Brain Shrinkage in Anti–β-Amyloid Alzheimer Trials

Barkhof, Frederik; Knopman, David S.

doi:10.1212/wnl.0000000000207268

Cited by 15 publications

(10 citation statements)

References 11 publications

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“…It has been shown previously that levels of synaptic proteins can predict the rate of cognitive decline in human AD patients when measured post mortem (27) or with positron emission tomography (PET) (28). Interestingly, the reduced brain volume detected by T2-weighted MRI in the ultrasound-treated mice is consistent with other studies that have shown significantly increased brain volume loss in AD patients in clinical trials (29). It has been speculated that plaque removal may explain the volume loss, but this is unlikely the to be the reason given the small volume of brain taken up by plaques compared to the magnitude of changes found on MRI.…”

Section: Discussionsupporting

confidence: 84%

Scanning ultrasound-mediated memory and functional improvements do not require amyloid-β reduction

Leinenga

Bodea

et al. 2023

Preprint

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A prevalent view in treating age-dependent disorders including Alzheimer disease (AD) is that the underlying pathology must be targeted for cognitive improvements. In contrast, we report here that repeated scanning ultrasound treatment at 1 MHz, can ameliorate memory deficits without reducing amyloid-beta (Abeta) burden in the APP23 mouse model of AD. No microbubbles were used to achieve blood-brain barrier opening. Intriguingly, the treatment was less effective at 286 kHz, which is within the frequency range currently explored in transcranial clinical trials in AD patients. Functional magnetic resonance imaging and quantitative proteomics revealed that ultrasound differentially induced long-term functional improvements in the brain. Together, our data suggest a dose-dependent effect of ultrasound on functional read-outs and a dissociation of cognitive improvement and Abeta clearance, with important implications for AD trial design.

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Section: Discussionsupporting

confidence: 84%

Scanning ultrasound-mediated memory and functional improvements do not require amyloid-β reduction

Leinenga

Bodea

et al. 2023

Preprint

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“…39 Lecanemab was not associated with loss of hippocampal volume, but ventricular enlargement and reductions in cortical thickness occurred in the treated group, 39 findings of uncertain significance. 40 The donanemab phase 2 trial, 29 the donanemab phase 3 trial (Lilly press release, 5-3-23), and the lecanemab phase 3 trial 36 imaging results (Figure 2) support a conjecture 41 that clinical success of the AAMAs is contingent on the thoroughness of amyloid removal as expressed by the percentage of treated Time in months is on the x-axis, and proportion of participants worsening by 1 global CDR point is on the y-axis for placebo group (black line) and lecanemab-treated group (green line). The numbers of at-risk participants are given for each group at each time point, below the x-axis.…”

Section: Amyloid Removal and Other Biomarkers In Aama Trialsmentioning

confidence: 99%

Section: Lecanemab Phase 3 Clinical Trial and Beyondmentioning

confidence: 99%

Implications of the Approval of Lecanemab for Alzheimer Disease Patient Care

Knopman

Hershey

2023

Neurology

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The amyloid cascade model of the pathogenesis of Alzheimer disease (AD) is wellsupported in observational studies. Its therapeutic corollary asserts that removal of amyloid-β peptide (“amyloid”) would provide clinical benefits. After two decades of pursuing the strategy of amyloid removal without success, clinical trials of the anti-amyloid monoclonal antibody (AAMA) donanemab and a phase 3 clinical trial of lecanemab have reported clinical benefits linked to amyloid removal. Lecanemab (trade name, LeqembiTM) is the only one with published phase 3 trial results.When administered intravenously every two weeks to patients with elevated brain amyloid and mild cognitive impairment or mild dementia, lecanemab delayed cognitive and functional worsening by about five months in an 18-month double-blind, placebo-controlled trial. The trial was well-conducted, and the results favoring lecanemab were internally consistent. The demonstration that lecanemab treatment delayed clinical progression in persons with mild symptoms due to AD is a major conceptual achievement, but a better appreciation of the magnitude and durability of benefits for individual patients will require extended observations from clinical practice settings. Amyloid related imaging abnormalities (ARIA) that were largely asymptomatic occurred in about 20%, slightly over half of which were attributable to treatment and the rest to underlying AD-related amyloid angiopathy. Persons who were homozygous for theAPOEe4 allele had greater ARIA risks. Hemorrhagic complications with longer term lecanemab use need to be better understood. Administration of lecanemab will place unprecedented pressures on dementia care personnel and infrastructure, both of which need to grow exponentially to meet the challenge.

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“…2,9 Alternative mechanistic explanations for the observed loss of brain volume induced by amyloid-lowering monoclonal antibodies include a decrease in amyloid plaque volume, cerebral fluid shifts, and reduction in periplaque inflammation. 10 Some of these explanations have been advanced to suggest that observed loss of brain volume may represent benign changes similar to pseudoatrophy observed in patients with multiple sclerosis treated with disease-modifying drugs. Although definitive explanations for these MRI changes may require detailed neuropathological studies, they should not preclude reporting of associated clinical outcomes at the end of the randomized clinical trials.…”

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confidence: 99%