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Neuroimaging in the early diagnosis of neurodegenerative disease Stoessl, A J Jan 13, 2012

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REVIEW Open AccessNeuroimaging in the early diagnosis ofneurodegenerative diseaseA Jon StoesslAbstractFunctional imaging may be useful for both the early diagnosis as well as preclinical detection ofneurodegenerative disease. Additionally, while structural imaging has traditionally been regarded as a tool toexclude alternate diagnoses, recent advances in magnetic resonance show promise for greater diagnosticspecificity. The role of MR and radionuclide imaging in early diagnosis and preclinical detection of dementia andparkinsonism are reviewed here.IntroductionNeurodegenerative disorders, of which Alzheimer’s (AD)and Parkinson’s (PD) diseases are the most common,take an enormous toll on affected patients and theirfamilies. For example, a recent analysis indicates thatdementia and PD combined affect more than 7.5 millionEuropeans, at an estimated annual cost of €120 billion[1] and incalculable suffering. While symptomatic thera-pies are currently available, they are at best imperfect(PD), at worst provide only modest benefit (dementia)and they do not have any convincing impact on theinexorable progression of the underlying disorder.Advances in basic neuroscience make it increasinglylikely that disease modifying therapies will be developedbut these are likely to have maximal impact if they areintroduced early in the course of the illness. Early dis-ease detection would permit the provision of such thera-pies to those most likely to benefit from them, at thetime that they are most likely to be effective. Early diag-nosis permits the identification of people appropriate forinclusion in clinical trials of novel therapies and theexclusion of those who are not. Finally, early diagnosisallows better prognostication and appropriate resourceutilization.A variety of neuroimaging techniques may be usefulfor the early diagnosis of neurodegenerative disorders,but one should first consider the goal. Early diagnosismay refer to the timely correct differentiation of aspecific disease entity from other conditions that maymimic it in early stages, or it may refer to the earlydetection of central nervous system dysfunction, prior tothe emergence of clinical symptoms. The latter applica-tion is more likely to be of interest in populations atincreased risk of disease, and could be useful for identi-fication of subjects to participate in trials of neuropro-tective agents, or ultimately to try and halt diseaseprogression once effective disease-modifying interven-tions have been identified.Early differential diagnosisParkinsonismIn the case of PD, the two major diagnostic considera-tions are either conditions that produce tremor but arenot associated with dopamine deficiency (i.e. essentialtremor or dystonic tremor) or other conditions thatresult in an akinetic-rigid syndrome, such as multiplesystem atrophy (MSA) or progressive supranuclear palsy(PSP). Imaging with radiotracers that assess presynapticdopamine function such as single photon emission com-puted tomography (SPECT) using the dopamine trans-porter (DAT) ligand [123I]FP-CIT (DaTscan) will reliablydifferentiate between PD and ET [2]. Several studies inwhich imaging was conducted as an outcome measurein patients thought to have early PD found that dopa-mine function (assessed using DAT SPECT or [18F]F-dopa PET) was preserved in approximately 15% ofpatients [3,4]. This phenomenon, which has becomeknown as Scans Without Evidence of Dopamine Defi-ciency (SWEDD) is now thought to mostly correlatewith dystonic tremor [5]. Such subjects do not showCorrespondence: jstoessl@mail.ubc.caPacific Parkinson’s Research Centre, University of British Columbia &Vancouver Coastal Health, 2221 Wesbrook Mall, Vancouver, BC, V6T 2B5,CanadaStoessl Translational Neurodegeneration 2012, 1:5http://www.translationalneurodegeneration.com/content/1/1/5 Translational Neurodegeneration© 2012 Stoessl; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.evidence of disease progression on serial DAT studies[6], are not dependent upon dopaminergic medication[7] and careful examination reveals the clinical featuresto be distinct from PD [8,9].The more challenging diagnostic consideration is theseparation of PD from other akinetic-rigid syndromes.While PD shows a characteristic pattern of impaireddopaminergic function that is asymmetric and affectsthe posterior more than the anterior striatum [10], thispattern may also be seen in MSA [11] and is thereforeinsufficient on its own to reliably differentiate betweenthe two conditions. However, MSA is typically asso-ciated with loss of dopamine receptors, which are pre-served in PD. Thus the combination of pre- and post-synaptic abnormalities of dopamine transmission mayhelp differentiate PD from the Parkinson-plus syn-dromes [11,12]. Two other radiotracer approaches areworth considering for the differentiation of PD fromother akinetic-rigid syndromes. PD is associated with acharacteristic pattern of increased glucose metabolismin basal ganglia and cerebellum with concurrent reduc-tions in multiple cortical regions, the so-called PDRelated Pattern (PDRP)[13]. This pattern is not seen inMSA, PSP or other akinetic-rigid conditions such ascorticobasal syndrome and the pattern of glucose meta-bolism can be used for diagnostic classification with ahigh degree of specificity [14,15]. Finally, PD is fre-quently associated with autonomic dysfunction reflectingdegeneration of sympathetic ganglia, whereas in MSA,the degeneration is predominantly central. Thus cardiacsympathetic imaging using [123I]MIBG (SPECT), or[11C]m-hydroxyephedrine or [18F]fluorodopamine (PET)is typically abnormal in PD, but preserved MSA andPSP [16-18], although the differentiation may not beentirely reliable [19].Traditional MRI changes of MSA (increased irondeposition in globus pallidus, rim of putaminal hyperin-tensity, “hot cross bun sign”)[20] and PSP ("humming-bird sign”)[21] may not be entirely reliable, particularlyin early disease. However, diffusion MRI may allow diag-nostic differentiation [22-24], and PSP may be identifiedby detailed measurements of the midbrain and superiorcerebellar peduncles [25]. Multimodal MR techniquesassessing diffusivity (microstructural damage), fractionalanisotropy (white matter tract integrity) and iron appearto separate PD from controls with a high degree of sen-sitivity and specificity [26] but have not yet been routi-nely applied to differential diagnosis.DementiaMRI may clearly be of help in differentiating betweenAlzheimer disease (AD) and multi-infarct dementia.Amongst the other degenerative causes of dementia,dementia with Lewy bodies (DLB) and frontotemporaldementias are the most important. Structural MRIshows atrophy of the hippocampus and entorhinal cor-tex in AD [27], as well as involvement of the lateral par-ietal, posterior superior temporal and medial posteriorcingulate cortices. This is in contrast to FTD, whereatrophy is more prominent in frontal or temporal poles.However, while the pattern of atrophy may help differ-entiate some variants of FTD, there is considerable over-lap between Pick complex and AD [28]. Newertechniques such as diffusion tensor imaging may be ofgreater help in the differential diagnosis of degenerativedementias. DTI has demonstrated abnormal white mat-ter in the parietal lobes of patients with DLB comparedto AD [29].Functional studies may be more sensitive in detectingabnormalities that differentiate various forms of demen-tia. Thus fMRI studies reveal reduced frontal butincreased cerebellar activation during performance of aworking memory task in FTD compared to AD [30]. Inrecent years, there has been increasing interest in net-works of connectivity that are present during rest. Activ-ity in the so-called default mode network, whichincludes precuneus, posterior cingulate cortex, orbito-frontal, medial prefrontal and ventral anterior cingulatecortex, as well as inferior parietal, left dorsolateral pre-frontal and left parahippocampal gyrus, is suppressedduring performance of a cognitive task [31]. Restingstate or task-free fMRI identifies networks whose activ-ity is correlated over time. Default mode network activ-ity is reduced in AD compared to controls [32]. Incontrast, behavioural variant FTD is associated withincreased activity in the default mode network butreduced activity in the so-called salience network, whichencompasses fronto-insular, cingulate, striatal, thalamicand brainstem nodes [33]. A detailed discussion of func-tional network disruption in degenerative dementias hasrecently appeared [34].[18F]fluorodeoxyglucose (FDG) PET shows reducedglucose metabolism in parietotemporal cortex in AD.FDG PET has a small positive influence on sensitivityand a modest influence on specificity compared withinitial clinical evaluation in AD. Positive and negativepredictive values for FDG PET compared to the goldstandard of pathological diagnosis are both approxi-mately 0.8 and PET significantly enhances the diagnosticaccuracy of clinical evaluation [35]. Dementia with Lewybodies results in a greater degree of occipital hypometa-bolism than AD and FDG PET may thus assist in thedifferentiation of the two disorders, as verified atautopsy [36]. Similarly, FDG PET may help improvediagnostic accuracy for FTD versus AD, as the formertypically affects frontal lobes, anterior temporal andanterior cingulate cortex [37]. Dementia with Lewybodies can also be differentiated from AD based onStoessl Translational Neurodegeneration 2012, 1:5http://www.translationalneurodegeneration.com/content/1/1/5Page 2 of 6imaging evidence of dopamine deficiency using dopa-mine transporter SPECT [38] or [18F]F-dopa PET [39].While patterns of glucose hypometabolism may behelpful 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 agentsthat label amyloid. The best known of these is [11C]labeled Pittsburgh Compound B (PiB), a thioflavin deri-vative that appears to be specific for b-amyloid deposi-tion [40]. A number of other [18F]-labeled agents havebeen developed and these may prove useful, particularlyfor centres at some distance from a cyclotron, given thelonger of half-life of [18F] (approximately 2 hours) com-pared with that of [11C] (approximately 20 minutes). PiBbinding is increased in widespread cortical and subcorti-cal regions in AD. This may clearly be helpful for thedifferentiation of AD from frontotemporal dementia,although a sizeable minority of FTD patients demon-strate increased PiB uptake and it is not clear whetherthis may represent concurrent AD pathology [41]. PiBbinding may also be present in patients with DLB orPD-dementia, but this appears to reflect binding to b-amyloid rather than to a-synuclein [42-44].Early detection of preclinical diseaseParkinson’s disease[18F]F-dopa PET shows evidence of asymptomatic dopa-mine dysfunction in subjects exposed to the nigral neu-rotoxin N-methyl-4-phenyl-1,2,3,6-tetrhydropyridine(MPTP)[45] and in unaffected twins of subjects withPD, particularly monozygotic [46]. In monozygotictwins, the rate of decline in dopamine function isgreater than normal, and some of these individuals willgo on to develop symptomatic disease [46]. Progressivedecline of F-dopa uptake is also seen in individualsexposed to MPTP, associated with emergence of newclinical signs [47].Radiotracer imaging shows evidence of abnormaldopaminergic function in asymptomatic individualsfrom families with known dominantly inherited PD,such as PD due to mutations in LRRK2[48]. Using stan-dard PET measures, reductions in dopamine transporter(DAT) binding appear early, sometimes many yearsprior to the expected age of onset, whereas the emer-gence of clinical signs is associated with reduced F-dopauptake [49]. However, by using longer scan times withF-dopa, one can determine effective dopamine turnoverand this appears to be the earliest indicator of abnorm-alities in LRRK2 mutation carriers [50]. Whether abnor-mal dopamine turnover is simply the earliest measurablereflection of dopamine dysfunction in those destined todevelop disease or whether it is directly related tomutated LRRK2 function in the absence of neuronaldysfunction is as yet unclear.Abnormal dopamine function has also been detectedin asymptomatic heterozygous carriers of recessivelyinherited mutations for PD [51,52]. The significance ofthis is unclear and scan abnormalities in such indivi-duals progress much more slowly than is the case foridiopathic PD, with no evidence of clinical manifesta-tions over 5 years of follow up [53]. However, asympto-matic heterozygous single mutation carriers for bothParkin and PINK1 have morphometric abnormalities(increased basal ganglia grey matter volume)[54] as wellas evidence for motor reorganization when performing atask of internally selected finger movements [55,56].Hyposmia is a common feature of PD and may bepresent for some years prior to the manifestation ofmotor abnormalities. A number of studies have demon-strated abnormalities of DAT binding in hyposmic 1stdegree relatives of patients with PD, some of whomthen go on to develop PD at follow up [57]. Transcra-nial sonography reveals increased echogenicity in thesubstantia nigra of patients with PD, thought to reflectincreased iron deposition [58]. Hyposmic individualswho also display abnormal nigral echogenicity have ahigh likelihood of demonstrating abnormal reductions inDAT binding [59].REM sleep behaviour disorder (RBD) is associatedwith the future development of neurodegenerative dis-ease, mostly PD, in more than 50% of subjects over aperiod of 12 years [60]. Patients with isolated RBD maydemonstrate reduced striatal dopamine function asassessed by DTBZ PET [61]. A recent longitudinal studyusing SPECT found reduced DAT binding at baseline in50% of subjects, a more rapid rate of decline in DATbinding in RBD subjects compared to controls, and theemergence of PD in 3/20 RBD patients (those with thelowest DAT binding) over the follow-up period of 3years [62]. RBD has also been associated with abnormalnigral echogenicity [63] and there are recent reports ofabnormal fractional anisotropy in the midbrain and pon-tine tegmentum [64] as well as microstructural changesin the white matter of the substantia nigra [65] of RBDsubjects.DementiaIn the last decade, there has been growing interest inthe use of imaging to determine which subjects withmild cognitive impairment (MCI) may go on to developAD. Measures of entorhinal cortex, superior temporalsulcus and anterior cingulate cortex were able to discri-minate approximately 75% of those subjects withrestricted memory impairment from those who con-verted to AD within 3 years in one study [66]. Volumebased morphometry confirms the presence of early atro-phy in medial temporal structures including amygdala,anterior hippocampus, entorhinal cortex and fusiformStoessl Translational Neurodegeneration 2012, 1:5http://www.translationalneurodegeneration.com/content/1/1/5Page 3 of 6gyrus in amnestic MCI subjects who progress to AD[67], but those who convert from MCI to AD also showsigns of atrophy outside the medial temporal lobes, par-ticularly lateral temporal and parietal cortex [68]. TheAlzheimer Disease Neuroimaging Initiative follows alarge cohort of subjects with multimodal imaging. Greymatter density is reduced in amygdala, hippocampusand insula as well as frontal and temporal cortex ofMCI converters compared to MCI with stable cognitivefunction. Cortical thickness in lateral temporal cortex,inferior parietal gyrus and precuneus also differentiatesbetween the two groups [69].Diffusion tensor imaging may prove more sensitivethan traditional structural MRI measures. A recentstudy found that amnestic MCI converters had changessimilar to those seen in established AD, whereas sub-jects who did not convert had patterns similar to healthycontrols. The two amnestic MCI groups (converters vs.non-converters) were distinguished by mean diffusivityin total grey and white matter, hippocampus, insula,frontal and parietal white matter, occipital grey andwhite matter, as well as fractional anisotropy of tem-poral white matter [70].Early stages of disease may be associated with adaptivechanges in an attempt to compensate for the functionaldeficit. It is therefore of interest that MCI may be asso-ciated with increased hippocampal blood flow duringperformance of a face-name encoding task, although theresponse is decreased in patients with established AD[71]. Mild cognitive impairment is associated with glu-cose hypometabolism out of proportion to the degree ofatrophy in entorhinal cortex [72]. Entorhinal cortexhypometabolism also predicts cognitive decline inhealthy subjects, particularly those who carry the ApoE4genotype [73,74]. Progression of MCI to AD is predictedby a combination of impaired episodic memory and glu-cose hypometabolism [75], or by combining multiplebiomarkers in the form of anatomical MRI, FDG PETand CSF measures of tau:Ab[76]. Somewhat more than50% of MCI patients have evidence of abnormal amyloiddeposition on PET [77,78] and this appears to be asso-ciated with an increased risk of conversion to AD[79-81].Concluding commentsThe differential diagnosis of neurodegenerative disordersis largely based on careful clinical assessment, but ima-ging techniques may provide useful adjunctive informa-tion. In the case of PD, radiotracer imaging can identifythose who have abnormal dopaminergic function, butrelatively specialized approaches are required to differ-entiate the various conditions that may result in parkin-sonism. Standard structural MRI is of relatively limitedutility in PD, but newer techniques that assessconnectivity and microstructural damage may play arole. In the dementias, volumetric analysis of regionaltissue loss may be useful for differential diagnosis, butthe specificity is likely to be enhanced when combinedwith fMRI or FDG PET measures of cerebral activationand connectivity, as well as diffusion tensor measures ofanatomical connectivity. In the case of AD, specific ima-ging markers of abnormal protein deposition are avail-able, but this is not yet the case for the otherdegenerative dementias or for the parkinsonian condi-tions. 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Translational Neurodegeneration 2012 1:5.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitStoessl Translational Neurodegeneration 2012, 1:5http://www.translationalneurodegeneration.com/content/1/1/5Page 6 of 6


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