Imaging Markers of Disease Progression in Multiple System Atrophy

Figures & data

Table 1. Neuroimaging markers used in multiple system atrophy progression studies to detect different features of neurodegeneration.

Imaging marker	Neurodegenerative feature
	Neuronal/axonal loss	Myelin disruption	Microglial activation/ gliosis	Iron content
Radiotracer imaging marker
FDG-PET	Reduced glucose metabolism
DAT-SPECT	Nigrostriatal denervation
PK11195-PET			Microglial activation
MRI marker
T1 sequences	Atrophy; diameter, area, volumes, automated volume analysis
T2 sequences	Atrophy		Signal increase	Signal decrease; R2 increase
Diffusion imaging	MD, FA, AD, FW	FA, RD	MD, FW
Iron-sensitive sequences				Signal decrease; different metrics ^†

Qualitative markers in italic and bold; quantitative markers in recte.

† Depending on the sequence (e.g., R2* with T2* or GRE sequences; phase shift values with SWI, iron percentage with SWI, SWI signal intensities).

AD: Axial diffusivity; DAT-SPECT: Dopamine transporter single-photon emission computed tomography; FA: Fractional anisotropy; FDG-PET: 18-F-fluorodeoxyglucose positron emission tomography; FW: Free water; GRE: Gradient echo sequences; MD: Mean diffusivity; R2: T2 relaxation rate; R2*: T2* relaxation rate; RD: Radial diffusivity; SWI: Susceptibility-weighted imaging.

Figure 1. Statistical parametric mapping transverse, sagittal and coronal maximum intensity projection F-maps rendered on to a stereotactically normalized MRI scan, showing within the scan interval areas of significant relative decline in [123I]β-CIT binding potential values in the caudate and anterior putamen of patients with Parkinsonian variant of multiple system atrophy compared with those with Parkinson’s disease, whereas no significant relative signal alteration was observed in the brainstem.

Numbers correspond to the x,y,z coordinates in Montreal Neurological Institute space.

Modified with permission from [11].

Figure 2. Progression of brain atrophy in Parkinsonian variant of multiple system atrophy in comparison with Parkinson’s disease.

There was no progression of brain atrophy in the Parkinson’s disease cohort and marked progression of brain atrophy in the Parkinsonian variant of multiple system atrophy cohort in regions including the striatum, midbrain, thalamus and cerebellum, as well as cortical regions such as the primary sensorimotor cortex, supplementary motor area, lateral premotor cortex, medial frontal gyrus, middle frontal gyrus, orbitofrontal cortex, insula, posterior parietal cortex and hippocampus (A) overlay onto a rendered brain surface; (B) glass brain view.

Modified with permission from [15].

Figure 3. Fluid registration of serial MRI scans was used to demonstrate regional atrophy in one multiple system atrophy patient with subsequently pathological confirmation.

This is a coronal MRI scan with voxel‐compression‐mapping overlay to demonstrate areas undergoing atrophy. The two scans revealed several differences between regions of increasing atrophy: the most prominent atrophy was found to be in the pons and middle cerebellar peduncles, as well as in the midbrain, medulla, vermis, cerebellar white matter, superior and inferior cerebellar peduncles, tegmentum and olives. Moreover, ventricular enlargement is also shown.

Reused with permission from [18].

Figure 4. Diffusivity maps at the level of mid-striatum in individual patients with the Parkinson variant of multiple system atrophy.

n = 2; (A) baseline; (B) follow-up in one patient; (C) baseline; (D) follow-up in another patient and Parkinson’s disease (E) baseline; (F) follow-up. Note the diffuse hyperintensity – corresponding to increased diffusivity – in the putamina of the patient with Parkinson variant of multiple system atrophy (arrows in A–D), which are increased at follow-up (B & D) compared with baseline examination (A & C). The Parkinson’s disease patient shows no increased diffusivity in the putamen, neither at baseline (E) nor at follow-up (F). Of the diffusivity changes during follow-up, only putaminal diffusivity increased significantly in the Parkinson variant of multiple system atrophy group, while none of the diffusivity values in the basal ganglia regions in the Parkinson’s disease patients changed at follow-up compared with baseline. Moreover, no progression of any putaminal abnormalities was shown using semiquantitative ratings of abnormalities on structural MRI.

Modified with permission from [24].

Table 2. Annual unified multiple system atrophy rating scale progression rates.

Study (year)	Cohort characteristics		Age	Disease duration	UMSARS-I		UMSARS-II		UMSARS-total		Ref.
	Subtype (n)	Diagnostic certitude	Mean ± SD	Mean ± SD	Mean ± SD	COV (%)	Mean ± SD	COV (%)	Mean ± SD	COV (%)
Wenning et al. (2013)	P > C (85)	Prob > poss	62.1 ± 7.7	5.5 ± 3.8	6.5 ± 6.0	92.3	8.2 ± 7.0	85.4	14.6 ± 11.8	80.8	[28]
Low et al. (2015)	P > C (79)	Prob	63.4 ± 8.6	NG	3.9 ± 5.8	148.7	4.6 ± 5.0	108.7	7.6 ± 8.4	110.5	[27]
Matsushima et al. (2016)^†	C > P (63)	Prob > poss	60.0 ± 8.3	3.8 ± 2.4	ND	238.6	ND	91.6	ND	ND	[30]
Low et al. (2014)^‡	C > P (50)	Prob > poss	61.1 ± 9.2	NG	5.6 ± 5.0	89.3	5.4 ± 6.6	122.2	10.8 ± 10.7	99.1	[29]
Poewe et al. (2015)^‡	P only (90)	Prob > poss	65.1 ± 8.6	3.7 ± 2.4	4.4 ± 5.7	129.5	3.5 ± 6.6	188.6	7.8 ± 10.4	133.3	[4]

† COV calculated from standardized response mean (i.e., mean score change divided by the SD of score change) given in the paper (i.e., 100%/standardized response mean).

‡ Progression rates refer to Placebo arm.

C: Cerebrellar multiple system atrophy; COV: Coefficient of variation; ND: Not determined; NG: Not given; P: Parkinsonian variant of MSA; Poss: Possible; Prob: Probable; SD: Standard deviation; UMSARS: Unified Multiple System Atrophy Rating Scale.

Figure 5. Sample size estimates based on established progression rates of clinical and neuroimaging markers.

This bar graph illustrates the number of patients per group needed in a parallel-group design trial to detect the effect of a drug with an anticipated ability to reduce the rate of progression of the clinical or neuroimaging marker by 30% over 1 year with a power of 90%.

DAT: Dopamine transporter; NNIPPS-PPS: Natural History and Neuroprotection in Parkinson plus syndrome: Parkinson Plus Scale; SEADL: Schwab and England Activity Daily Living scale; UMSARS: Unified multiple system atrophy rating scale.

Modified with permission from [5].

Table 3. Measuring disease progression with neuroimaging.

Study (year)	Cohort size	Interscan time (years; MSA-cohort)	Marker	Main results (in MSA)		Ref.
				Imaging progression	Progression rate for MSA (COV)
Nocker et al. (2012)	PD n = 11/MSA-P n = 7	1.1 ± 0.5 in MSA-P; 1.4 ± 0.6 in PD	DAT-SPECT	• Compared with PD, a relative decline of DAT binding was evident in the caudate and anterior putamen of MSA-P versus PD • No significant relative signal alteration was observed in the brainstem • No correlation of imaging progression rates with any clinical parameter (e.g., disease duration, motor progression as assessed with UPDRS)	• Relative loss of caudate DAT-binding: 26 ± 19% (73%) • Relative loss of putamen DAT-binding: 17 ± 18% (COV: 106%)	[11]
Dodel et al. (2010)	MSA-P n = 8: minocycline n = 3/ placebo n = 5	0.5	[^11C](R)-PK11195-PET	• Attenuated microglial activation in minocycline group compared with placebo (p = 0.07) • PK11195 binding correlated with none of the clinical ratings	• Significant increase of the voxel-weighted sum of [^11C](R)-PK11195 binding: 0.041 ± 0.038; (COV: 92%)	[12]
Lee et al. (2012)	MSA-C n = 33: placebo n = 17/ MSC n = 16 ^†	1	[^18F]FDG-PET	• Cerebellar glucose metabolism in FDG-PET was significantly lower at day 360 compared with baseline in both groups • Placebo group showed extensive areas of reduced glucose metabolism in the cerebellum and various cortical regions • Less decreased cerebellar glucose metabolism in the MSC-treated group	• n.a.	[13]
Brenneis et al. (2007)	PD n = 14/MSA-P n = 14	1.0 ± 0.5 in MSA- P 1.4 ± 0.6 in PD	VBM	• MSA-specific pattern of progression includes cortical areas as well as subcortical areas • Positive correlation between progression of brain atrophy and disease duration in several cortical regions • Negative correlation between progression of brain atrophy of striatum and disease duration • No correlation of brain atrophy in any region with UPDRS-III scores	• n.a.	[15]
Lee et al. (2012)	MSA-C n = 33: placebo n = 17/MSC n = 16 ^†	1	VBM	• Cerebellar gray matter density was significantly lower at day 360 compared with baseline in both groups • Placebo group showed extensive areas of reduced gray matter density in the cerebellum and various cortical regions • Less decreased gray matter density in cerebellum and different cortical areas in the MSC-treated group	• n.a.	[13]
Minnerop et al. (2010)	MSA-C n = 10/ MSA-P n = 4/ controls n = 14	1.2 ± 0.25 in MSA; 1.4 ± 0.5 in controls	VBM	• Decline of callosal thickness over time in MSA, mainly in the isthmus, but not in MSA	• n.a.	[16]
Paviour et al. (2006a)	PSP n = 24/ MSA-P n = 11/ PD n = 12/ controls n = 18	0.7 ± 0.05	BSI	• Similar atrophy rates in PD and controls • Greater regional rates of atrophy of infratentorial structures than whole-brain rates of atrophy in both PSP and MSA-P • Increase in the UPDRS-III was associated with increased rates of pontine atrophy • Increased rates of pontine, cerebellar, midbrain and whole-brain atrophy rates were associated with different neuropsychological outcome measures	• Annualized whole brain atrophy rate 1.0% ± 1.1 (COV: 110%) • Annualized pontine atrophy rate 4.5% ± 3.2 (COV: 71%) • Annualized cerebellar atrophy rate 3.2% ± 1.9 (COV: 59%)	[19]
Guevara et al. (2016)	Controls n = 10/ PD n = 20/PSP n = 12/ MSA n = 8	1.03 ± 0.08	Volumetric MRI technique (SIENA)	• Similar whole brain atrophy rates in PD and controls • Greater whole brain atrophy rates in both PSP and MSA • No significant correlations were found between annual whole brain atrophy rates and annualized clinical assessments (UPDRS III, H&Y and CGI-S)	• Annualized whole brain atrophy rates: 1.65% ± 1.1 (COV: 66.7%)	[22]
Sunwoo et al. (2014)	MSA-C n = 26: placebo n = 15/MSC n = 11 ^†	1	Automated volumetric analysis	• Significant decrease of volumes of caudate, putamen, pallidum and thalamus at 1-year follow-up • No significant difference in subcortical deep gray matter volumes of caudate, putamen and thalamus between the groups • Cortical thinning in the placebo group was more extensive • Declines in MoCA scores and phonemic fluency during the follow-up period were significantly correlated with cortical thinning of the frontal and posterior temporal areas and anterior temporal areas in the placebo group only	• Longitudinal change of putaminal volume in placebo arm: 378.20 ± 216.43 mm^3; lowest COV compared with longitudinal change of other subcortical deep gray matter volumes (COV: 57%)	[17]
Reginold et al. (2014)	MSA-P n = 12/ PSP n = 6/ controls n = 18	2.3 ± 1.4 in MSA-P; 1.6 ± 0.5 in controls	DWI ^‡ , GRE, planimetry	• No change over time in GRE and diffusivity measures (putamen, pons, MCP) in MSA-P • Significant decrease of midsagittal pontine area in MSA-P • No change over time in other planimetric measures (putamen, lateral ventricle, caudate, MCP, midbrain) • Increase of UPDRS-III values correlated with increase of diffusivity in the MCP over time in MSA-P	• Longitudinal decrease of pontine area (over 2 years of follow-up): 0.53 ± 0.33 cm^2 (COV: 62%)	[21]
Seppi et al. (2006)	MSA-P n = 10/ PD n = 10	1.3 ± 0.5 in MSA-P, 1.2 ± 0.6 in PD	DWI	• Longitudinal diffusion changes in the basal ganglia of MSA-P versus PD revealed a significant increase of putaminal diffusivity over time in MSA-P • Putaminal diffusivity change in MSA-P correlated with motor progression assessed by the UPDRS	• Increase of putaminal diffusivity: 0.09 ± 0.02 × 10^-3 mm^2/s (COV: 26%)	[24]
Pellecchia et al. (2011)	MSA-P n = 7/ MSA-C n = 4	1.0 ± 0.25	DWI	• Most prominent increase in diffusivity values in the putamen • Increases of diffusivity over time in the pons, cerebellar white matter, thalamus and frontal white matter • UPDRS III and UMSARS II did not correlate with percent changes of Trace (D) values in any brain region	• Relative increase of putaminal diffusivity: 8.8% ± 5.2% (COV: 59%)	[23]

† Same patient cohorts.

‡ In this study, diffusivity refers to the ADCs, which were measured in the slice direction only.

ADC: Apparent diffusion coefficient; BSI: Boundary shift integral; COV: Coefficient of variation; DAT-SPECT: Dopamine transporter single-photon emission computed tomography; DWI: Diffusion weighted imaging; FDG-PET: 18-F-fluorodeoxyglucose positron emission tomography; GRE: Gradient echo imaging; H&Y: Hoehn and Yahr; MSA-C: Cerebellar variant of MSA; MSA-P: Parkinsonian variant of MSA; MSC: Mesenchymal stem cells; n: Number; n.d.: Not determined; n.a.: Not applicable; PD: Parkinson’s disease; PSP: Progressive supranuclear palsy; SMA: Supplementary motor area; UPDRS: Unified Parkinson’s Disease Rating Scale; UMSARS: Unified Multiple System Atrophy Rating Scale; VBM: Voxel-based morphometry.

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