. 2018 Jun 28;7(2):265–285. doi: 10.1007/s40120-018-0103-2

Table 1.

Application of imaging techniques for the monitoring of disease progression

Technique^a	Findings^b	Limitations	Evidence of application for disease progression monitoring
T2W and FLAIR sequences	Brain WM: PP-MS: T2-LL at baseline did not predict the rate of clinical progression at 15 years FU [19] SP-MS: T2-LL at baseline correlated with disability at 20 years FU. The annual rate of WM lesion accumulation was higher in patients developing SP-MS [20]	Detection of exclusive macroscopic damage. Not a good correlation between lesion aspects and pathological findings	Present
Spinal cord: PMS: cervical spinal cord lesion load was higher compared to RR-MS, and related to clinical disability [100] PP-MS: the presence of spinal cord lesions predicted conversion from RIS to PP-MS [102]
Post-contrast FLAIR	Cortex: SP-MS: leptomengingeal infiltrates were more frequent compared to RR-MS and tended to remain stable over time [58–60]		Absent
T1W sequences	Cortex: PMS: global cortical atrophy was more prominent compared to other ClPh and was related to motor and cognitive impairment [20, 57, 84] SP-MS: temporal cortical atrophy was accelerated [85]	Need of standardized protocols including high resolution images. The need of a reproducible and reliable method to quantify atrophy	Present Whole brain, GM and spinal cord atrophy have been used in clinical trials [30, 87–89, 116, 117]
Spinal cord: PMS: higher cervical and thoracic spinal cord atrophy compared to RR-MS and it correlated to clinical disability [100, 111] PP-MS: cervical spinal cord atrophy did not correlate with brain lesion or volume [16] SP-MS: cross-sectional area at the level of C7 presented the greatest difference compared to RR-MS [112] Results of longitudinal studies were discordant (see text)
Cerebellum: PP-MS: higher rate of atrophy compared to HC over 5 years, with greater volume loss in patients with disease progression [125, 126] SP-MS: GM volume was reduced compared to HC and atrophy of specific lobules correlate with clinical disability [123, 124]
DGM: PP-MS: atrophy of the thalami was detected since the early years and correlate with global and frontal lobe lesion load [16, 125, 133] Longitudinal studies gave discordant results across different ClPh (see text)
MT imaging	Brain WM: PMS: NAWM damage assessed by MTR was higher compared to other ClPh but did not differ between SP and PP-MS [24, 25] PP-MS: MTR values of NAWM were lower compared to HC. MTR values of the lesions were decreased compared to NAWM. Lower NAWM MTR values at baseline predicted a more severe disability progression [22, 23, 27, 28]	MTR could be influenced by several factors (axonal loss, inflammation, edema) MTR responsiveness to changes seems to be limited	Present MTR has been used in clinical trials [29–31]
Cortex: PMS: demyelination at the level of the normal appearing GM, assessed by MTR, correlated with clinical disability and was sensitive to treatment effects [27, 31, 33, 70]
Spinal cord: PMS: damage assessed by MTR was more pronounced in the pial and subpial regions compared to other ClPh. Damage was comparable between PP- and SP-MS patients [26, 103]
DTI	Brain WM: PMS: NAWM damage, assessed by diffusion imaging, was less affected in PP-MS compared to SP-MS [38, 42] PP-MS: DTI metrics were altered compared to HC. No overlap between diffusivity and T2 lesion maps suggests axonal damage and focal lesions are independent processes [38, 41] SP-MS: diffusion abnormalities were more pronounced compared to RR-MS [38, 40]	Lack of pathological specificity Need of variable sample size depending on the specific metric and area of the brain. The need to use advanced models to better describe the complexity of brain tissue and to characterize different pathological processes	Present Diffusion based MRI parameters have been used in clinical trials [30, 31, 43]
Cortex: PMS: changes in DTI metrics were more severe compared to RR-MS. DTI parameters could detect increased damage over 1 year, not correlated with T2 lesion load and brain atrophy [42, 71, 72]
Spinal cord: PMS: among PP, SP and RR patients the former had the most marked decrease of FA values in the cervical segment over a mean of 2.4 years FU [106] PP-MS: DTI metrics were altered compared to HC [105] SP-MS: DTI metrics were altered both at the level of the posterior columns and GM of the spinal cord compared to RR-MS patients. GM RD correlated with disability [103]
Cerebellum: PP-MS: altered DTI metrics at the level of the middle cerebellar peduncle compared to HC and RR-MS. They correlated with clinical disability [121]
MR spectroscopy	Brain WM: PP-MS: NAA of NAWM was found lower compared to HC but not when compared to other ClPh [47, 48]		Absent MR spectroscopy has been used in clinical trials [49]
Cortex: PMS: A NAA decrease has been found in the cortical GM [41, 82]. Longitudinal studies gave negative results [49, 83]
PET with TSPO	Brain WM: PMS: increased uptake in NAWM, related to clinical severity and patient age [52] SP-MS: the uptake was increased in NAWM compared to HC suggesting persisting inflammation [53]	Invasive and expensive tool	Absent
Cortex: PMS: persistent cortical inflammation at the level of the cortex and cortical lesions, related to clinical disability [52]
SWI/T2*	Cortex: PMS: a gradient of cortical pathology has been showed, with superficial layers involved early compared to deeper ones [81]		Absent
DGM: PMS: studies on the iron content at the level of DGM gave discordant results (see text)

Technique^a

Findings^b

Limitations

Evidence of application for disease progression monitoring

T2W and FLAIR sequences

Brain WM:

PP-MS: T2-LL at baseline did not predict the rate of clinical progression at 15 years FU [19]

SP-MS: T2-LL at baseline correlated with disability at 20 years FU. The annual rate of WM lesion accumulation was higher in patients developing SP-MS [20]

Detection of exclusive macroscopic damage.

Not a good correlation between lesion aspects and pathological findings

Present

Spinal cord:

PMS: cervical spinal cord lesion load was higher compared to RR-MS, and related to clinical disability [100]

PP-MS: the presence of spinal cord lesions predicted conversion from RIS to PP-MS [102]

Post-contrast FLAIR

Cortex:

SP-MS: leptomengingeal infiltrates were more frequent compared to RR-MS and tended to remain stable over time [58–60]

Absent

T1W sequences

Cortex:

PMS: global cortical atrophy was more prominent compared to other ClPh and was related to motor and cognitive impairment [20, 57, 84]

SP-MS: temporal cortical atrophy was accelerated [85]

Need of standardized protocols including high resolution images.

The need of a reproducible and reliable method to quantify atrophy

Present

Whole brain, GM and spinal cord atrophy have been used in clinical trials [30, 87–89, 116, 117]

Spinal cord:

PMS: higher cervical and thoracic spinal cord atrophy compared to RR-MS and it correlated to clinical disability [100, 111]

PP-MS: cervical spinal cord atrophy did not correlate with brain lesion or volume [16]

SP-MS: cross-sectional area at the level of C7 presented the greatest difference compared to RR-MS [112]

Results of longitudinal studies were discordant (see text)

Cerebellum:

PP-MS: higher rate of atrophy compared to HC over 5 years, with greater volume loss in patients with disease progression [125, 126]

SP-MS: GM volume was reduced compared to HC and atrophy of specific lobules correlate with clinical disability [123, 124]

DGM:

PP-MS: atrophy of the thalami was detected since the early years and correlate with global and frontal lobe lesion load [16, 125, 133]

Longitudinal studies gave discordant results across different ClPh (see text)

MT imaging

Brain WM:

PMS: NAWM damage assessed by MTR was higher compared to other ClPh but did not differ between SP and PP-MS [24, 25]

PP-MS: MTR values of NAWM were lower compared to HC. MTR values of the lesions were decreased compared to NAWM. Lower NAWM MTR values at baseline predicted a more severe disability progression [22, 23, 27, 28]

MTR could be influenced by several factors (axonal loss, inflammation, edema)

MTR responsiveness to changes seems to be limited

Present

MTR has been used in clinical trials [29–31]

Cortex:

PMS: demyelination at the level of the normal appearing GM, assessed by MTR, correlated with clinical disability and was sensitive to treatment effects [27, 31, 33, 70]

Spinal cord:

PMS: damage assessed by MTR was more pronounced in the pial and subpial regions compared to other ClPh. Damage was comparable between PP- and SP-MS patients [26, 103]

DTI

Brain WM:

PMS: NAWM damage, assessed by diffusion imaging, was less affected in PP-MS compared to SP-MS [38, 42]

PP-MS: DTI metrics were altered compared to HC. No overlap between diffusivity and T2 lesion maps suggests axonal damage and focal lesions are independent processes [38, 41]

SP-MS: diffusion abnormalities were more pronounced compared to RR-MS [38, 40]

Lack of pathological specificity

Need of variable sample size depending on the specific metric and area of the brain.

The need to use advanced models to better describe the complexity of brain tissue and to characterize different pathological processes

Present

Diffusion based MRI parameters have been used in clinical trials [30, 31, 43]

Cortex:

PMS: changes in DTI metrics were more severe compared to RR-MS. DTI parameters could detect increased damage over 1 year, not correlated with T2 lesion load and brain atrophy [42, 71, 72]

Spinal cord:

PMS: among PP, SP and RR patients the former had the most marked decrease of FA values in the cervical segment over a mean of 2.4 years FU [106]

PP-MS: DTI metrics were altered compared to HC [105]

SP-MS: DTI metrics were altered both at the level of the posterior columns and GM of the spinal cord compared to RR-MS patients. GM RD correlated with disability [103]

Cerebellum:

PP-MS: altered DTI metrics at the level of the middle cerebellar peduncle compared to HC and RR-MS. They correlated with clinical disability [121]

MR spectroscopy

Brain WM:

PP-MS: NAA of NAWM was found lower compared to HC but not when compared to other ClPh [47, 48]

Absent

MR spectroscopy has been used in clinical trials [49]

Cortex:

PMS: A NAA decrease has been found in the cortical GM [41, 82].

Longitudinal studies gave negative results [49, 83]

PET with TSPO

Brain WM:

PMS: increased uptake in NAWM, related to clinical severity and patient age [52]

SP-MS: the uptake was increased in NAWM compared to HC suggesting persisting inflammation [53]

Invasive and expensive tool

Absent

Cortex:

PMS: persistent cortical inflammation at the level of the cortex and cortical lesions, related to clinical disability [52]

SWI/T2*

Cortex:

PMS: a gradient of cortical pathology has been showed, with superficial layers involved early compared to deeper ones [81]

Absent

DGM:

PMS: studies on the iron content at the level of DGM gave discordant results (see text)

^aT1W/T2W T1/T2-weighted, FLAIR fluid-attenuated inversion recovery, MT magnetization transfer, DTI diffusion tensor imaging, MR magnetic resonance, PET positron-emission tomography, TSPO translocator protein, SWI susceptibility-weighted imaging

^bWM White matter, PP-MS primary progressive multiple sclerosis, RIS radiologically isolated syndrome SP-MS secondary progressive multiple sclerosis, RR-MS relapsing–remitting multiple sclerosis, PMS progressive multiple sclerosis, T2-LL T2-lesion load, FU follow-up, DGM deep grey matter, NAWM normal-appearing white matter, HC healthy controls, GM grey matter, MTR magnetization transfer ratio, NAA N-acetyl-aspartate, ClPh clinical phenotypes, RD radial diffusivity, FA fractional anisotropy