Longitudinal cognitive function and brain metabolites in women receiving chemotherapy for stage 1 to 3 breast cancer: Observational study.

Few proton magnetic resonance spectroscopy studies have explored chemotherapy-related biochemical changes in brain regions. This observational study aimed to longitudinally assess short-term cognitive changes and brain metabolite concentrations in women undergoing chemotherapy for breast cancer. We analyzed 11 women with newly diagnosed stage 1 to 3 breast cancer. Patients were evaluated via objective cognitive testing, and patient self-report tests. Patients were examined using single voxel proton magnetic resonance spectroscopy in the medial frontal cortex, posterior cingulate gyrus, and left thalamus at baseline and after the completion of chemotherapy on a 1.5 Tesla scanner. At the posttreatment evaluation as compared to baseline, 7 of the 10 (70%) patients reported worsening memory on the MD Anderson symptom inventory (annualized change = 1.82 ± 2.88, P = .08), while the delayed recall raw score of the Rey Osterrieth complex figure test did not change from pre- to post-chemotherapy (mean annualized change = 5.00 ± 14.38, P = .30). The annualized change in the creatine concentration in the posterior cingulate gyrus was statistically significant. The annualized change in the MD Anderson symptom inventory was negatively correlated with the annualized change in the medial frontal N-acetylaspartate (Spearman correlation coefficient [rho] = -0.78, P = .01) and positively correlated with the annualized change in the posterior cingulate gyrus creatine (rho = 0.66, P = .04). Annualized changes in the Rey Osterrieth complex figure test were positively correlated with annualized changes in choline (rho = 0.83, P = .01) in the medial frontal cortex, choline (rho = 0.76, P = .04) in the left thalamus, and creatine (rho = 0.73, P = .02) in the medial frontal cortex. Our data suggest that chemotherapy may lead to the worsening of self-reported memory function, which is associated with alterations in brain metabolites.

Do magnetic resonance imaging features differ between persons with multiple sclerosis of various races and ethnicities?

Those of African American or Latin American descent have been demonstrated to have more severe clinical presentations of multiple sclerosis (MS) than non-Latin American White people with MS. Concurrently, radiological burden of disease on magnetic resonance imaging (MRI) in African Americans with MS has also been described as being more aggressive. Here, we review MRI studies in diverse racial and ethnic groups (adult and pediatric) investigating lesion burden, inflammation, neurodegeneration, and imaging response to disease modifying therapy. We also discuss why such disparities may exist beyond biology, and how future studies may provide greater insights into underlying differences.

Coexistence of multiple sclerosis and spinocerebellar ataxia type-8.

Cerebellar dysfunction is likely to cause severe and treatment-resistant disability in multiple sclerosis (MS). Certain spinocerebellar ataxia (SCA)-related alleles can increase MS susceptibility, and channel polymorphisms can impact disability measures. Following an index patient with the coexistence of MS and SCA Type-8 (SCA8) in the MS clinic, an institutional engine search for MS and hereditary ataxia coexistence was conducted but did not reveal any other cases. This extremely rare coexistence of MS and SCA8 in our index patient may be incidental; however, a yet-to-be-identified contribution of coexistent hereditary ataxia(s) to the susceptibility of a prominent progressive ataxia MS phenotype cannot be ruled out.

Smoking, early menopause and multiple sclerosis disease course.

Smoking is associated with an increased risk of multiple sclerosis (MS), and smoking and early menopause are related to poor outcomes in MS. Smoking is also associated with early menopause. To explore this intricate relationship between smoking status, age at menopause and disease course in MS, 137 women with MS and 396 age-matched controls were included in this case-control study. Age at menopause (median 49.0 vs. 50.0 years; p = 0.79) and smoking status (40.3% vs. 47.6%; p = 0.15) were similar among MS and control women. Relapsing MS onset was earlier in ever-smoker women with early menopause compared to the rest of the women (median 30.4 vs. 37.0 years; p = 0.02) and also compared to ever-smoker women with normal age at menopause (median 30.4 vs. 41.0 years; p = 0.008) and never-smoker women with early menopause (median 30.4 vs. 41.5 years; p = 0.004). Progressive MS onset was also earlier in ever-smoker women with early menopause compared to ever-smoker women with normal age at menopause (median 41.1 vs. 49.4 years; p = 0.05) and never-smoker women with early menopause (median 41.1 vs. 50.1 years; p = 0.12). Our results suggest that smoking and menopause associate with MS disease course, including the onset of relapsing and progressive MS in women.

The radiologically isolated syndrome: revised diagnostic criteria.

The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1-2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.

Selective vulnerability of brainstem and cervical spinal cord regions in people with non-progressive multiple sclerosis of Black or African American and European ancestry.

BACKGROUND: We evaluated imaging features suggestive of neurodegeneration within the brainstem and upper cervical spinal cord (UCSC) in non-progressive multiple sclerosis (MS). METHODS: Standardized 3-Tesla three-dimensional brain magnetic resonance imaging (MRI) studies were prospectively acquired. Rates of change in volume, surface texture, curvature were quantified at the pons and medulla-UCSC. Whole and regional brain volumes and T2-weighted lesion volumes were also quantified. Independent regression models were constructed to evaluate differences between those of Black or African ancestry (B/AA) and European ancestry (EA) with non-progressive MS. RESULTS: 209 people with MS (pwMS) having at least two MRI studies, 29% possessing 3-6 timepoints, resulted in 487 scans for analysis. Median follow-up time between MRI timepoints was 1.33 (25th-75th percentile: 0.51-1.98) years. Of 183 non-progressive pwMS, 88 and 95 self-reported being B/AA and EA, respectively. Non-progressive pwMS demonstrated greater rates of decline in pontine volume (p < 0.0001) in B/AA and in medulla-UCSC volume (p < 0.0001) for EA pwMS. Longitudinal surface texture and curvature changes suggesting reduced tissue integrity were observed at the ventral medulla-UCSC (p < 0.001), dorsal pons (p < 0.0001) and dorsal medulla (p < 0.0001) but not the ventral pons (p = 0.92) between groups. CONCLUSIONS: Selectively vulnerable regions within the brainstem-UCSC may allow for more personalized approaches to disease surveillance and management.

Gastrointestinal motility disorders in patients with multiple sclerosis: A single-center study.

BACKGROUND: Most prevalent gastrointestinal symptoms in multiple sclerosis (MS) relate to lower bowel dysfunction, often in association with bladder manifestations. OBJECTIVE: To assess clinical and objective gastrointestinal motor dysfunctions in patients with MS. METHODS: This was a single-center, retrospective study of 166 patients evaluated between 1996 and 2020. We reviewed characterization of the MS, gastrointestinal and neurological symptoms, measurements of gastrointestinal and colonic transit, and anorectal manometry. KEY RESULTS: At the time of the gastrointestinal evaluations of the 166 patients with MS (138 women; 83%), 111 were in the relapsing-remitting phase and 52 were in the progressive phase. In 3 patients, disease phase was not assigned due to insufficient data. Constipation was identified in 82% (136/166) of patients. Most [103/116 (88%)] patients with bladder symptoms also had constipation or fecal incontinence. Delayed gastric emptying at 4 h and colonic transit at 24 h was identified in 16% and 7% of the cohort, respectively; 22% had accelerated gastric emptying. On anorectal manometry, resting anal sphincter pressure >90 mm Hg and rectoanal pressure differential below -50mm Hg suggested evacuation disorder in patients with constipation. CONCLUSIONS AND INFERENCES: In addition to slow colonic transit and anorectal dysfunction leading to constipation in MS, 22% of patients had accelerated gastric emptying.

1H MR spectroscopy biomarkers of neuronal and synaptic function are associated with tau deposition in cognitively unimpaired older adults.

Proton magnetic resonance spectroscopy (1H MRS) may provide information on pathophysiological changes associated with tau deposition in cognitively unimpaired older adults. In this study, the associations of posterior cingulate gyrus tau and amyloid beta (Aß) deposition on PET with 1H MRS metabolite ratios acquired from bilateral posterior cingulate gyri were investigated in cognitively unimpaired older adults. Participants (n = 40) from the Mayo Clinic Study of Aging underwent single-voxel sLASER 1H MRS from the posterior cingulate gyrus at 3 Tesla, 18F-flortaucipir, and 11C- Pittsburgh Compound B (PiB) PET. An increase in posterior cingulate gyrus tau deposition, but not elevated Aß, was associated with lower N-acetylaspartate/total creatine (tCr) and glutamate (Glu)/tCr ratios, and sex by tau interaction was observed in association with Glu/tCr. Higher tau levels in cognitively unimpaired older adults are associated with biomarkers of neural and synaptic injury even in the absence of cognitive impairment and these relationships appear to be stronger in women than in men.

Comparison of 11C-Pittsburgh Compound B and 18F-Flutemetamol White Matter Binding in PET.

PET imaging with ß-amyloid ligands is emerging as a molecular imaging technique targeting white matter integrity and demyelination. ß-amyloid PET ligands such as 11C-Pittsburgh compound B (11C-PiB) have been considered for quantitative measurement of myelin content changes in multiple sclerosis, but 11C-PiB is not commercially available given its short half-life. A 18F PET ligand such as flutemetamol with a longer half-life may be an alternative, but its ability to differentiate white matter hyperintensities (WMH) from normal-appearing white matter (NAWM) and its relationship with age remains to be investigated. Methods: Cognitively unimpaired (CU) older and younger adults (n = 61) were recruited from the community responding to a study advertisement for ß-amyloid PET. Participants prospectively underwent MRI, 11C-PiB, and 18F-flutemetamol PET scans. MRI fluid-attenuated inversion recovery images were segmented into WMH and NAWM and registered to the T1-weighted MRI. 11C-PiB and 18F-flutemetamol PET images were also registered to the T1-weighted MRI. 11C-PiB and 18F-flutemetamol SUV ratios (SUVrs) from the WMH and NAWM were calculated using cerebellar crus uptake as a reference for both 11C-PiB and 18F-flutemetamol. Results: The median age was 38 y (range, 30-48 y) in younger adults and 67 y (range, 61-83 y) in older adults. WMH and NAWM SUVrs were higher with 18F-flutemetamol than with 11C-PiB in both older (P < 0.001) and younger (P < 0.001) CU adults. 11C-PiB and 18F-flutemetamol SUVrs were higher in older than in younger CU adults in both WMH (P < 0.001) and NAWM (P < 0.001). 11C-PiB and 18F-flutemetamol SUVrs were higher in NAWM than WMH in both older (P < 0.001) and younger (P < 0.001) CU adults. There was no apparent difference between 11C-PiB and 18F-flutemetamol SUVrs in differentiating WMH from NAWM in older and in younger adults. Conclusion:11C-PiB and 18F-flutemetamol show a similar topographic pattern of uptake in white matter with a similar association with age in WMH and NAWM. 11C-PiB and 18F-flutemetamol can also effectively distinguish between WMH and NAWM. However, given its longer half-life, commercial availability, and higher binding potential, 18F-flutemetamol can be an alternative to 11C-PiB in molecular imaging studies specifically targeting multiple sclerosis to evaluate white matter integrity.

Sleep quality and cortical amyloid-ß deposition in postmenopausal women of the Kronos early estrogen prevention study.

Hormone therapy improves sleep in menopausal women and recent data suggest that transdermal 17ß-estradiol may reduce the accumulation of cortical amyloid-ß. However, how menopausal hormone therapies modify the associations of amyloid-ß accumulation with sleep quality is not known. In this study, associations of sleep quality with cortical amyloid-ß deposition and cognitive function were assessed in a subset of women who had participated in the Kronos early estrogen prevention study. It was a randomized, placebo-controlled trial in which recently menopausal women (age, 42-58; 5-36 months past menopause) were randomized to (1) oral conjugated equine estrogen (n = 19); (2) transdermal 17ß-estradiol (tE2, n = 21); (3) placebo pills and patch (n = 32) for 4 years. Global sleep quality score was calculated using Pittsburgh sleep quality index, cortical amyloid-ß deposition was measured with Pittsburgh compound-B positron emission tomography standard uptake value ratio and cognitive function was assessed in four cognitive domains 3 years after completion of trial treatments. Lower global sleep quality score (i.e., better sleep quality) correlated with lower cortical Pittsburgh compound-B standard uptake value ratio only in the tE2 group (r = 0.45, P = 0.047). Better global sleep quality also correlated with higher visual attention and executive function scores in the tE2 group (r = -0.54, P = 0.02) and in the oral conjugated equine estrogen group (r = -0.65, P = 0.005). Menopausal hormone therapies may influence the effects of sleep on cognitive function, specifically, visual attention and executive function. There also appears to be a complex relationship between sleep, menopausal hormone therapies, cortical amyloid-ß accumulation and cognitive function, and tE2 formulation may modify the relationship between sleep and amyloid-ß accumulation.

Diagnosis of Progressive Multiple Sclerosis From the Imaging Perspective: A Review.

Importance: Although magnetic resonance imaging (MRI) is useful for monitoring disease dissemination in space and over time and excluding multiple sclerosis (MS) mimics, there has been less application of MRI to progressive MS, including diagnosing primary progressive (PP) MS and identifying patients with relapsing-remitting (RR) MS who are at risk of developing secondary progressive (SP) MS. This review addresses clinical application of MRI for both diagnosis and prognosis of progressive MS. Observations: Although nonspecific, some spinal cord imaging features (diffuse abnormalities and lesions involving gray matter [GM] and ≥2 white matter columns) are typical of PPMS. In patients with PPMS and those with relapse-onset MS, location of lesions in critical central nervous system regions (spinal cord, infratentorial regions, and GM) and MRI-detected high inflammatory activity in the first years after diagnosis are risk factors for long-term disability and future progressive disease course. These measures are evaluable in clinical practice. In patients with established MS, GM involvement and neurodegeneration are associated with accelerated clinical worsening. Subpial demyelination and slowly expanding lesions are novel indicators of progressive MS. Conclusions and Relevance: Diagnosis of PPMS is more challenging than diagnosis of RRMS. No qualitative clinical, immunological, histopathological, or neuroimaging features differentiate PPMS and SPMS; both are characterized by imaging findings reflecting neurodegeneration and are also impacted by aging and comorbidities. Unmet diagnostic needs include identification of MRI markers capable of distinguishing PPMS from RRMS and predicting the evolution of RRMS to SPMS. Integration of multiple parameters will likely be essential to achieve these aims.

Cerebral Venous Sinus Thrombosis in Women: Subgroup Analysis of the VENOST Study.

BACKGROUND: Early diagnosis of cerebral venous sinus thrombosis (CVST) associated with reproductive health-related risk factors (RHRF) including pregnancy, puerperium, and oral contraceptive (OC) use can prevent severe neurological sequelae; thus, the symptoms must be documented in detail for each group. METHODS: Out of 1144 patients with CVST, a total of 777 women were enrolled from a multicenter for the study of cerebral venous sinus thrombosis (VENOST). Demographic, biochemical, clinical, and radiological aspects were compared for 324 cases with RHRF and 453 cases without RHRF. RESULTS: The mean age of the RHRF (-) group (43.2 ± 13 years) was significantly higher than of the RHRF (+) group (34 ± 9 years). A previous history of deep venous thrombosis (3%), isolated cavernous sinus involvement (1%), cranial neuropathy (13%), comorbid malignancy (7%), and its disability scores after 12 months (9%) were significantly higher in the RHRF (-) group. The RHRF (+) group consisted of 44% cases of puerperium, 33% cases of OC users and 23% of pregnant women. The mean age was found to be higher in OC users (38 ± 9 years). A previous history of deep venous thrombosis was slightly higher in the pregnancy subgroup (4%). Epileptic seizures were more common in the puerperium group (44%). CONCLUSION: The results of our study indicate that the risk of CSVT increases parallel to age, OC use, and puerperium period. In addition, when considering the frequency of findings and symptoms, epileptic seizures in the puerperium subgroup of the RHRF (+) group and malignancies in the RHRF (-) group may accompany the CSVT. In daily practice, predicting these risks for the CSVT and early recognition of the symptoms will provide significant benefits to patients.

African Americans experience disproportionate neurodegenerative changes in the medulla and upper cervical spinal cord in early multiple sclerosis.

OBJECTIVE: To compare the temporal changes in the 3-dimensional (3D) structure of the medulla-upper cervical spinal cord region in African American (AA) and white multiple sclerosis (MS) patients to identify early patterns of anatomical change prior to progressive symptom development. METHODS: Standardized 3-Tesla 3D brain MRI studies were performed at two time points on AA and white MS patients along with controls. Longitudinal changes in volume, surface area, tissue compliance, and surface texture measured in total and within ventral and dorsal compartments were studied. Independent regression models were constructed to evaluate differences between groups. RESULTS: Thirty-five individuals were studied, 10 AA with MS (female (F): 8; median age [IQR]=33.8 years (y) [10.9], median disease duration: 11.8y [11.3]), 20 white MS patients (F: 10; 35.6y [17.4], 7.23y [8.83], and 5 controls (F: 2, 51.8y [10.2]). Expanded Disability Status Scale scores were 0.0 at baseline and at the second MRI time point. Within the medulla-upper cervical spinal cord, AA versus white MS patients exhibited greater rates of atrophy in total (p<0.0001) and within the ventral (p<0.0001) and dorsal (p<0.0001) compartments, reduced surface area (p<0.0001), and reduced tissue compliance in the ventral (p=0.002) and dorsal (p=0.0005) compartments. The rate of change at the dorsal surface, but not the ventral surface, between MRI time points was also greater in AA relative to white MS patients (p<0.0001). CONCLUSION: Structural changes in distinct anatomical regions of the medulla-upper cervical spinal cord may be reflective of early and disproportionate neurodegeneration in AA MS as compared to whites.

Sex effects across the lifespan in women with multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.