Aducanumab recently underwent two large phase III clinical trials that were stopped prematurely by the sponsor Biogen. One trial was trending positive while the other showed no benefits from ...aducanumab. Post hoc analyses led the sponsor to assert that there was a sufficient efficacy signal to justify a new drug application as a treatment for Alzheimer's disease. The sponsor claimed that subsets of participants receiving sufficiently high doses of aducanumab demonstrated benefits in both trials. In contrast, we identified alternative accounts for the apparent drug benefits in post hoc subgroups that are unrelated to dose effects. Biomarker data were consistent with target engagement, but no evidence was presented to correlate biomarker changes to cognitive benefits. Our analysis supports the conduct of a third, phase III trial with high‐dose aducanumab. Aducanumab's efficacy as a treatment for the cognitive dysfunction in Alzheimer's disease cannot be proven by clinical trials with divergent outcomes.
The skills of an expert clinician are needed at this second decision point to weigh multiple sources of information, assign a provisional clinical syndrome, and propose a provisional causal ...hypothesis. The physician must decide whether more information is needed to establish with higher certainty what the underlying cause is or, alternatively, if the clinically evident features are sufficiently elucidated to guide the treatment and management approach. DSK serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study; was an investigator in Alzheimer clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California, and is currently an investigator in a trial in frontotemporal degeneration with Alector; has served as a consultant for Roche, AriBio, Linus Health, Biovie, and Alzeca Biosciences, but receives no personal compensation; and receives funding from the National Institutes of Health.
Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, ...variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n = 892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain's modular organization and assign each region to a "meta-modular" group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer's dementia and 56 cognitively normal elderly subjects matched 1:2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer's disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer's dementia.
Classification and epidemiology of MCI Roberts, Rosebud; Knopman, David S
Clinics in geriatric medicine,
11/2013, Letnik:
29, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Mild cognitive impairment (MCI) is an intermediate stage in the trajectory from normal cognition to dementia. Despite controversies about the classification of MCI, recent published criteria for MCI ...allow better comparison of the prevalence, incidence, and outcomes of MCI. Subjects with MCI have a high rate of progression to dementia over a relatively short period. In this review, we present an overview of the classification of MCI, estimates of the incidence and prevalence of MCI, risk factors for MCI, and the outcomes following an MCI diagnosis.
Mild cognitive impairment and mild dementia are common problems in the elderly. Primary care physicians are the first point of contact for most patients with these disorders and should be familiar ...with their diagnosis, prognosis, and management. Both mild cognitive impairment and mild dementia are characterized by objective evidence of cognitive impairment. The main distinctions between mild cognitive impairment and mild dementia are that in the latter, more than one cognitive domain is invariably involved and substantial interference with daily life is evident. The diagnosis of mild cognitive impairment and mild dementia is based mainly on the history and cognitive examination. The prognosis for mild cognitive impairment and mild dementia is an important motivation for diagnosis because in both, there is a heightened risk for further cognitive decline. The etiology of mild cognitive impairment and mild dementia can often be established through the clinical examination, although imaging and other laboratory tests may also contribute. Although Alzheimer disease is the most common cause of both, cerebrovascular disease and Lewy body disease make important contributions. Pharmacological treatments are of modest value in mild dementia due to Alzheimer disease, and there are no approved pharmacological treatments for mild cognitive impairment of any etiology. Nonetheless, new-onset cognitive impairment is a worrisome symptom to patients and families that demands answers and advice. If a patient is having difficulties managing medications, finances, or transportation independently, diagnosis and intervention are necessary to ensure the health and safety of the patient.
Summary In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD ...biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.
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