by Elena Moro
For March 2018, we have selected: Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 2018;378:321-330.
Alzheimer’s disease (AD) pathology can be related to either excessive production or reduced elimination of beta amyloid (Aβ), which eventually results in oligomers, fibrils, and neuritic Aβ plaques. Therefore, treatments able to interfere with the Aβ pathology could be neuroprotective in AD patients. Solanezumab, a humanized immunoglobulin G1 monoclonal antibody that binds to the mid-domain of the Aβ peptide, could facilitate the removal of soluble Aβ from the brain. Two previous phase 3 studies (EXPEDITION and EXPEDITION 2) have shown that solanezumab did not have any impact on progression of cognitive decline in mild to moderate AD patients but in a pooled analysis, patients with mild AD seemed to have some benefit.
In this double-blind randomized multicenter trial (EXPEDITION 3), the effects of solanezumab were investigated in a large population of mild AD patients with a Mini-Mental-State-Examination (MMSE) score between 20 and 26, and biomarker proof of cerebral amyloid deposition. The latter was determined either with florbetapir positron-emission tomography (PET) scan or Aβ1-42 dosage in the cerebrospinal fluid (CSF). Patients aged between 55 and 90 years were randomized to receive intravenous infusion of 400 mg solanezumab or placebo every 4 weeks for 76 weeks. The main outcome was the change in the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14) from baseline to 80 weeks. Secondary outcomes comprised changes in the MMSE, the Alzheimer’s Disease Cooperative Study Activities of daily Living Inventory, the Clinical Dementia Rating-Scale-Sum of Boxes, the Functional Activities Questionnaire. Statistical analysis included a modified intention-to-treat analysis, with the main outcome determined using a mixed-model repeated-measures analysis.
Between August 2013 and October 2016, 2129 mild AD patients were randomized in 210 sites of 11 countries. A total of 1822 patients completed the study, 914 from the solanezumab group and 908 from the placebo group. At 80 weeks, no difference was found in the ADAS-cog-14 scores between the two groups (change, 6.65 in the solunazemab group and 7.44 in the placebo group; difference, -0.80; 95% CI, -1.73 to 0.14; p=0.10). Therefore, secondary outcomes were not fully statistically analyzed. Overall, these measures worsened in both groups. Adverse events were frequent (>80%) in both groups. Three patients presented with asymptomatic amyloid-related abnormality of edema or effusion on brain MRI, one patient from the solanezumab group and two from the placebo group.
“Unfortunately, this large study failed to show that solanezumab is effective in slowing down cognitive decline in patients with mild AD”, says Prof. Daniela Galimberti, Neurodegenerative Disease Unit, Policlinico Hospital, University of Milan, Italy “This negative outcome might be related to several factors. There was no impact of solanezumab-related reduction of free plasma Aβ concentration on cognitive functions, suggesting that this reduction is not sufficient to reduce deposited brain amyloid, neuronal atrophy or the biologic events related to clinical decline. On the other hand, outcome measures are not sensitive enough to detect small changes between groups. Moreover, the dose of solunazemab could have been too low or the disease already too advanced to be modified.”
“Although there may be trial-specific factors that led to these results, it is another call for more research into other possible targets in Alzheimer’s disease”, says Prof. Carmela Tartaglia, Division of Neurology, University of Toronto, Ontario, Canada. “Maybe it is time to take a more multi-pronged approach and target amyloid and tau simultaneously or focus on the tau in AD pathology.”
The other nominees for the March 2018 paper of the month are:
- Venegas C, Kumar S, Franklin BS, et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 2017;552:355-362. This paper supports the role of inflammosome activation on seeding and spreading of amyloid- β pathology in Alzheimer’s disease (AD). Activation of the NACHT-, LRR- and pyrin (PYD)-domain-containing protein 3 (NLRP3) inflammasome, a central antenna for danger signals, has recently been found in AD. After activation, NLRP3 recruits the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) via interactions with the PYD domain of ASC, which activates ASC helical fibrillary assemblage. ASC fibrils then recruit the effector caspase-1 via CARD interactions leading to autoproteolytic activation and consequent assembly of ASC fibrils into a big paranuclear ASC speck. NLRP3 inflammasome activity also induces the release of assembled ASC specks that in the intercellular space can be taken up by adjacent myeloid cells to endure constant immune response. In this study the authors show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPSwePSEN1dE9
- Powers WJ, Rabinstein AA, Ackerson T, et al., on behalf of the American Heart Association Stroke Council. 2018 Guidelines for the early management of patients with acute ischemic stroke. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. 2018;49:eXXX–eXXX. doi: 10.1161/STR.0000000000000158. These evidence-based guidelines deeply deal with prehospital care, urgent and emergency evaluation and treatment of acute ischemic stroke, including secondary prevention measures within the first 2 weeks.
- Headache Classification Committee of the International Headache Society (HIS). The international classification of headache disorders, 3rd edition (ICHD-3). Cephalagia 2018;38:1-211. In this paper, published 30 years after the first edition of ICHD-I, the new classification of headache is presented. It is based on new scientific evidence, in a very systematic way, including explicit diagnostic criteria for each disease entity.