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The evaluation of MRI diffusion values of active demyelinating lesions in multiple sclerosis

 Multiple Sclerosis and Related Disorders, Volume 10, November 2016, Pages 97–102

Abstract

Background

Gadolinium (Gd) enhancement of lesions is the main radiologic marker for detection of activity in Multiple Sclerosis (MS). This study compares Diffusion weighted imaging (DWI) characteristics and enhancement to determine whether DWI can be used as an alternative to Gd administration.

Methods

A retrospective study of 72 patients who had MRI with Gd and DWI. Visual assessment and comparison of the Apparent Diffusion Coefficient (ADC) values on Gd+ lesions, all lesions showing restricted diffusion, 2 Gd− lesions and 1 area of normal-appearing white matter (NAWM) in each MRI were performed.

Results

DWI values were measured on 275 T2 lesions, 68 Gd+ and 207 Gd− lesions, as well as 104 NAWM. 34 Gd+ lesions showed restricted diffusion. The median ADC-minimum of Gd+ lesions was significantly lower than NAWM and even lower than Gd− lesions. Most DWI restricted lesions were also Gd+(specificity≥94%), however many Gd+ lesions did not show visually detectable restriction in DWI (sensitivity≤34%). The median ADC-minimum of symptomatic lesions was lower than asymptomatic lesions.

Conclusion

While Gd+ lesions have lower ADC-minimum, visual DWI assessment cannot replace Gd administration for identifying active lesions. Gd+ lesions showing restricted diffusion are clinically important as they are more likely associated with neurological symptoms.

Highlights

  • Diffusivity is heterogeneous in Gd+ MS lesions compared to Gd− lesions.
  • Visually restrict lesions in ADC map often enhance with Gd on T1-weighted images.
  • Visually restrict lesions in ADC map is a weak surrogate marker for enhancement.
  • Gd− enhanced study cannot be replaced by DWI/ADC.
  • Lower ADC values of lesions did correlate more tightly with the symptomatic lesions.

Keywords: Multiple sclerosis, Diffusion magnetic resonance imaging, Gadolinium, Magnetic resonance imaging, Restricted diffusion, Detection of new MRI activity.

1. Background and purpose

Conventional MRI sequences including T2/FLAIR hyperintensities and gadolinium (Gd) administration is an established paraclinical tool in diagnostic criteria of multiple sclerosis (MS) (Polman et al., 2011). MRI findings have also been widely used as surrogate markers for the monitoring of treatment efficacy in patients (Freedman et al., 2013). The importance of new activity in the course of MS was indicated in the recent revision of International Advisory Committee on Clinical Trials of MS (Lublin et al., 2014).

The gold standard in the detection of active demyelinating lesions over the course of the disease is the focal enhancement in a T1–weighted MRI after Gd injection. Serial MRI studies have shown that Gd− enhancement occurs in almost all new lesions in patients with relapsing remitting (RR) or secondary progressive (SP) forms of MS and can be sometimes detected even before the onset of clinical symptoms. Most lesions enhanced for less than 1 month and no longer than 6 months (Miller et al., 1988a, 1988b). The number of enhancing lesions increases shortly before and during clinical relapses and clinical relapses predict subsequent MRI activity (Molyneux et al., 1998). The majority of enhancing lesions however are asymptomatic (Miller et al., 1998) and are commonly seen even when there are no clinical suggestions of disease activity. The detection of a new T2 lesion, although more sensitive to detect interval activity, can be tricky in a clinical setting to monitor activity (i.e. due to long interval between serial scanning, different MRI technique, positioning or the presence of confluent lesions). It is certainly more time consuming than detecting Gd+ lesions and requires prior similarly acquired images for comparison (Sormani et al., 2013).

There are some concerns regarding using Gd− based contrast agents (GBCAs), which may justify considering an alternative MRI sequence as a substitute for a contrast enhanced MRI (CE MRI). GBCAs are sometimes, although rarely, contraindicated in situations such as in patients with acute or chronic severe renal insufficiency (glomerular filtration rate below 30 mL/min/1.73 m2) who are at increased risk for developing nephrogenic systemic fibrosis, and in patients with an allergy to GBCAs. More recently it was noted that Gd gets deposited in the body and parts of the brain and the long term effects of these deposits are not known (McDonald et al., 2015). There are not enough evidence-based studies regarding the safety of GBCAs during fetal development, and therefore these agents should be administered in pregnancy only in exceptional cases in which their usage is considered critical and the potential benefits justify the potential risk to the unborn fetus (Kanal et al, 1990, Manual on Contrast Media v9, 2014, and Thomsen et al, 2013). Lastly, the use of Gd increases the cost of MRI by some estimates of about 30% (MRI Private Costs - Scans and Rates, 2014), involving not only the cost of the GBCA but the time and personnel involved to infuse it and monitor for reactions.

Diffusion-weighted Imaging (DWI) is now routinely being used as part of the scanning protocol in MS patients and has been proposed as an adjunct for screening disease activity in MS. In some centers, restriction of diffusion in lesions has been proposed as a substitute for contrast-enhanced T1-weighted imaging to detect active or new lesions. Conflicting results have been obtained when comparing enhancing and non-enhancing lesions with respect to their appearance on DWI; some studies have reported higher apparent diffusion coefficient or mean diffusivity in non-enhancing compared with enhancing lesions (Roychowdhury et al, 2000 and Werring et al, 1999) whereas other studies of large numbers of patients and lesions have reported no significant difference between Gd+ and Gd− lesions (Filippi et al., 2000). The purpose of this study was to investigate the relationship of DWI metrics to the status of Gd− enhancement of demyelinating lesions in MS patients.

2. Patients and methods

2.1. Patients and study design

Patients were recruited via a clinical monitoring software (IMED, version 6.1) (iMed, 2014) that collects clinical and paraclinical data on more than 5000 outpatients attending the Ottawa Hospital MS Clinic since 1999. Our hospital research ethics board has approved this study and waived individual patients’ consent (OHSN-REB 20140268-01H). We screened 466 patients who attended the MS Clinic between 2007 and 2014 since the MRI scanner was updated in 2007. All patients met current international criteria for a diagnosis of MS or clinically isolated syndrome (CIS) by an experienced neurologist with the exclusion of other possible alternative diseases (such as acute disseminated encephalomyelitis or neuromyelitis optica). Only patients who had undergone MRI with Gd enhanced T1-weighted sequence and DWI protocols with available imaging in our PACS (Radiology Information System with Integrated Solutions, 2015) were included in the study. A review of the patients’ charts was performed and Expanded Disability Status Scale (EDSS) score (Kurtzke, 1983) at the time of MRI study and any clinical relapse 6 months before to 1 month after MRI studies were recorded.

2.2. MRI sequences and imaging analysis

The MRI studies were performed on either 1.5 or 3T Siemens MR Scanners. The brain MRI sequences included sagittal and axial T1, axial T2 fat suppressed, and T2-fluid-attenuated inversion recovery (T2-FLAIR) in the axial plane. DWI was acquired with a single-shot echo planar sequence in three orthogonal directions with diffusion gradients b-value of 0, 500 and 1000 s/mm2. Apparent diffusion coefficient (ADC) maps were automatically generated. The DWI was performed prior to administration of the Gd with a slice thickness of 5 mm. The ADC values are a quantitative measure of diffusivity and will have lower values in areas of restricted diffusion. These areas will appear hypointense (dark) in ADC map. Gd enhanced T1-weighted images were acquired in the axial and coronal planes after intravenous injection of 0.1 mmol/kg of Gd after approximately 5 min of injection.

The images were evaluated to detect Gd+ lesions and lesions showing restricted diffusion in DWI (hyperintense in DWI and hypointense in the ADC map). The ADC values was measured on Gd+ lesions, on all lesions showing restricted diffusion in DWI, 2 Gd− lesions, and 1 area of normal-appearing white matter (NAWM)in all MRI studies. To capture the most restricted part of the lesions, ADC measurements were performed with a sufficiently large regions-of-interest (ROIs) that included the lesions and the perilesional edema (Fig. 1) and minimum ADC values were used. This was especially useful for lesions demonstrating more heterogeneity. The maximum and average ADC values represent contribution from inflammatory edema in active lesions or gliosis in chronic lesions..

Fig. 1

Fig. 1

Method used for screening of lesions and measurement of ADC values

in ADC map.

 

2.3. Statistical analysis

Statistical analysis was performed using GraphPad Prism version 6.00 for Windows (GraphPad Prism version 6.01 for Windows). Given nonparametric pattern of measured ADC values as continuous variables, Mann-Whitney rank sum test and Wilcoxon matched-paired signed rank test were performed to compare the ADC values of lesions and NAWM. Differences in the distribution of categorical variables were also tested for statistical significance using the Fisher's exact tests. Significance was set at a P value of less than 0.05.

3. Results

Between January 2007 and July 2014, out of 466 screened patients, 72 patients (16 men, 56 women) met the inclusion criteria of having an MRI with Gd as well as DWI and available images in the PACS (It is not routine at our institution to administer Gd with every scan and often is at the discretion of the neuroradiologist). A total of 104 MRI studies were included in the analysis. The median patient age at the time of MRI was 41 years (interquartile range-IQR=18.6). The median duration of the disease at the time of the MRI study was 8.5 years (IQR=12.89 years). Median EDSS was 3 (IQR=2). More detailed patient demographic data are displayed in Table 1.

Table 1

Demographic findings of studied group.

 

Characteristic of patients (n=72) Mean±SD or Number (%)
Gender:
 Male 16(22%)
 Female 56(78%)
Age at onset 41±12.17
Disease duration 8.5±7.90
Disease course at the time of MRI (104)
 CIS 6(5.8%)
 RR 77(74%)
 SP 20(19%)
 PP 1(0.96%)
EDSS Score at the time of MRI 3±1.8

A total of 379 ADC measurements (ADC values max/min/avg/SD) were recorded on 275 lesions and 104 areas of NAWM. Out of the 275 lesions analyzed, 68 were Gd+ and 207 were Gd−. In visual assessment of DWI imaging and ADC map, 34 lesions appeared to show diffusion restriction and 241 showed no restriction (Table 2).

Table 2

Numbers of the different types of studied lesions.

 

Data analyzed Gd+ lesions Gd− lesions Total
Restricted lesions in ADC map 23 11 34
Non-restricted lesions in ADC map 45 196 241
Total 68 207 275

Diffusion restriction corresponds to lower ADC values (Le Bihan et al., 1986). As MS lesions show heterogeneous diffusion, the minimum ADC values from ROI were used as a quantitative marker for restricted diffusion depicting the most restricted part of each lesion. The median of ADC-minimum values was 626×106 mm2/s (IQR=109) for Gd+ and 936×10−6 mm2/s (IQR=213) for Gd− lesions. Corresponding values in the NAWM was 646.5×106 mm2/s (IQR=60). Pairing of data were performed between lesional and NAWM measurements in each MRI. There was a significant difference between median of ADC-minimum of Gd+ lesions versus NAWM (Difference =−20.50×106 mm2/s, P=0.0209 in unpaired and P=0.0126 in paired test). The median of ADC-minimum values in the DWI restricted and non-restricted group were 600×106 mm2/s (IQR=124.8) and 830×106 mm2/s (IQR=254) respectively (Difference=230×10−6 mm2/s, P=<0.0001). There was also a significant difference between median of ADC-minimum values of lesions showing restriction versus NAWM (Difference=−46×106 mm2/s, P=0.0093). (Table 3, Fig. 2).

Table3

Analysis of ADC metrics of different types of lesions.

 

Median 1/IQR (×10−6 mm2/s) Median2/IQR (×10−6 mm2/s) Actual Diff (Mann-Whitney)/Median of Diff (Wilcoxon test) P value (Mann- Whitney)/Median of Diff (Wilcoxon test) Sig. P<0.05
Gd+ vs. NAWM ADC min 626/109 646.5/60 −20.50/−20.50 0.0209/0.0126 Yes
ADC max 1293/439 800/130.3 493/483.5 <0.0001/<0.0001 Yes
ADC Avg 897.5/148.3 708.5/86.3 189/158.5 <0.0001/<0.0001 Yes
Gd− vs. NAWM ADC min 936/213 646.5/60 289.5/268.5 <0.0001/<0.0001 Yes
ADC MAX 1167/315 800/130.3 365.5/382 <0.0001/<0.0001 Yes
ADC AVG 1075/257.2 708.5/86.3 366.3/333 <0.0001/<0.0001 Yes
Gd+ vs. Gd− ADC min 626/109 936/213 −310/−291.5 <0.0001/<0.0001 Yes
ADC max 1293/439 1167/315 126.5/169.5 0.0020/0.0012 Yes
ADC avg 897.5/148.3 1075/257.2 −177.3/−137 <0.0001/<0.0001 Yes
ADC SD 150/92.8 80/47.75 70/62.50 <0.0001/<0.0001 Yes
Fig. 2

Fig. 2

ADC-minimum of Gd enhancing lesions vs. NAWM and non-enhancing lesions.

 

Analysis of the association of observed numbers of restricted lesions in ADC map with number of Gd+ lesions was done with Fisher’s test. Most restricted lesions showed enhancement in CE T1-weighted images (high specificity≥94%), but many Gd+ lesions showed no evidence of restricted diffusion in ADC-map (low sensitivity≤34%) (Table 4, Fig. 3). So, a visually evident lesion with restricted diffusion (hyperintense in DWI and hypointense in the ADC map) strongly predicted Gd+ lesion. However, though many Gd+ lesions quantitatively showed reduced ADC values, these changes were difficult to appreciate visually. This resulted in missing many Gd+ lesions if one were to assess activity using only DWI rather than Gd− enhancement..

Table 4

Sensitivity and specificity of restriction in ADC map for Gd enhancement.

 

Gd+ Gd−
ADC Restricted lesions 23 11
ADC non-Restricted lesions ≥45 ≥196
Total ≥68 ≥207
Sensitivity and specificity Fisher’s exact test (Significant P<0.05)
Sensitivity ≤0.3382
Specificity ≥0.9469
Positive predictive value 0.6765
Negative predictive value ≥0.8133
Relative risk ≥3.623
Odds ratio ≥9.107
Fig. 3

Fig. 3

Visually apparent ADC Restricted lesions in DWI and enhancement pattern.

 

We also observed that the median of maximum and average of ADC values were significantly higher in Gd+ vs. Gd− lesions compared to the NAWM. The mean ADC max/avg was 1293(IQR=439)/897(IQR=148)×10−6 mm2/s for Gd+ lesions, 1167(IQR=315)/1075(IQR=257)×10−6 mm2/s for Gd− lesions and 800(IQR=130)/708.5(IQR=86)×10−6 mm2/s for corresponding NAWM. The median of SD of Gd+ lesions was also significantly higher than Gd− lesions illustrating higher values in maximum ADC and lower values in minimum ADC in Gd+ vs. Gd− lesions (Table 3, Fig. 4).

Fig. 4

Fig. 4

ADC-max, ADC-average with Standard Deviation of Gad enhancing vs. non-enhancing lesions and NAWM.

 

A total of 43 relapses were recorded during the study period. In 29 recorded relapses the enhancing or restricted lesions were not able to explain anatomically the presenting symptoms or signs at the time of relapse; i.e. they were considered “asymptomatic”. In the other 12 relapses enhancing lesions seen at the time of MRI were deemed related to the presenting symptoms or signs and thus were considered “symptomatic”. Out of those, 7 relapses correlated with lesions that showed both restricted diffusion on the DWI as well as Gd− enhancement and the other 5 lesions were non-restricted in DWI. There were 2 relapses solely related to the lesions showing restricted diffusion without evidence of corresponding Gd enhancement (Fig. 5). In addition, there was a weakly significant difference (P=0.042) between median ADC min of symptomatic vs. asymptomatic lesions in the Gd+ lesions. Our data did not show a significant difference between ADC maximum/average of symptomatic versus asymptomatic lesions (Table 5, Fig. 6) in the Gd+ lesions...

Fig. 5

Fig. 5

Symptomatic vs asymptomatic lesions in Gd enhancing or restricted lesions.

 

Table 5

Analysis of ADC values of symptomatic vs. asymptomatic lesions in enhancing lesions.

 

Median 1/IQR Symptomatic (×10−6 mm2/s) Median 2/IQR Asymptomatic (×10−6 mm2/s) Actual Diff (Mann-Whitney) P value (Mann- Whitney) Sig. P<0.05
Gd+ symptomatic vs. Gd+ asymptomatic lesions ADC min 578.5/87.5 630/100 −51 0.0421 Yes
ADC max 1235/665.5 1224/509 10.50 ns NO
ADC avg 837.5/206.5 871/207 −34 ns NO
Fig. 6

Fig. 6

ADC values of symptomatic vs asymptomatic enhancing lesions.

 

4. Discussion

DWI as an in vivo measure of molecular motion of water (Le Bihan et al., 1986), has been widely used to diagnose acute ischemic infarction (Warach et al., 1996) and also to detect diffusion alterations in active inflammatory lesions (Filippi et al., 2003). DWI can provide quantitative estimates of tissue damage in MS because the permeability and structural barriers to the diffusion of water are changed in the disease. DWI and analysis of the apparent diffusion coefficient (ADC) have provided evidence for subtle progressive alterations in tissue integrity several weeks before focal leakage of the BBB and plaque formation (Werring et al., 2000). Previous limited studies have shown a possible correlation between lesion enhancement and their degree of restricted diffusion (Eisele et al., 2012). Our data is in keeping with other studies that have shown that diffusivity is higher in chronic MS plaques than in NAWM, and diffusion characteristics of chronic lesions differ from those of acute lesions (Larsson et al, 1992 and Christiansen et al, 1993).

In prior limited studies of patients with MS and acute disseminated encephalomyelitis (ADEM), a reduction of the ADC has been documented in the very early phase in acute MS lesions, with cytotoxic edema mimicking the radiological features of acute stroke (Balashov et al, 2011, Bugnicourt et al, 2010, and Rosso et al, 2006). The possible mechanisms of reduced ADC include infiltration of inflammatory cells (mainly T-lymphocytes and macrophages/microglial cells) and associated macromolecules as well as cytotoxic cell swelling and disturbances of energy metabolism, , leading to reduced extracellular space (Eisele et al, 2012, Balashov et al, 2011, Rosso et al, 2006, Lucchinetti et al, 2000, Rigby et al, 2012, and Tievsky et al, 1999).

The reduced ADC signal is transient and appears only in the early stage of an acute lesion and may revert to normal or increased signal within one to two weeks (Eisele et al, 2012, Balashov et al, 2011, and Rigby et al, 2012). We believe the ADC restriction might appear before the stage of enhancement and normalizes much before the disappearance of enhancement. In our study 2 lesions showing restricted diffusion without enhancement might elude to this concept. ADC restriction is present before MRI signs of tissue destruction become prominent and might be predominantly related to parenchymal inflammation, in keeping with mitochondrial dysfunction and subsequent electrical compromise in ADC restricted lesions. Theoretically, these events might even take place in the absence of demyelination, which may be more prominent in slightly later stages of the lesion development (Eisele et al., 2012). In a serial MRI study, MS patients presenting with new symptoms and an associated lesion with reduced ADC, a characteristic sequence of signal-intensity changes was observed: 1) days 0–7: slight T2 hyperintensity and prominent ADC restriction (maximum, −66%), faint or no enhancement on postcontrast T1-weighted images; 2) days 7–10: prominent T2 hyperintensity and contrast enhancement, ADC normalization/pseudonormalization; 3) up to 4 weeks: elevated ADC values, prominent enhancement on post-contrast images; 4) after 4 weeks: partial reversibility of T2 hyperintensity, ADC elevation, and resolution of contrast enhancement (Eisele et al., 2012).

One important observation from our study was the difficulty of appreciating diffusion restriction on visual analysis of the images, though the quantitative minimum ADC values correlated well with Gd enhancement. Most lesions showing restriction in ADC maps upon visual analysis also showed Gd enhancement (specificity>94%), but relying only on the visual appearance of lesions showing restricted diffusion was a weak screening method to find Gd+ lesions, as many Gd+ lesions did not correlate with restricted diffusion on the ADC map (sensitivity<34%).

Our data did show that Gd+ lesions had lower ADC values than Gd− lesions that might differentiate active “symptomatic” lesions from older inactive or “asymptomatic” lesions. The median ADC-minimum value of Gd+ lesions was significantly, though slightly, lower than NAWM. This slight difference might not be easily visible in visual screening of DWI/ADC map, but this difference is more striking when comparing Gd+ and Gd− lesions, being lower in the former.

We observed that the ADC max of Gd+ lesions is significantly higher than ADC max of NAWM and even somewhat higher than in Gd− lesions making it a good screening tool for finding demyelinating lesions, but the difference with Gd− lesions is weak, making it a poor differentiation method between Gd+ and Gd− lesions. However, we noted wider differences between ADC values of Gd+ vs. Gd− lesions. This discrepancy confirms the variability of tissue damage in new enhancing lesions and might reflect different lesion ages (Dousset et al., 1998). A recent cohort of CIS patients suggested hyperintensity on DWI as a possible screening method for enhancing lesions (Lo et al., 2014), but most of the DWI hyperintense lesions of MS patients are old and inactive. Some areas of active lesions have elevated diffusion resulting from disruption of myelin and increased extracellular space (vasogenic) edema (Roychowdhury et al, 2000, Tievsky et al, 1999, Lo et al, 2014, and Castriota-Scanderbeg et al, 2002). The hyperintensity due to alterations of water diffusion in the lesions is more sensitive and lasts longer (may persist several months) than lesion enhancement due to transient blood-brain-barrier (BBB) disruption (which usually lasts 4–6 weeks) (Roychowdhury et al, 2000, Eisele et al, 2012, and Rosso et al, 2006). However, the persistent hyperintensity on DWI may suggest residual extracellular edema with increased diffusion, prolongation of T2 relaxation time, and the T2 shine-through effect (Lo et al., 2014).

In our study, most Gd+ lesions or visually restricted lesions did not correlate with the clinical presentation (symptoms or signs) of patients, but we observed lower ADC minimum of symptomatic Gd+ vs. asymptomatic lesions. Our study illustrates again the clinical-imaging paradox in conventional MRI sequences (with many enhancing or apparent restricted lesions being asymptomatic) and might suggest the added value of DWI quantitative data in structural study of active demyelinating lesions.

One of the main limitations of this study was that it was a retrospective study; the group was limited to what we encounter in real clinical setting, including patients of different clinical stages (i.e. early, relapsing or progressive MS) on various previous treatments including corticosteroids and immunomodulators. Another is that Gd is not routinely used for either diagnosing MS or monitoring the response to therapy at our institution. There was also a wide range between the timing of the MRI study and the presenting clinical symptoms in assessing “symptomatic” vs. “asymptomatic” lesions. Further prospective studies in a more homogenous group and more closely timed scans to clinical relapses would be needed to validate our results. Although an in-house standard MRI protocol was being followed, different MRI machines and technicians performed the studies, which produced variability in the picture quality. The definition of the ROI in many Gd+ lesions varied and contained NAWM in perilesional areas. This affected measurements, especially min & avg.-ADC of lesions. We only measured 2 Gd− lesions for every patient as a sample of Gd− lesions and more sampling might have yielded different results since the correlation of restriction in ADC-map and Gd+ lesions with clinical presentation was calculated in this limited group of measurements. Out of 104 MRI studies, 45 studies were done while patients were on DMDs. This study was underpowered to assess possible effect of DMDs on the DWI. DWI is not routinely used to evaluate the spinal cord in conventional MRI studies and was not included in our study given the technical difficulty and poor resolution of images. Spinal cord lesions tend to be more likely symptomatic and differences in diffusivity of Gd+ lesions may correlate better than they did in brain lesions.

5. Conclusion

Our study shows that diffusivity is heterogeneous in Gd+ MS lesions, which have lower minimum ADC values (restricted) and higher maximum ADC values compared to Gd− lesions as well as NAWM. Lesions that visually restrict diffusion on DWI (hyperintense in DWI and hypointense in the ADC map) often enhance with Gd on T1-weighted images (high specificity). However, though most Gd+ lesions quantitatively show decreased ADC values, it is difficult to visually appreciate diffusion restriction in these lesions resulting in a low sensitivity to predict the presence of enhancement. This makes the DWI/ADC a poor surrogate marker for enhancement and practically a Gd− enhanced study cannot be replaced by DWI/ADC. Lower ADC values of lesions did correlate more tightly with the lesions that were symptomatic. Further prospective studies in a more homogenous group and more closely timed scans to clinical relapses would be needed to validate this correlation.

Conflict of interest

We certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript.

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Footnotes

a University of Ottawa, Canada

b Department of Radiology, University of Ottawa, Department of Medical Imaging, The Ottawa Hospital, Canada

c Ottawa Hospital, General Campus, University of Ottawa, Canada

d The Ottawa Hospital Research Institute and the University of Ottawa, Canada

Corresponding author.