Marco Meglio

 was published online by sister publication NeurologyLive. 

Data from a Danish nationwide register-based cohort study demonstrated an increased risk of developing multiple sclerosis (MS) in the children of mothers with 

, corroborating the view that has been shown in previous studies.

A team of investigators led by Nete Nielsen, PhD, adjunct associate professor, Statens Serum Institut, pooled all 1,633,436 singletons born in Denmark between 1978-2008 to examine MS risk in offspring of diabetic mothers.

The analysis included overall data and data according to type of maternal diabetes mellitus (pregestational or gestational), as well as examined MS risk among offspring of diabetic fathers.

They found that the individuals whose mothers had pregestational diabetes had a 2.3-fold increased risk of MS compared with that among individuals with nondiabetic mothers (hazard ratio [HR], 2.25; 95% CI, 1.35–3.75).

The study authors noted, “regardless of the mechanism, our study suggests that the contribution of maternal diabetes mellitus to the absolute risk of MS in their offspring is only modest.”

They noted that in a prior work from 2005, the estimated sporadic absolute risk of MS among women and men in Denmark was 0.5% and 0.3%, respectively.

"With a roughly 2.3-fold increased relative risk, cautious estimates of the absolute (lifetime) risk of developing MS among daughters and sons of diabetic mothers are therefore likely in the order of 1.2% and 0.7%, respectively,” Nielsen and colleagues wrote.

For mothers with gestational diabetes, the MS risk was deemed statistically non-significant (HR, 1.03; 95% CI, 0.49–2.16).

Offspring of diabetic fathers also showed statistically non-significant results (HR, 1.40; 95% CI, 0.78–2.54).

The study had a total of 2332 MS cases identified, 1634 among females and 698 among males. Information about parental diabetes diagnoses were obtained from the Danish National Patient Register (NPR).

Using Cox proportional hazards regression analysis, the investigators found that the MS risk among cohort members whose mothers were recorded in the NPR as obese before or during pregnancy was 65% higher than that among other cohort members using the initial unadjusted analyses (HR, 1.65; 95% CI, 1.05–2.60).

Furthermore, they found a statistically significant association between birth weight and MS risk (test for homogeneity, 

They noted though that “another limitation is incomplete information concerning obesity in the NPR. However, while not all cases of obesity in the general population are recorded in the NPR, we believe that obese pregnant women are likely to have their obesity recorded in the NPR during the course of pregnancy.”

Additional analyses included comparison between MS risk between individuals exposed to maternal pregestational diabetes mellitus and nondiabetic mothers.

All told, the relative risk of MS among those exposed to pregestational type 1 diabetes and type 2 diabetes showed HRs of 2.21 (95%, 1.28–3.83) and 2.57 (95% CI, 0.64–10.6), respectively, compared with individuals born to nondiabetic mothers.

Cohort members who were born to mothers (n = 25,598) or fathers (n = 17,316) who had been diagnosed with any autoimmune disease other than diabetes and MS either before or during pregnancy were not any unusual risk of developing MS (maternal exposure: HR, 1.40; 95% CI, 0.92–2.13; paternal exposure: HR, 1.01; 95% CI, 0.57–1.78).

Mothers with pregestational inflammatory bowel diseases (IBD) were at a 2.1-fold increased risk of MS (HR, 2.12; 95% CI, 1.14–3.94) when restricting the analyses to IBD alone.

However, there was no unusual risk of MS for children of fathers with IBD (HR, 1.42; 95% CI, 0.64–3.17) nor children of mothers with gestational IBD (HR, 0.93; 95% CI, 0.13–6.62).

"An advantage of our study is that we relied on routinely collected patient information about the exposure variable, diagnoses of parental diabetes, obtained from records of the Danish NPR, thereby eliminating any potential influence of differential recall problems that may have influenced findings in prior studies relying on self-reported data,” Nielsen and team wrote.

Maternal diabetes and risk of multiple sclerosis in the offspring: A Danish nationwide register-based cohort study

Articles

The study finds that individuals with mothers who had pregestational diabetes had a 2.3-fold increased risk of MS compared to those with non-diabetic mothers.

Children of Diabetic Mothers Have Greater Risk of Developing Multiple Sclerosis

This article, "Masitinib Meets Primary End Point in Alzheimer Disease," was originally published in NeurologyLive.

The results of a new study suggests masitinib could help reduce Alzheimer disease (AD) patients who reached the severe dementia stage of the disease.

AB Science announced that its investigational oral agent masitinib met its primary end point in a phase 2b/3 study in patients with mild and moderate Alzheimer disease (AD).

Treatment with masitinib 4.5 mg/kg/day (n = 182) generated a significant treatment effect on the primary endpoint of change from baseline in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) compared to those in the control arm (n = 176; 

 = .0003). AB Science noted that it plans to present the full detailed results at an upcoming meeting.

In addition to the effect on cognition and memory, masitinib 4.5 mg/kg/day generated a significant change from baseline in the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) score, an instrument that assesses self-care and activities of daily living (

"There is a vacuum of treatment options for patients with Alzheimer’s disease and today very few attempts to address the population with confirmed mild or moderate dementia associated with Alzheimer’s disease. These data are very encouraging and may provide new hope for patients with Alzheimer’s disease,” Bruno Dubois, MD, PhD, professor of neurology, Neurological Institute, Salpétrière University Hospital, and coordinating investigator of the study, said in a statement.

Among the notable data points presented, fewer patients who received masitinib 4.5 mg/kg/day reached severe dementia stage (defined as Mini-Mental State Exam [MMSE] <10) compared with placebo after 24 weeks of treatment (

Dubois added, “the fact that masitinib could significantly reduce the proportion of patients reaching the stage of severe dementia is particularly interesting because this stage of the disease represents a significant burden for the society.”

The safety analysis showed that masitinib 4.5 mg/kg/day was acceptable and consistent with its known tolerability profile. In total, 79.5% and 74.6% of patients in the masitinib and control arms, respectively, experienced at least 1 adverse event (AE). Serious AEs, which were non-fatal, were observed in 5.9% of patients in the masitinib arm compared to 2.9% in the control. Incidence of at least 1 serious AE was present in 18.9% of patients in the masitinib arm compared to 16.8% in the control arm.

The trial was a randomized, placebo-controlled trial that compared the efficacy and safety of masitinib relative to placebo after 24 weeks when administered as an add-on therapy to a cholinesterase inhibitor (donepezil, rivastigmine, or galantamine) and/or memantine. There was a 4.5 mg/kg/day masitinib group along with a 4.5 mg/kg to 6.0 mg/kg/day titrated dose group, each having an independent control arm along with it.

Jeffrey Cummings, MD, ScD, director emeritus, Lou Ruvo Center for Brain Health, Cleveland Clinic, vice chair, Department of Brain Health, University of Nevada-Las Vegas, said in a statement, “The preliminary results from this study support efficacy on important outcomes assessing both cognition and function. The observed patient tolerability is encouraging. Masitinib’s mechanism is novel in its targeting of the innate immune system via mast cells and microglia. A growing body of evidence suggests that microglia play a central role in Alzheimer’s disease and other neurodegenerative disorders.”

Proof of concept for masitinib in AD was established in a 35-patient, double-blind, placebo-controlled phase 2 study. Results from that study showed the rate of clinically relevant cognitive decline, or ADAS-Cog response, was significantly lower with masitinib compared with placebo after 12 and 24 weeks (6% versus 50% for both; 

Patients in the placebo arm also experienced worsening mean ADAS-Cog, ADCS-ADL, and MMSE scores, whereas the masitinib arm reported improvements with statistical significance at weeks 12 and 24.

Masitinib has been evaluated in other neurological disorders such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). In February, AB Science announced that the 

 in a phase 2b/3 study (AB07002) of patients with primary progressive MS (PPMS) and nonactive secondary progressive MS (SPMS).

FDA accepted an investigational new drug (IND)

 application for masitinib, allowing AB Science to proceed with a phase 3 study to test the agent in patients with ALS. The study was intended to confirm results from the first phase 2b/3 AB10015 study which demonstrated that masitinib, at 4.5 mg/kg/day in combination with riluzole, significantly slowed decline as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R).

Fewer patients who received masitinib 4.5 mg/kg/day reached severe dementia stage.

Masitinib Shows Promise in Alzheimer Disease Study

This article, " Health-Deficit Accumulation Affects Risk for Mild Cognitive Impairment, Dementia," was originally published in NeurologyLive.

Using a frailty index score could enable clinicians to identify patients at risk for 

, making it an important marker for prognostic value.

Newly published data suggests health-deficit accumulation, specifically among older Americans, affects the likelihood of progressive cognitive impairment, as well as the likelihood of cognitive improvement independent of the 

Lead author David D. Ward, PhD, postdoctoral fellow, geriatric medicine research, Centre for Health Care of the Elderly, Nova Scotia Healthy Authority, and colleagues calculated a frailty index score using the deficit-accumulation approach in participants aged 50 years and older from the National Alzheimer’s Coordinating Center (NACC).

Among those not cognitively impaired (NCI; n = 9773), each 0.1 increment increase in score were associated with a higher risk of developing mild cognitive impairment (MCI) and a higher risk of developing dementia.

In total, there were 14,490 participants in the study with a mean age of 72.2 years. In the MCI subsample (n = 4717) at baseline, there was a higher degree of frailty that was associated with a lower probability of being reclassified as NCI from MCI, a higher risk of returning to MCI in those who were reclassified as NCI, and a higher risk of progressing to dementia.

"We conclude that frailty is a key risk factor for age-related cognitive dysfunction and dementia, representing both a target for interventions aimed at the prevention of age-related cognitive impairment and possible prognostic marker among those who have MCI,” the authors wrote.

The score is a health-state measure, incorporating information from multiple physiological systems, and closely reflects an individual’s risk for adverse health events and mortality independently of chronological age. A higher frailty index score indicated accumulation of more age-related health deficits while approximating biological age.

The researchers aimed to detail the dynamic nature of cognitive functioning by calculating the likelihood of transitions between cognitive states in both directions over a 12-month period. Decline of cognitive function was considered forward transition, whereas improvement of cognitive functioning was defined as backwards transition.

The investigators also assessed whether frailty index score and 

 ε4 allele carrier status exerted independent or interactive effects on cognitive-state transition probabilities.

They found no statistically significant interactions between these variables for any transition in the NCI subsample. However, in the MCI subsample, the association of the frailty index score and the risk of progressing to dementia was significantly weaker in those carrying an 

 ε4 allele than in non-carriers (interaction hazard risk [HR], 0.88; 95% CI, 0.80–0.97).

There were no meaningful differences in these associations when participants whose race was other than white were removed from the analytical sample. Notably, associations of the frailty index score with transition probabilities did not differ significantly between men and women.

Over 12 months, NCI subsample participants maintained their prior state 43,086 times (90.6%) and transitioned between states 4491 times (9.4%), 3086 (68.7%) of which were transitions between cognitive states, with 1405 (31.3%) transitions to death. Of the cognitive-state transitions in the NCI subsample, 80.9% were forward transitions, and 19.1% were backward transitions. In the MCI subsample, 70.5% were forward compared to 29.5% who experienced backwards transition.

"This work supports an emerging conceptualization of late-onset dementia as a complex outcome of aging that often is intimately related to an individual’s general health, as well as genetic risk factors,” the authors wrote.

Investigators find frailty is a key risk factor for age-related cognitive dysfunction and dementia.

Researchers Find New Method to Measure Cognitive Impairment, Dementia

This article, "Lower Dementia Rates Linked to Angiotensin-II Stimulating Antihypertensives," was originally published in NeurologyLive.

New data shows angiotensin-II stimulating antihypertensive treatments could reduce the rates of 

Post-hoc analysis of the preDIVA trial published in 

 showed support of the angiotensin hypothesis, with results demonstrating lower dementia rates in angiotensin-II stimulating antihypertensive users compared with those on angiotensin-II inhibiting antihypertensives.

The use of angiotensin-II stimulating antihypertensives (thiazides, dihydropyridine calcium channel blockers [DiCCB], and angiotensin-1 receptor blockers [ARB]) led to a 5.6% (n = 27) dementia incidence rate, compared to 8.2% (n = 59) in angiotensin-II inhibiting (angiotensin-converting enzyme inhibitors [ACEIs], beta blockers, and non-dihydropyridine calcium channel blockers [non-DiCCB]) users for a hazard ratio (HR) of 0.57 (95% CI, 0.35–0.93; 

Senior author Edo Richard, PhD, neurologist, University of Amsterdam, and colleagues used Cox regression analyses of incident dementia (and/or mortality as competing risk) during 6–8 years of follow-up among 1909 non-demented community-dwelling individuals (54% women), aged 70–78 (mean ±2.5) years.

Angiotensin-II stimulating antihypertensive users had a 45% lower incident dementia rate (HR, 0.55; 95% CI, 0.34–0.89) without excess mortality (HR, 0.86; 95% CI, 0.64–1.16) compared to angiotensin-II inhibiting antihypertensive users after adjusting for dementia risk factors including blood pressure and medical history. This corresponded to an approximate absolute risk reduction (ARR) of 3.6% (HR, 0.57; 95% CI, 0.6–5.4).

"If replicated, the beneficial effects associated with angiotensin-II-stimulating antihypertensives could have major influence on clinical practice, providing a treatment strategy that is easy and cheap to implement on a large scale and could markedly reduce dementia risk on a population level,” the authors wrote.

Overall, the dementia incidence rate was 6.9% (46 of 669) for users on both types of antihypertensives. Individuals using both types had a non-significant 20% lower dementia rate (HR, 0.80; 95% CI, 0.53–1.20) without excess mortality (HR, 0.97; 95% CI, 0.76–1.24) compared to angiotensin-II inhibiting antihypertensive users.

Midlife hypertension has been associated with an increased risk of incident dementia. After 6–8 years of follow-up (median, 6.7 years; interquartile range, 5.8–7.0), dementia outcome was available for 98% (1870 of 1909) and mortality for >99% (1904 of 1909) of participants.

Model 3 of the regression analyses adjusted for other dementia risk factors including body mass index (BMI), cholesterol lowering medication use, estimated glomerular filtration rate (eGFR), and trial intervention allocation to ensure the trial intervention did not influence the results.

Within this model, researchers found there was an interaction with the history of cardiovascular disease (CVD) for both angiotensin-II-stimulating (

 = .04) groups. These suggested that the lower dementia risk for angiotensin-II-stimulating (HR, 0.50; 95% CI, 0.28–0.90) agents versus angiotensin-II-inhibiting antihypertensives (HR , 1.08; 95% CI 0.46–2.53) was particularly evident in individuals without CVD.

Researchers also noted that the HR was neutral in individuals without CVD (HR, 0.95; 95% CI, 0.58–1.58) and markedly lower in those with CVD (HR, 0.55; 95% CI, 0.26–1.14) in the angiotensin-mixed group, but the difference was deemed non-significant.

Exploratory analyses comparing individual antihypertensive subclasses showed no statistically significant associations with dementia risk. Thiazide, DiCCB, ARB, non-DiCCB, ACEIs, and loop diuretics all had HRs for dementia ≤1 but only angiotensin-II-stimulating (thiazides, DiCCB and ARB) also had a HR ≤1 for mortality and dementia/mortality combined.

“Our findings warrant replication in other longitudinal cohorts. Being observational, they cannot establish definitive causal relationships. Causality could be strengthened by combining clinical observations with dementia-associated neuropathology,” the authors wrote.

The study authors noted that dementia prevention could become a compelling indication for older individuals receiving antihypertensive treatment.