity and have been used extensively to map regional brain activity in various diseases and thus also to detect functional impairment in dementia disorders. CBF measured with SPECT (SPECT-CBF) is a common additional investigation in dementia evaluation, but the added clinical value of SPECT-CBF in the diagnostic process is questioned.

In one study of patients with pathologically verified AD, Jagust et al. found that SPECT-CBF significantly improved the diagnostic accuracy of AD (ref. 3). In a study of patients with different dementia disorders, Talbot et al. suggested SPECT-CBF was most useful in distinguishing AD from vascular dementia and frontotemporal dementia, and least useful in differentiating between Alzheimer’s disease and Lewy body disease (ref. 4).

No added clinical value over MRI

However, when comparing SPECT-CBF to MRI in a population based sample, Scheltens et al. concluded that SPECT did not have an added clinical value over MRI (ref. 5). Measuring regional CMRglc with PET and the glucose tracer FDG in a large multicenter study, Herholz et al. found that PET had a sensitivity of 84% and a specificity of 93% in detecting very mild AD (ref. 6).

Herholz et al. used an automated statistical method, but visual methods have yielded similar results (95% and 71%, respectively) in mild or questionable dementia (ref. 7). Taken together, these studies suggests that SPECT-CBF and PET-FDG may have a role in the early detection and in the differential diagnosis of AD, but data on these methods’ added clinical value are scarce.

The degree of metabolic dysfunction measured by PET-FDG at the initial evaluation seems to be correlated to the subsequent progression of the cognitive dysfunction, suggesting that functional scanning may be helpful in establishing the prognosis for the individual patient (ref. 7).

Neurotransmitter deficit

The most prominent specific neurotransmitter deficit in AD is found in the cholinergic system. Using tracers for the nicotinic system in AD patients, reductions have been found in AchE activity as well as in nicotinic receptors (ref. 8, ref. 9, ref. 10, ref. 11, ref. 12).

Longitudinal PET scans repeated after two years have demonstrated a progressive loss of AchE activity (ref. 10). Further, treatment with AchE inhibitors have been shown to displace ligands binding to AchE as well as upregulate nicotinic receptors (ref. 9, ref. 12), suggesting that PET studies of the nicotinic system are able to monitor treatment with AchE inhibitors.

Other receptor systems are affected in AD, but at the moment it is not clear to what extent functional imaging of these systems may be used as a surrogate marker for the disease type or stage. Using PET and tracers for both the serotonin receptors as well as the dopamine receptors changes have been found in patients with AD (ref. 13, ref. 14, ref. 15).

Although serotonin dysfunction did not correlate to co-existing depression (ref. 13), reasonable correlations between dopaminergic changes and severity of extrapyramidal or psychotic symptoms have been established (ref. 14, ref. 15).

However, some receptor subtypes seem to be upregulated, while others are downregulated, and further studies are needed to clarify whether serotonin and dopamine receptor studies are of value as surrogate markers for different neuropathological or clinical subtypes of AD.

Using SPECT and PET tracers for the dopamine transporter, significant lower uptake in striatum has been found in Lewy body dementia and Parkinson dementia when compared to AD and to controls (ref. 16, ref. 17).

These few neuroimaging studies suggest that presynaptic dopamine uptake might prove useful in the differential diagnosis between AD and Lewy body dementia.

Imaging specific disease process

Extracellular deposition of beta-amyloid is one of the key neuropathological features of AD. Tracing the beta-amyloid load in the brains of AD patients with PET is one of the most promising strategies for imaging the specific disease process in AD.

Using a PET tracer of beta-amyloid in a small series of AD patients, significant increase in cortical tracer binding was found in the patient group with an inverse correlation between amyloid tracer binding and regional glucose metabolism, especially in the parietal cortex (ref. 18).

Using a different tracer that binds to both neurofibrillary tangles and amyloid plaques, a greater accumulation of tracer was observed in brain areas rich in tangles and plaques and the accumulation correlated with lower memory performance scores (ref. 19).

Tracers that target glia cell activation and thus map the gliosis following neurodegenerative diseases are currently also under investigation in dementia. In patients with AD significantly increased regional binding of a glia cell marker was found in the entorhinal, temporoparietal, and cingulate cortex (ref. 20).

Although these tracers still need further validation, it is likely that in the near future such PET tracers will be used in the early diagnosis of dementia disorders, as well as more specific markers for disease progression in trials of new therapeutic strategies.

STRUCTURAL IMAGING MARKERS

Neurodegeneration does not occur uniformly in the brain in primary degenerative disorders such as Alzheimer’s disease, Lewy body dementia or frontotemporal dementia. In particular in AD there is a pattern of hierarchical vulnerability to the pathological processes with mesial temporal (MTL) structures, i.e. hippocampus and entorhinal cortex, affected early in the disease.

Both CT and MRI are able to image this progressive neuronal loss as localized atrophy. Atrophy can be rated visually or quantitatively by volumetric measurements, however, the latter method is applicable in MRI only. (Excellent overviews of these techniques as diagnostic tools can be found in ref. 21 and ref. 22)

High quality CT studies of MTL atrophy are scarce and the increase in the diagnostic accuracy is only small to moderate. In contrast, MRI studies of MTL structures seem to be of more value. Atrophy of these structures is more easily identified on coronal MRI sections. Several studies have addressed this issue and generally, the increase in diagnostic accuracy is moderate to good (ref. 21).

Visual inspection less time consuming

From a clinical perspective, simple visual inspection of MRI is less time consuming than volumetry. In a study of AD patients and healthy controls that compared visual inspection to volumetric measurements, Wahlund et al. found that visual inspection correctly classified 96% of AD patients compared to 93% using volumetry (ref. 23), suggesting that visual inspection can be used in daily clinical practice.

As atrophy of MTL structures might occur even before symptoms of AD become evident, MRI may be used to predict the prognosis of patients with memory problems not fulfilling criteria for dementia (mild cognitive impairment – MCI).

In patients with MCI, the conversion rate to AD within 3 years increased from 15% in MCI patients with normal or above normal hippocampal volume to 46% in MCI patients with decreased hippocampal volume compared to healthy controls (ref. 24).

The same group reported a 2.5 times greater loss of hippocampal volume over one year in a longitudinal study of AD patients (ref. 25), which suggests that the rate of hippocampal atrophy may be used as a marker for disease progression.

Not specific for AD

Atrophy of MTL structures is not specific for AD. Studies which have compared MTL atrophy among different neurodegenerative disorders generally yield lower diagnostic accuracy than studies which compare AD to controls, because the specificity is lower.

Thus, Barber et al. compared patients with AD, Lewy body dementia, and vascular dementia to controls and found that the absence of MTL atrophy had a specificity of 100% and 88% for separating DLB from AD and vascular dementia respectively, but only a sensitivity of 38% (ref. 26).

In other words, MTL atrophy may be a sensitive surrogate marker for early AD when compared to healthy ageing but may not be useful in the differential diagnosis of different dementia disorders.

CONCLUSIONS

Structural imaging is considered obligatory in dementia evaluation due to its ability to detect the few cases of space-occupying lesions and to show cerebrovascular disease.

Further, there is convincing evidence that structural MRI of medial temporal lobe atrophy increases diagnostic accuracy, especially in AD vs. healthy ageing.

Functional imaging of CBF is often used as an additional tool for differential diagnosis, but in this respect evidence-based reviews show that SPECT and PET have a modest effect on the diagnostic accuracy.

However, both functional and structural imaging is increasingly being used for detecting and monitoring specific neurotransmitter deficits, characteristic neuropathological processes, and structural changes in small areas of the brain especially vulnerable to a particular disease.

Today, these imaging markers have some value with respect to their ability to detect early disease and to differentiate between different disorders, but much more information needs to be gathered in order for these techniques to be applied in daily clinical practice.

However, in the future, specific surrogate imaging markers may prove useful in early diagnosis and in monitoring therapeutic approaches that slow down disease progression.

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