Tag: dementia

Conversion from CIS to MS Research
1. “Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study”: J Kuhle et al
-”At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres”
1. “The relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis: a monthly MRI study after triple-dose gadolinium-DTPA”: Andrea Paolillo
-”Twenty-four (39%) developed clinically definite MS by month 18. Thirty-eight (61%) were relapsefree and completed the MRI follow-up. Relapse-free patients showed a progressive median increase between baseline and month 18 in T1-LL (25%, p<0.001), but not in T2-LL (8.5%, p=ns). PBVC decreased by 1.1% (p<0.001) in a time-dependent pattern (Kendall coefficient of concordance=0.85). Exploratory subgroup analyses showed a trend towards progressive decreases in brain volume in active patients (i. e., those with at least one newly active lesion during monthly MRI scanning; Spearman’s R=-0.61; p<0.001), but not among inactive patients (Spearman’s R=-0.10; p=0.53). Significant differences in median brain volume changes between the active and inactive patient groups were found at months 12 and 18; the difference detected at month 6 was not significant. The cumulative number and volume of new Gd-enhancing lesions developed during the 6 months of frequent MRI scanning were highly correlated with PBVC over the 18-month period (Spearman R values were 0.73 and 0.85, respectively). The strongest predictor of PBVC at 18 months was the cumulative volume of newly active lesions during frequent MRI scanning [ss=-0. 83, standard error (SE)=0.07, p<0.001].”

-”This study shows that visible inflammation as detected by monthly, triple-dose Gd-enhanced MRI is an important factor in the pathogenesis of brain tissue loss in CIS patients. However, inflammation and brain atrophy do not proceed in parallel: atrophy appeared only after a delay of months following acute inflammation. Frequent MRI scanning allows for the detection of CIS patients who will develop brain atrophy in the short-term.”
1. “Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis”: L K Fisniku et al
-”Clinically isolated syndromes (CIS), such as optic neuritis, brainstem or spinal cord syndromes are frequently the first clinical presentations of multiple sclerosis. However, not all CIS patients develop multiple sclerosis and in those who do, disability is highly variable. In previous follow-up studies, brain lesions on T2-weighted MRI are associated with increased risk of multiple sclerosis and to an extent disability. We evaluated the longitudinal relationships between the MRI lesions and clinical course over a period of 20 years. CIS patients were recruited between 1984 and 1987 and previously followed up after 1, 5, 10 and 14 years. Of the 140 subjects who were initially recruited with a CIS for a baseline MRI study, we followed up 107 patients after a mean of 20.2 years (range 18-27.7). Multiple sclerosis was diagnosed as clinically definite on clinical grounds only and disability determined using the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) score. Clinically definite multiple sclerosis developed in 67 out of 107 (63%) overall: 60 out of 73 (82%) with abnormal and 7 out of 34 (21%) with normal baseline MRI. Multiple sclerosis was still relapsing-remitting in 39 (58%)–including 26 (39%) with a ‘benign’ course (EDSS < or = 3)–whilst 28 (42%) had developed secondary progression.”
1. “Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis”: G Filippini
-”Authors’ conclusions: Very low-quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses. The advantage of early treatment compared with delayed on disability-worsening was heterogeneous depending on the actual drug used and based on very low-quality evidence. Low-quality evidence suggests that the chances of relapse are less with early treatment compared with delayed. Early treatment reduced the hazard of conversion to CDMS compared either with placebo, no treatment or delayed treatment, both in short- and long-term follow-up. Low-quality evidence suggests that early treatment is associated with fewer participants with at least one serious AE compared with placebo. Very low-quality evidence suggests that, compared with placebo, early treatment leads to more withdrawals or treatment discontinuation due to AEs. Difference between drugs on short-term benefit and safety was uncertain because few studies and only indirect comparisons were available. Long-term safety of early treatment is uncertain because of inadequately reported or unavailable data.”
1. “Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis (Review): Filippini G (Cochrane Review, 2017)
-”There was a small, non-significant advantage of early treatment compared with placebo in disability worsening (6.4% fewer (13.9 fewer to 3 more) with Rebif

-”We did not find evidence of differences between early and delayed treatments for disability-worsening at a maximum of five years follow up)

-”Very low quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses.”

-”is early treatment better than later treatment”; Avonex, Betaferon, Copaxone or Rebif; “the great variability between the studies and the low quality of the evidence makes our confidence in this result low”
1. “MRI characteristics are predictive for CDMS in monofocal but not in multifocal patients with a clinically isolated syndrome:: Jessica M Nielsen et al
-”in monofocal patients, the risk for CDMS over 2 years was significantly higher when greater than or equal to 9T2 lesions or at least one Gd-enhancing lesion were present at the first even tor 3 or 6 months after the first event” (*This is M’s situation*)
1. “The Prognostic Utility of MRI in Clinically Isolated Syndrome: A Literature Review” by C. Odenthal et al
-”Published rates of conversion CIS to CDMS differ according to length of study follow-up. Five studies were identified in which subjects were followed for greater than 6 years. For follow up of 6.9, 7.2, 7.3, 14 and 20 years, total conversion rates were 48%, 60%, 85%, 68%, and 63%.

-”The risk of conversion to CDMS is greater in patients presenting with abnormal T2WI. Subjects with CIS subjects in the range of 50-70% with abnormal T2WI.”

-”Fisniku et al followed 107 subjects with CIS to 20.2 years; 82% with abnormal baseline MRI converted to CDMS, compared with 21% with normal MRI imaging”

-”In another study, 88% of subjects with abnormal MR imaging converted by 14 years, compared to 19% of those with normal scans”

-”A recent meta-analysis concluded that abnormal T2WI, regardless of lesion number, was associated with increased risk of conversion”

-”In addition to T2 lesions, increased risk of conversion to MS is associated with the presence of gadolinium-enhancing lesions”

-”The presence of at least 1 Gd-enhancing lesion is predictive of time to CDMS in monofocal but not in multifocal presentations”

-”the prognostic significance of T1 lesions has been infrequently addressed. Summers et al found that in addition to Gd-enhancing lesions, T1 lesions were predictive of cognitive dysfunction after 7 years”

-”Baseline T2 lesion number is associated with EDSS at long-term follow up to 14 years”

-”while baseline T2 lesion number was not associated with disability, the increase in T2 lesion number over the first year after presentation was predictive of EDSS at 6 years”

-”The risk of disease progression is associated with lesion location, with periventricular, callosal and cerebellar distributions being most associated with conversion to CDMS”

-”Infratentorial lesion location may be associated with increased risk of disease and disability. Since infratentorial lesions are likely to affect clinically eloquent areas, they may have greater contribution to future disability.”

-”In a large multicenter study of 468 subjects with CIS, infratentorial lesions (including the brainstem and cerebellum) were not associated with increased risk of conversion”

-”It is uncertain whether neurodegeneration is present in subjects with CIS”

-”Subjects with CIS who convert to CDMS demonstrate a greater T2LV at presentation compared with those who do not convert”

-”baseline T2LV was an independent predictor of conversion to MS by 4 years”

-”T2LV is associated with the development of future disability”

-”the rate of increase in T2LV in the first year is associated with greater long-term disability”

-”T2 lesion volume may be better suited to the prediction of disability scores other than EDSS….(T1 lesion volume) did correlate with the Multiple Sclerosis Functional Composite at 6 years. Another study found that both T1 lesion number and volume were predictive of future cognitive dysfunction”

-”reported volume reduction in a number of deep GM structures of subjects with CIS, compared with controls, including the thalamus and caudate nucleus.

-”cerebellar volume was associated with baseline tests of cerebellar function”

-”A recent study of 212 subjects did find that increased T2LV was associated with reduced volume of a number of deep GM structures”

-”In a longitudinal study of 24 subjects with CIS, Audoin et al found that the midsagittal corpus callosal area was significantly reduced at 12 months. Callosal area also correlated with progression in EDSS….in a larger cohort of 220 subjects with CIS, change in callosal area in the first 6 months after presentation was predictive of conversion to CDMS by 2 years”

-”patients with CIS had increased mean diffusivity in all WM tracts”

-”widespread reduced fractional anistropy in the WM of subjects with CIS”

-”the magnetization transfer ratio of patients with CIS differed significantly from healthy controls”

-”magnetization transfer ratio has been shown to be predictive of conversion to CDMS”

-”NAA is a metabolite considered to be exclusive to neurons”

-”Other studies found that only those patients with clinical progression demonstrated reduced NAA at presentation”

-”Myo-inositol (MIns or Ins) is a metabolite primarily concentrated in glial cells

–”They demonstrated baseline reduced NAA and increased choline”

-”The rate of increase in MIns concentration in normal-appearing WM over the first year was predictive of poor executive function at 7.2 years”

-”Functional cortical changes are present from the earliest stages of CIS. Compared with healthy controls, subjects with CIS demonstrate increased cortical activation in both cerebral hemispheres”

-”T2 hypointensity, attributable to iron deposition, is a frequent finding in subjects with MS”

-”While regional atrophy is not present at patient presentation (CIS), changes in DTI and MR spectroscopy parameters demonstrate that there is functional change occurring in normal-appearing brain tissue. Widespread increased motor cortical activation visualized on fMRI suggests that neuroplasticity is already a factor at initial presentation”

-”subjects with CIS demonstrate brain iron deposition, a feature that is characteristic of MS”
1. “Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis”: M Filippi
-”Although axonal pathology is recognized as one of the major pathological features of multiple sclerosis, it is less clear how early in its course it occurs and how it correlates with MRI-visible lesion loads. To assess this early axonal pathology, we quantified the concentration of whole-brain N-acetylaspartate (WBNAA) in a group of patients at the earliest clinical stage of the disease and compared the results with those from healthy controls. Conventional brain MRI and WBNAA using unlocalized proton magnetic resonance spectroscopy were obtained from 31 patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis and paraclinical evidence of dissemination in space, and from 16 matched controls. An additional conventional MRI scan was obtained in all patients 4-6 months later to detect dissemination of lesions in time. The mean WBNAA concentration was significantly lower in patients compared with the controls (P < 0.0001). It was not significantly different between patients with and without enhancing lesions at the baseline MRI or between patients with and without lesion dissemination in time. No correlation was found between WBNAA concentrations and lesion volumes. Widespread axonal pathology, largely independent of MRI-visible inflammation and too extensive to be completely reversible, occurs in patients even at the earliest clinical stage of multiple sclerosis. This finding lessens the validity of the current concept that the axonal pathology of multiple sclerosis is the end-stage result of repeated inflammatory events, and argues strongly in favour of early neuroprotective intervention.”
1. “Combined analysis of global and compartmental brain volume changes in early multiple sclerosis in clinical practice: A Pichler
-”At baseline, all the brain volume metrics, except cGMV, were significantly lower; and the T2-LL was significantly higher, in patients with MS rather than CIS. During the follow-up, only the PBVC was higher in MS (p = 0.008) and this difference was driven by converters from CIS to MS. Quartiles of PBVC did not allow us to predict conversion to MS, but were associated with the degree of disability.”
1. “Cognitive impairment in clinically isolated syndrome: A systematic review”: Carolina Fiorin Anhoque
-”Seven studies fulfilled the selection criteria adopted in this review. The pattern of cognitive abnormalities in CIS resembles that found in patients with MS and is characterized by attention deficit, reduced information processing speed and impaired working memory and executive functions. The frequency of cognitive impairment in CIS seems to be lower than in MS.”
1. “Cognitive impairment in patients with clinically isolated syndrome”:
Carolina Fiorin Anhoque

-” CIS patients had significantly worse performance on the Paced Auditory Serial Addition Test (PASAT) 2 seconds (P=0.009) and on verbal fluency tests (P=0.0038) than controls.”

-”CIS patients had worse cognitive performance than controls on neuropsychological tests evaluating executive functioning”
1. “Cortical involvement determines impairment 30 years after a clinically isolated syndrome”: Lukas Haider
-”Many studies report an overlap of MRI and clinical findings between patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), which in part is reflective of inclusion of subjects with variable disease duration and short periods of follow-up. To overcome these limitations, we examined the differences between RRMS and SPMS and the relationship between MRI measures and clinical outcomes 30 years after first presentation with clinically isolated syndrome suggestive of multiple sclerosis. Sixty-three patients were studied 30 years after their initial presentation with a clinically isolated syndrome; only 14% received a disease modifying treatment at any time point. Twenty-seven patients developed RRMS, 15 SPMS and 21 experienced no further neurological events; these groups were comparable in terms of age and disease duration. Clinical assessment included the Expanded Disability Status Scale, 9-Hole Peg Test and Timed 25-Foot Walk and the Brief International Cognitive Assessment For Multiple Sclerosis. All subjects underwent a comprehensive MRI protocol at 3 T measuring brain white and grey matter (lesions, volumes and magnetization transfer ratio) and cervical cord involvement. Linear regression models were used to estimate age- and gender-adjusted group differences between clinical phenotypes after 30 years, and stepwise selection to determine associations between a large sets of MRI predictor variables and physical and cognitive outcome measures. At the 30-year follow-up, the greatest differences in MRI measures between SPMS and RRMS were the number of cortical lesions, which were higher in SPMS (the presence of cortical lesions had 100% sensitivity and 88% specificity), and grey matter volume, which was lower in SPMS. Across all subjects, cortical lesions, grey matter volume and cervical cord volume explained 60% of the variance of the Expanded Disability Status Scale; cortical lesions alone explained 43%. Grey matter volume, cortical lesions and gender explained 43% of the variance of Timed 25-Foot Walk. Reduced cortical magnetization transfer ratios emerged as the only significant explanatory variable for the symbol digit modality test and explained 52% of its variance. Cortical involvement, both in terms of lesions and atrophy, appears to be the main correlate of progressive disease and disability in a cohort of individuals with very long follow-up and homogeneous disease duration, indicating that this should be the target of therapeutic interventions.”

12) “Differential Gray Matter Vulnerability in the 1 Year Following a Clinically Isolated Syndrome”: Ismail Koubiyr et al

-At baseline, GM volumes did not differ between PwCIS and HC, but hippocampal MD (mean diffusivity) was higher in PwCIS than HC (p < 0.01). Over 1 year, GM alterations became more widespread with putamen and hippocampus volumes decreasing in PwCIS (p < 0.01), and cortical thinning in different parts of the cortex along with a significant increase of MD. Hippocampus MD at baseline could predict its volume loss (R² = 0.159; p < 0.05) and cortical thinning was associated to microstructural damage (Spearman’s rho ranging from −0.424 to −0.603 with p < 0.003).

-Along with MS being a diffuse inflammatory disease, GM showed a differential vulnerability at the early stage spreading from hippocampus to the cortex. Hippocampus volume loss could be predicted by its MD at baseline.
1. “A 30-Year Clinical and Magnetic Resonance Imaging Observational Study of Multiple Sclerosis and Clinically Isolated Syndromes” by Karen K Chung, MBBS et al
-used 2010 McD criteria

-120 participants over 30 years; 80 developed MS by 30 years; in terms of EDSS:

42% remained full ambulatory (EDSS scores less than or equal to 3.5), all of

whom had RRMS; 4% had RRMS and EDSS greater than 3.5; 34% had SPMS with

EDSS greater than 3.5; and MS contributed to death in 20%

-the strongest early predictors (within 5 years of presentation) of secondary

progressive MS at 30 years were presence of baseline infratentorial lesions and

deep white matter lesions at 1 year

-people presenting with a brainstem CIS were at greater risk than those

presenting with either ON or transverse myelitis; this was consistent with the higher proportion of brainstem subjects with baseline IT lesion present compared to ON and transverse myelitis; the change in EDSS scores from nadir to 5 years was also largest in the brainstem CIS group

–Baseline EDSS scores were not significantly associated with 30-year outcome

-5-year EDSS scores greater than or equal to 2.5 was a significant predictor of SPMS following a CIS

-13 of 14 (93%) of people who progressed by greater than or equal to 2 EDSS points between nadir and 5 years had transitioned to SPMS

-for predicting 30-year EDSS score less than or equal to 3.5 vs EDSS score greater than 3.5 outcome, EDSS scores at nadir and 5 years were significant, more so than EDSS changes between these time points, and the predictive value of EDSS scores at 5 years was, unsurprisingly, greater than at earlier time points

-a greater proportion of people with nadir EDSS scores greater than or equal to 2.5 progressed to 3 year EDSS scores greater than 3.5

-the strongest early MRI predictors of 30-year EDSS scores greater than 3.5 were the presence of (1) baseline IT lesions, with 86% progressing to EDSS scores greater than 3.5 by 30 years vs 34% of those without and (2) 1 year DWM lesions, with 60% reaching EDSS scores greater than 3.5 vs 13% of those without

-30 year outcomes could, in part, be predicted by early EDSS scores and more robustly by MRI-derived regional lesion counts

-MRI lesion counts provided to be better predictors than EDSS scores and lesion location was more important than lesion number

-it was early IT and DWM lesions that had the greatest long term prognostic value…in people with baseline IT and DWM lesions by 1 year, the chances of having SPMS were 94%…those with 1 or more IT lesions by 1 year were 5 times more likely to have died due to MS than the rest of the cohort

-IT lesions have previously been linked with less favorable outcomes in people with MS after a mean follow-up of 7.7 years
1. “Differential Gray Matter Vulnerability in the 1 Year Following a Clinically Isolated Syndrome” by Ismail Koubiyr et al
-at baseline, GM volumes did not differ between PwCIS and HC, but hippocampal MD (mean diffusivity) was higher in PwCIS than HC

-over 1 year, GM alterations became more widespread with putamen and hippocampal volumes decreasing in PwCIS and cortical thinning in different parts of the cortex along with a significant increase of MD

-Hippocampus MD at baseline could predict its volume loss and cortical thinning was associated to microstructural damage

-GM showed a differential vulnerability at the early stage spreading from hippocampus to the cortex; hippocampus volume loss could be predicted by its MD at baseline

-in order to study the selective vulnerability of GM, diffusion tensor imaging (DTI) allows to explore the microstructural integrity of the structures; a few studies used this technique in CIS, showing abnormal results in the thalamus, hippocampus, and cerebellum, suggesting microstructural changes from the early stages of MS

-there was a differential vulnerability of the hippocampus compared to the rest of the GM

-in PwCIS lateral ventricles volumes increased, reflecting deep brain atrophy, whereas putamen and hippocampus volumes significantly decreased

-the mean CTh significantly decreased in 1 year; regionally, multiple brain areas of significant cortical thinning in both hemispheres were observed; this cortical thinning was noticed in the bilateral frontal and temporal lobes, left insula and right parietal lobe

-regarding microstructural changes, PwCIS showed significantly higher MD in the left frontal, left temporal, left cingulate and bilateral parietal lobes

-baseline hippocampus MD was able to predict hippocampus volume loss after 1 year; T2 LL was taken into account in this model and was not responsible for the volume loss

-mean diffusivity change from year 0 to year 1 was strongly correlated to the cortical thinning in the left frontal lobe, the right parietal lobe, and the left temporal lobe

-no correlation found between EDSS and MRI (volumetric and DTI) abnormalities; these abnormalities were not able to predict the conversion to MS after 1 year

-the present study showed differential GM vulnerability as microstructural damage spread from the deep gray matter (hippocampus) to the cortex 1 year after the CIS; this microstructural damage occurred before irreversible gray matter atrophy

-at baseline, there was no sign of GM atrophy in PwCIS compared to HC; however, microstructural damage was already present and the hippocampus was the first and only GM structure altered; the hippocampus showed increased MD compared to controls

-the damage occurring to the hippocampus was further confirmed by a significant volume loss after 1 year of follow up; the putamen showed also a significant volume loss at follow up

-the hippocampus MD was able to predict its volume loss independently of lesion volume

-microstructural abnormalities as detected by DTI in the hippocampus, preceding volume loss and predicting it, suggested that a primary tissue alteration within this structure is involved in the neurodegenerative process

-activation of microglia/macrophages, associated with demyelination and neurodegeneration, has been pathologically observed in DGM, including the hippocampus, in MS

-in EAE, microglial activation within the hippocampus has been observed in association with neuronal dysfunction and memory impairment independently of demyelination

-the persistence of the prediction after adjustment on lesion load suggests an independent mechanism

-it is well-established that GM atrophy including cortical and DGM atrophy is mainly responsible for the development of the whole brain atrophy

-it has also been suggested that meningeal inflammation and microglial activation could lead to direct pathology of the GM and some evidence of this mechanism has been observed in progressive MS

-in 1 study showing some level of DGM atrophy, lesion volume was superior to 2 cm cubed

-in another study, CIS patients with lesion load superior to 4.49 cm cubed had lower DGM volumes than those with a median lesion load inferior to 4.49cm cubed

-this suggests that in the CIS samples with lower lesion load, the pre-clinical stage developed before CIS was shorter, explaining why atrophy was not developed

-we did not observe significant cortical thinning at baseline

-we observed some cortical thinning during the follow-up period in bilateral frontal lobes, bilateral temporal lobes and left insular and right parietal lobes; these results are in line with the study by Rocca et al showing GM atrophy of frontal, temporal, and parietal lobes in CIS patients 1 year after the onset of the disease; microstructural abnormalities in the cortex appeared only after 1 year of follow up as opposed to hippocampuses

-MD of bilateral parietal lobes, left frontal, left temporal and left cingulate lobes was not only significantly increased after 1 year in PwCIS; this result did not only reflect atrophy because of CSF contamination

-A recent studying using 7 Tesla MRI showed the existence of a gradient of pathology in the cortex of MS patients, suggesting that the pathological process was driven from the pial surface and supported the role of inflammation within the cortex in relation with meningeal inflammation

-cortical volume loss seems to parallel DGM volume loss at these very early stages of MS; however, microstructural damage starts within the hippocampus first
1. “Cortical involvement determines impairment 30 years after a clinically isolated syndrome” by Lukas Haider et al
-63 patients were studied 30 years after their initial presentation with a clinically isolated syndrome; 27 developed RRMS; 15 SPMS; and 21 experienced no further neurological events

-at the 30-year follow-up, the greatest differences in MRI measures between SPMS and RRMS were the number of cortical lesions, which were higher in SPMS (the presence of cortical lesions had 100% sensitivity and 88% specificity), and grey matter volume, which was lower in SPMS

-across all subjects, cortical lesions, grey matter volume and cervical cord volume explained 60% of the variance of the EDSS; cortical lesions alone explained 43%

-grey matter volume cortical lesions and gender explained 43% of the variance of T25FW

-reduced cortical magentization transfer ratios emerged as the only significant explanatory variable for the SDMT and explained 52% of its variance

-cortical involvement, both in terms of lesions and atrophy, appears to be the main correlate of progressive disease and disability in a cohort of individuals with very long follow-up and homogenous disease duration

-cortical MTR emerged as the strongest significant predictive factor in all models to explain cognitive outcome measures

-cortical lesions were the clearest determinant of a progressive disease course and that cortical involvement 30 years after symptom onset was the dominant factor explaining both physical and cognitive outcomes

-cortical lesions were absent in all individuals who remained CIS; found in 3 of 27 who developed RRMS; present in all 15 individuals who developed SPMSe

-subpial demyelination accounted quantitatively for most of the cortical involvement

-leukocortical lesions only reveal the tip of the iceberg

-primary cortical demyelination is highly specific for MS

-disability measures were frequently explained by grey matter related to MRI measures

-a dominant role for cortical involvement for prediction of current and future disability

-current structural MRI sequences are relatively insensitive to biologically and clinically relevant aspects of tissue injury, and the networked nature of the brain

-thalamic atrophy has been repeatedly suggested as an early correlate of present and subsequent disability in MS; group differences for thalamic volume in our study were significant comparing CIS and RRMS and CIS and SPMS, RRMS compared with SPMS was far from the significance level

-cortical involvement was the main MRI feature that distinguished SPMS from RRMS
1. “Lesion location across diagnostic regions in multiple sclerosis” by Viola Pongratz et al
-in patients with CIS, lesion clusters in white matter tracts in the subcortical area have been shown to predict conversion to RRMS as did lesion clusters in the diagnostic regions

-a new subcortical lesion in a follow up MRI of a patient with CIS demonstrates dissemination in time according to the diagnostic criteria and has also been interpreted as active disease in pivotal clinical trials

-supratentorial white matter lesions neither directly abutting the ventricles nor the cortical ribbon were classified as subcortical lesions

-at baseline: subcortical lesions found in 93%

-follow up EDSS correlated with total lesion numbers in all regions but not with the number of new lesions; EDSS at baseline correlated with periventricular lesion volume only
January 21, 2025

dementia, health, mental-health, mri, multiple-sclerosis
Brain Atrophy in MS Research
1. “Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes”: N De Stefano et al
-” There was marked heterogeneity of the annualized PBVC (PBVC/y) across MS subtypes (p = 0.003), with higher PBVC/y in SP than in CIS (p = 0.003). However, this heterogeneity disappeared when data were corrected for the baseline normalized brain volume. When the MS population was divided into trial and nontrial subjects, the heterogeneity of PBVC/y across MS subtypes was present only in the second group, due to the higher PBVC/y values found in trial data in CIS (p = 0.01) and RR (p < 0.001). The estimation of the sample sizes required for demonstrating a reduction of brain atrophy in patients in a placebo-controlled trial showed that this was larger in patients with early MS than in those with the progressive forms of the disease.”

-”This first large study in untreated patients with multiple sclerosis (MS) with different disease subtypes shows that brain atrophy proceeds relentlessly throughout the course of MS, with a rate that seems largely independent of the MS subtype, when adjusting for baseline brain volume.”
1. “Reduced brain atrophy rates are associated with lower risk of disability progression in patients with relapsing multiple sclerosis treated with cladribine tablets”: N De Stefano et al
-”Compared with placebo (-0.70% ± 0.79), PBVC/y was reduced in patients treated with cladribine tablets 3.5 mg/kg (-0.56% ± 0.68, p = 0.010) and 5.25 mg/kg (-0.57% ± 0.72, p = 0.019). After adjusting for treatment group, PBVC/y showed a significant correlation with the cumulative probability of disability progression (HR = 0.67, 95% CI = 0.571, 0.787; p < 0.001), with patients with lower PBVC/y showing the highest probability of remaining free from disability progression at 2 years and vice versa”

-”Cladribine tablets given annually for 2 years in short-duration courses in patients with RMS in the CLARITY study significantly reduced brain atrophy in comparison with placebo treatment, with residual rates in treated patients being close to the physiological rates.”
1. “Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study”: Cecilie Jacobsen et al
-”Over 5 years, patients with disability progression showed significantly increased loss of whole brain (-3.8% vs -2.0%, p<0.001), cortical (-3.4% vs -1.8%, p=0.009) and putamen volume changes (-10.6% vs -3.8%, p=0.003) compared to patients with no disability progression. No significant change in white matter (WM) volume was observed when comparing progressing and non-progressing patients. Over 10 years, there was a trend for greater decrease in whole brain volume (-5.5% vs -3.7%, p=0.015) in the progressing patients. No significant changes in LV measures were detected between the patients with and without disability progression.”

-”This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow-up. Overall, GM atrophy showed better association with disease progression than WM atrophy over 5-year and 10-year follow-up”
1. “Brain atrophy and lesion load predict long term disability in multiple sclerosis”: Veronica Popescu et al
-”In the whole patient group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS and disease modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10 year EDSS with R(2)=0.74 in the whole group and R(2)=0.72 in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients (R(2)=0.68), lesion volumes in moderately impaired relapse onset patients (R(2)=0.21) and whole brain atrophy in primary progressive MS (R(2)=0.34).”

-”This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.”
1. “Eight-year follow-up study of brain atrophy in patients with MS”: E Fisher et al
-”Brain atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up. Brain atrophy at follow-up was related to lesion volumes measured during the original trial.”

-”The relation between atrophy progression and subsequent neurologic disability status suggests that atrophy progression during RRMS is clinically relevant. Therefore, atrophy progression may be a useful marker for disease progression in clinical trials. The relation between lesions and subsequent atrophy indicates that brain atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to atrophy remain undefined.”
1. “A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG)”: J H Simon
-”Significant increases were detected in third ventricle width at year 2 and lateral ventricle width at 1 and 2 years. Significant decreases in corpus callosum area and brain width were also observed at 1 and 2 years. Multiple regression analyses suggested that the number of gadolinium-enhancing lesions at baseline was the single significant contributor to change in third ventricle width. Atrophy over 1 and 2 years as indicated by enlargement of the third and lateral ventricle and shrinkage of the corpus callosum was greater for patients entering the trial with enhancing lesions. Greater disability increments over 1 and 2 years were associated with more severe third ventricle enlargement.”

-”In patients with relapsing MS and only mild to moderate disability, significant cerebral atrophy is already developing that can be measured over periods of only 1 to 2 years. The course of cerebral atrophy in MS appears to be influenced by prior inflammatory disease activity as indicated by the presence of enhancing lesions. Brain atrophy measures are important markers of MS disease progression because they likely reflect destructive and irreversible pathologic processes.”
1. “Cerebral atrophy and disability in relapsing-remitting and secondary progressive multiple sclerosis over four years”: Benjamin Turner
-”Pathology and magnetic resonance imaging (MRI) studies have provided evidence of widespread axonal loss and reductions of cerebral and spinal cord volume in multiple sclerosis (MS). Atrophy measures on MRI may be a useful surrogate marker of worsening disability in MS, but the published studies are of relatively short duration. Change in brain volume (atrophy) was measured over a four-year period in 20 patients with relapsing-remitting (RR) and 18 with secondary progressive (SP) MS using three-dimensional (3D) MRI acquired during treatment trials of interferon-beta-1a (Rebif). Brain parenchymal and lateral ventricle volume changes were determined and correlated with clinical measures. Over four years, brain parenchymal volume (BPV) decreased in RRMS and SPMS patients by 0.9% (P = 0.006) and 0.3% (P = 0.118), respectively, and the lateral ventricle volumes increased by 15% (P < 0.0001) and 13% (P < 0.0001), respectively. In RRMS patients both lateral ventricle volume (r = 0.63, P = 0.004) and BPV change (r = -0.47, P = 0.037) were related to disability change, as measured by the Expanded Disability Status Scale. Even though a small study and despite the possible confounding effects of interferon treatment, this study demonstrated an association between measures of cerebral atrophy and worsening disability. The data also provides evidence that brain atrophy can be detected early in the disease course and central white matter atrophy as reflected by ventricle enlargement appears to be a continuous process.”
1. “Cortical atrophy is relevant in multiple sclerosis at clinical onset” by Massimiliano Calabrese et al
-”Cortical thinning is a diffuse and early phenomenon in MS already detectable at clinical onset. It correlates with clinical disability and is partially independent from WM inflammatory pathology”
1. “Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes” by Catherine M Dalton et al
-”change in GMF correlated only modestly with the change in T2 lesion volume from baseline to year 3”

-”these results suggest that progressive grey matter, but not white matter, atrophy is seen in the earliest clinically observable stages of relapse onset multiple sclerosis and this is only moderate related to lesion accumulation”
1. “Brain atrophy at onset and physical disability in multiple sclerosis”: Juan Ignacio Rojas et al
-”Brain atrophy rates during the first year of disease were predictive of disease progression in our population.”
1. “Correlation of clinical findings and brain volume data in multiple sclerosis”: Yara Dadalti Fragoso
-”There was a significant correlation between higher disability and decreased brain volume (total and grey matter). Increased lesion load in the brain and higher number of relapses in the previous year were also independently correlated with decreased brain tissue volume and with increased disability. “
1. “Combined analysis of global and compartmental brain volume changes in early multiple sclerosis in clinical practice: A Pichler
-”At baseline, all the brain volume metrics, except cGMV, were significantly lower; and the T2-LL was significantly higher, in patients with MS rather than CIS. During the follow-up, only the PBVC was higher in MS (p = 0.008) and this difference was driven by converters from CIS to MS. Quartiles of PBVC did not allow us to predict conversion to MS, but were associated with the degree of disability.”

-”PBVC is the most sensitive marker of progressing atrophy and a higher PBVC was generally associated with more active disease; however, it did not serve to predict the course of MS on an individual basis, in this study.”
1. “Cortical atrophy is relevant in multiple sclerosis at clinical onset”: Massimiliano Calabrese
-”We found a significant global cortical thinning in p-MS (2.22 +/- 0.09 mm), RR-MS (2.16 +/- 0.10 mm) and SP-MS (1.98 +/- 0.11 mm) compared to CIS (2.51 +/- 0.11 mm) and HV (2.48 +/- 0.08 mm). The correlations between mean CTh and white matter (WM) lesion load was only moderate in MS (r = -0.393, p = 0.03) and absent in p-MS (r = -0.147, p = 0.422). Analysis of regional CTh revealed that the majority of cortical areas were involved not only in MS, but also in p-MS. The type of clinical picture at onset (in particular, pyramidal signs/symptoms and optic neuritis) correlated with atrophy in the corresponding cortical areas”

-”Cortical thinning is a diffuse and early phenomenon in MS already detectable at clinical onset. It correlates with clinical disability and is partially independent from WM inflammatory pathology.”
1. “Brain atrophy in relapsing-remitting multiple sclerosis: relationship with ‘black holes’, disease duration and clinical disability”: A Paolillo
-”MS patients had significantly lower supratentorial, infratentorial brain volume and corpus callosum area than healthy subjects (P<0.01). Supratentorial brain volume was significantly related to corpus callosum area (r=0.58; P<0.01) and T1 hypointense lesion load (r=0.48; P<0.01), but not with T2 hyperintense lesion load. Infratentorial/supratentorial ratio was significantly associated with disease duration and EDSS score (r=-0.34; P=0.02 and r=-0.49; P<0.01, respectively). This study documents that brain atrophy is an early MRI finding in RR MS and it is closely related to ‘black holes’ burden. The use of relative values (infratentorial/supratentorial ratio) may increase the conspicuity of correlation between clinical and MRI findings.”
1. “Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study”:
Cecilie Jacobsen

-”Over 5 years, patients with disability progression showed significantly increased loss of whole brain (-3.8% vs -2.0%, p<0.001), cortical (-3.4% vs -1.8%, p=0.009) and putamen volume changes (-10.6% vs -3.8%, p=0.003) compared to patients with no disability progression. No significant change in white matter (WM) volume was observed when comparing progressing and non-progressing patients. Over 10 years, there was a trend for greater decrease in whole brain volume (-5.5% vs -3.7%, p=0.015) in the progressing patients. No significant changes in LV measures were detected between the patients with and without disability progression.”

-”This long-term study shows that whole brain, cortical and putamen atrophy occurs throughout the 10-year follow-up of this MS cohort and is more pronounced in the group that showed disability progression at 5, but not at 10 years of follow-up. Overall, GM atrophy showed better association with disease progression than WM atrophy over 5-year and 10-year follow-up.”

14) “Brain Atrophy Is Associated with Disability Progression in Patients with MS followed in a Clinical Routine”: E Ghione et al

-”All brain volume measures differentiated MS and healthy individuals and were associated with disability progression, but the lateral ventricle volume assessment was the most feasible”

15) “Grey matter pathology in clinically early multiple sclerosis: evidence from magnetic resonance imaging”:

Declan Chard

-”In multiple sclerosis (MS) it is emerging that the most visible element of pathology, white matter (WM) lesions, represents only a fraction of the disease burden borne by the brain; non-lesional WM is also damaged, as is the grey matter (GM). Evidence is also accruing that GM damage may be a major determinant of longer-term outcomes in MS, and that such damage occurs from the earliest clinical stages of the disease”
1. “Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis”: R Zivadinov
-”Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy”
1. “Optical coherence tomography reflects brain atrophy in multiple sclerosis: A four-year study”: Shiv Saidha
-”Rates of ganglion cell + inner plexiform layer (GCIP) and whole-brain (r = 0.45; p < 0.001), gray matter (GM; r = 0.37; p < 0.001), white matter (WM; r = 0.28; p = 0.007), and thalamic (r = 0.38; p < 0.001) atrophy were associated. GCIP and whole-brain (as well as GM and WM) atrophy rates were more strongly associated in progressive MS (r = 0.67; p < 0.001) than relapsing-remitting MS (RRMS; r = 0.33; p = 0.007). However, correlation between rates of GCIP and whole-brain (and additionally GM and WM) atrophy in RRMS increased incrementally with step-wise refinement to exclude ON effects; excluding eyes and then patients (to account for a phenotype effect), the correlation increased to 0.45 and 0.60, respectively, consistent with effect modification. In RRMS, lesion accumulation rate was associated with GCIP (r = -0.30; p = 0.02) and inner nuclear layer (r = -0.25; p = 0.04) atrophy rates.”

-”Over time GCIP atrophy appears to mirror whole-brain, and particularly GM, atrophy, especially in progressive MS, thereby reflecting underlying disease progression.”
1. “Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes”: Catherine M Dalton
-”While brain atrophy occurs early in the clinical course of multiple sclerosis, exactly how early, which tissues are affected and the rate at which early atrophy occurs are unclear. Regional brain atrophy was investigated in 58 patients recruited within 3 months of onset of a clinically isolated syndrome (CIS) suggestive of multiple sclerosis, who were followed-up for 3 years. At 3 years, 31 subjects had developed multiple sclerosis as defined by the McDonald criteria, while 27 had not (13 had MRI-visible brain lesions and 14 did not). In those who developed multiple sclerosis, the mean decrease in grey matter fractional volume (GMF, as a fraction of total intracranial volume) was -0.017 (-3.3%) and was significantly larger than in the combined lesion-positive and lesion-negative CIS subjects [-0.005 (-1.1%), P = 0.001]. No decrease in white matter fractional volumes (WMF) was seen. Change in GMF correlated only modestly with the change in T2 lesion volume from baseline to year 3 (r = -0.428, P = 0.004). These results suggest that progressive grey matter, but not white matter, atrophy is seen in the earliest clinically observable stages of relapse onset multiple sclerosis, and this is only moderately related to lesion accumulation. Longer-term follow-up is required to determine whether early grey matter atrophy is associated with subsequent disability or cognitive impairment.”
1. “The longitudinal relation between brain lesion load and atrophy in multiple sclerosis: a 14 year follow up study”: D T Chard
-”Change in lesion load in the first five years was more closely correlated to disease related brain atrophy at 14 years than later changes in lesion load, although the correlation was only moderate (Spearman correlation = -0.528, p = 0.004”

-” From this, it appears that early rather than later focal lesion accumulation relates to subsequent brain atrophy, but factors unconnected directly with lesion formation probably also play a significant role in determining such atrophy”
1. “Brain atrophy in clinically early relapsing-remitting multiple sclerosis”: D T Chard
-” These results indicate that significant brain atrophy, affecting both grey and white matter, occurs early in the clinical course of multiple sclerosis. The lack of correlation between lesion load measures and WMF suggests that pathological changes in white matter may occur by mechanisms which are at least partly independent from overt lesion genesis in early multiple sclerosis.”
1. “Deep gray matter volume loss drives disability worsening in multiple sclerosis”: Arman Eshaghi
-”Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001).”

-”This large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions.”
1. “Regional brain atrophy evolves differently in patients with multiple sclerosis according to clinical phenotype”: Elisabetta Pagani
-”During follow-up, patients with relapsing-remitting MS (RRMS) differences significant atrophy around the ventricular system; pericerebellar spaces; cerebellar tentorium; putamen; corpus callosum; cingulate sulcus; hippocampus; parieto-occipital fissure; lateral fissure; and frontal, parietal, temporal, and occipital cortex. Patients with secondary progressive MS developed significant atrophy of the cingulate sulcus; pulvinar; caudate nucleus; anterior orbital gyrus; mammillary body; fourth ventricle; and regions of frontal, parietal, temporal, and occipital cortex. Patients with primary progressive MS developed significant atrophy of the bilateral central sulcus; caudate nucleus; prepontine and quadrigeminal cisterns; lateral ventricle; and regions of frontal, parietal, temporal, and occipital cortex. In all phenotypes, the development of atrophy in some regions was significantly correlated with the accumulation of T2- and T1-visible lesions and clinical disability (r = -0.57 to -0.86).”

-”In MS, brain atrophy develops involving different structures in the different phenotypes. While ventricular enlargement is predominant in RRMS, cortical atrophy seems to be more important in the progressive forms. Measures of regional brain atrophy were significantly correlated with disability, suggesting that this approach is promising for bridging the gap between clinical and MR imaging findings in MS.”
1. “Accelerated evolution of brain atrophy and “black holes” in MS patients with APOE-epsilon 4”: Christian Enzinger
-”Apolipoprotein E (APOE)-epsilon4 has been associated with an unfavorable course of multiple sclerosis (MS). The mechanisms responsible for this are unclear, although cross-sectional MRI demonstrated a higher extent of “black holes” (BHs) in such patients. Here, we have studied the impact of the APOE genotype on both the longitudinal evolution of focal (BH ratio) and global (brain volume change [BVC]) brain tissue damage. Ninety-nine MS patients underwent ApoE genotyping, clinical examination, and magnetic resonance imaging at baseline and after 2.7 +/- 1.1 years to assess lesion load (LL) and BVC. In APOE-epsilon4 patients, the annual reduction in brain volume was fivefold higher (-0.65 +/- 0.61%) than in those without APOE-epsilon4 (-0.13 +/- 0.36%; p = 0.0001). At baseline, T(2) LL and T(1) LL were non-significantly higher in epsilon4 carriers, despite a shorter disease duration and absence of significant clinical differences. During follow-up, T(1) LL increased from 1.2 +/- 2.3 ccm to 1.7 +/- 2.7 ccm in the epsilon4 group, although T(2) LL did not change, leading to a significantly higher increase in the BH ratio [(T(1) LL/T(2) LL) x 100] from 5.5 to 12.4% (p = 0.005). BH ratio remained almost constant in non-epsilon4 patients (5.0 vs 5.7%). Accelerated brain tissue loss and a higher proportion of lesions evolving into BH therefore provide magnetic resonance imaging evidence for more pronounced tissue destruction in MS patients with APOE-epsilon4.”
1. “Eight-year follow-up study of brain atrophy in patients with MS”: E Fisher
-”Brain atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up. Brain atrophy at follow-up was related to lesion volumes measured during the original trial.”

-”The relation between atrophy progression and subsequent neurologic disability status suggests that atrophy progression during RRMS is clinically relevant. Therefore, atrophy progression may be a useful marker for disease progression in clinical trials. The relation between lesions and subsequent atrophy indicates that brain atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to atrophy remain undefined.”
1. “A serial 10-year follow-up study of brain atrophy and disability progression in RRMS patients”: Robert Zivadinov
-”In multiple sclerosis (MS) patients with CDP compared to those without, the greatest effect size percentage volume change from baseline to follow-up was detected for WB (d = 0.55, -7.5% vs -5.2%, p < 0.001), followed by vCSF (d = 0.51, +41.1% vs +25.7%, p < 0.001), cortical (d = 0.49, -7.7% vs -6.2%, p = 0.001), and GM (d = 0.40, -7.1% vs -5.8%, p = 0.006) volumes. Mixed-effects model analysis, adjusted for age, sex, and treatment change, showed significant interactions between CDP status and percentage changes for WB and vCSF (p < 0.001), cortical (p = 0.02), and GM (p = 0.04) volumes.”

-”WB and cortical atrophy, and enlargement of vCSF spaces are associated with development of CDP on serial yearly MRI assessments over a period of 10 years.”
1. “A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis”: R Zivadinov
-” In the 2 years of the study the mean change for T2 and T1 lesion volumes and brain parenchymal volumes were +1.7 ml (95% confidence interval (95% CI) 1.3-2.2, p=0.005, (29.8%); +0.2 ml, 95% CI 0.15-0.26, p=0.004, (25%); and -32.3 ml, 95% CI 24.2-42.3, p<0.0001, (2.7%), respectively. Overall, 14 patients (26.4%) were judged to be cognitively impaired at baseline and 28 (52.8%) at the end of the follow up. Of the 18 neuropsychological tests and subtests employed in the study, patients with multiple sclerosis failed 5.8 (SD 2.3) tests at the baseline and 8.4 (SD 2.9) (p<0.0001) tests at the end of the study. When the cognitive changes were examined in individual patients, five (9.4%) of them were considered cognitively improved, 33 (62.3%) remained stable, and 15 (28.3%) worsened over 2 years. T2 and T1 volume changes in improved, stable, and worsened patients did not show any significant difference, whereas brain parenchymal volume decrease in cognitively worsened patients was significantly greater (-66 ml (5.4%), 95% CI 37-108.9, p=0.0031). The cognitive impairment was independently predicted over 2 years only by the change of brain parenchymal volumes (R=0.51, p=0.0003). Ten patients (18.9%), who worsened by one or more points in the EDSS during the follow up period had significant decreases in brain parenchymal volumes (-99 ml (8%), 95% CI 47.6-182.3, p=0.005). At the end of the study the loss of brain parenchyma correlated significantly with change in EDSS (r= 0.59, p<0.0001).”

-”In the early phase of relapsing-remitting multiple sclerosis the cognitive deterioration relies more on the development of brain parenchymal volume atrophy than on the extent of burden of disease in the brain. The loss of brain parenchymal volume underlies the progressive accumulation of physical disability from the initial phase of the disease, which becomes more demonstrable only if studied with longer observation periods. Probably, the main pathological substrate of brain atrophy in the early stage of the disease is early axonal loss, which causes the progression of neurological deficits and the development of cognitive impairment. These data support the debated opinion that disease modifying therapy should be initiated as early as possible.”
1. “Brain Atrophy Is Associated With Disability Progression in Patients with MS Followed in a Clinical Routine”: E Ghione et al
-brain atrophy assessment is an important biomarker in MS because of its relationship with neurodegeneration and disability progression

-is partially independent from lesion burden

-predicts development of physical and cognitive disability

-patients with CIS showed the highest annualized cumulative percentage LVV (lateral ventricle volume)change among all 3 study groups-

-a greater LVV change in patients with CIS who developed CDMS compared w those who remained stable was found within 1 year of follow-up

-brain atrophy rates are independent of MS phenotype
1. “Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options” by Athina Andravizou et al
-tissue loss in the CNS represents the net effect of all destructive pathogenic processes during the disease course

-neurons occupy 46% of the tissue volume; myelin: 24%; and glial and other cells: 30%

-GM holds much less myelin than WM (about 1/10th) while neurons comprise the most abundant component

-atrophy rates may also be influenced to some extent by the genetic makeup of a person; HLA genotypes considered as ‘high risk for MS” (DRB1 and DQB1) have been associated with significantly lower WM and GM volumes alongside with higher mean annualized percentage of brain volume change compared with medium and low risk HLA genotypes

-the correlation between demyelination foci and whole brain atrophy is still a matter of debate; some studies have found a strong association while others have not, suggesting that separate pathologic processes may also contribute to tissue destruction

-a longitudinal 14-year study found that atrophy is more related to early rather than late focal lesion volumes

-microglia activation, meningeal inflammation, iron deposition, oxidative stress and diffuse axonal damage in the NAWM are additional mechanisms that are at least partly independent from WM injury; the lack of a significant relationship between white matter fraction (WMF) and T2 lesion load further support this hypothesis; biopsy studies also confirm that atrophy may proceed even in the absence of inflammation

-it has been suggested that the pathogenic trajectory of brain atrophy changes with disease progression from primarily inflammatory to less inflammatory and primarily neurodegenerative in the late stages of the disease

-NfL protein is only expressed in neurons; reflects the axonal integrity and stability of neurons

-whole brain atrophy has a significant imaging association with physical disability as measured by EDSS

-brain volume changes during the first year after disease onset, estimated by PBVC, were the best predictor of future neurologic impairment regardless of the intermediate relapse rate

-increased BVL has been correlated with disability progression independent from the number of previous relapses or the T2 lesion load in RRMS

-when patients with CDMS were compared to patients with CIS, at baseline, all brain volume metrics except for cortical GM were significantly lower in the MS cohort; over a mean follow-up period of about 3 years, the annual PBVC values were significant lower in CIS patients when compared to the MS cohort

-changes of brain parenchymal fraction (BPF) have been shown to predict cognitive impairment over 2 years in patients with MS

-cortical atrophy was the best predictor of poor cognitive functioning even while mild impairment was detected; poor cognitive functioning has been associated with significant cortical thinning, esp in the fronto-parietal cortical and subcortical regions

-brain atrophy occurs as early as CIS
January 21, 2025

brain, dementia, health, mental-health, multiple-sclerosis
Gray Matter Atrophy, Damage, and Disability in MS Research
1. “Gray matter atrophy in multiple sclerosis: a longitudinal study”: Elizabeth Fisher et al
-”Subjects included 17 healthy control subjects, 7 patients with clinically isolated syndromes, 36 patients with relapsing-remitting MS (RRMS), and 27 patients with secondary progressive MS (SPMS). Expressed as fold increase from control subjects, GM atrophy rate increased with disease stage, from 3.4-fold normal in clinically isolated syndromes patients converting to RRMS to 14-fold normal in SPMS. In contrast, white matter atrophy rates were constant across all MS disease stages at approximately 3-fold normal. GM atrophy correlated with disability. MRI measures of focal and diffuse tissue damage accounted for 62% of the variance in GM atrophy in RRMS, but there were no significant predictors of GM atrophy in SPMS.”

-”Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disabillity. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS. These findings demonstrate the clinical relevance of gray matter atrophy in MS, and underscore the need to understand its causes.”
1. “Impact of Focal White Matter Damage on Localized Subcortical Gray Matter Atrophy in Multiple Sclerosis: A 5-Year Study”: T.A. Fuchs et al
– When we controlled for whole-brain volume and T2-lesion volume, WM tract disruption explained little additional variance of subcortical gray matter atrophy and was a significant predictor for only 3 of 14 regions cross-sectionally (ΔR2 = 0.004) and 5 regions longitudinally (ΔR2 = 0.016). WM tract disruption was a significant predictor for even fewer regions when correcting for multiple comparisons.

-WM tract disruption accounts for a small percentage of atrophy in connected subcortical gray matter when controlling for overall disease burden and is not the primary driver in most cases.
January 21, 2025

alzheimers, dementia, health, mental-health, mri

Tag: dementia

Conversion from CIS to MS Research

Brain Atrophy in MS Research

Gray Matter Atrophy, Damage, and Disability in MS Research