Can Cognitive Fluctuations Offer Insight Into Alzheimer’s Disease Neurobiology?

While Alzheimer’s disease is generally characterized as a steady progression of cognitive decline, some patients have marked periods of lucidity and normal function lasting for minutes or even days before lapsing back into their impaired state. These so-called cognitive fluctuations (CFs) may also manifest as periods of pronounced confusion or increased somnolence. Strikingly, CFs are even more common in dementia with Lewy bodies (DLB) and are even a core feature in its clinical diagnosis.

Cleveland Clinic neurologist Jagan Pillai, MD, PhD, Director of the Cleveland Alzheimer’s Disease Research Center, was recently awarded a $4.9 million research grant from the National Institutes of Health (NIH) to lead a multicenter research project over four years focused on characterizing CFs in Alzheimer’s disease and DLB.

“CF is an underrecognized yet clinically significant symptom that lacks objective measures,” Dr. Pillai explains. “A better understanding of these spontaneous changes in cognition, attention, arousal and function could potentially improve diagnosis, monitoring and clinical trials for both Alzheimer’s disease and DLB.”

The need for a new direction

Up to now, costly drug development and clinical trials for Alzheimer’s disease have led to only modest clinical gains. Dr. Pillai points out that a difficulty in studying this disease is the intra- and interindividual variability in clinical presentations and rates of cognitive decline. Variability between patients, he explains, may reflect underlying differences in the disease, potentially confounding clinical trial results by mixing distinct populations. At the individual level, CFs could cause inconsistent observations and answers to assessments taken periodically, also skewing results.

CFs are poorly characterized, with no identified biomarkers or tools to measure their occurrence. Relying mostly on observer report, they are found in 30% to 60% of people with early DLB. They are less common in Alzheimer’s disease, and individuals who experience them are likelier to be diagnosed with mild rather than more severe disease.

“CFs offer a window into the brain — when patients become lucid, it tells you that some normal functioning is preserved,” Dr. Pillai says. “If we understood them better, perhaps we could modulate something, maybe with exercise or medications, to help periods of clarity last longer or occur more consistently.”

His newly funded research is using a variety of measures to try to objectively and reliably characterize CFs to better understand how they occur.

Study design

The study is a Cleveland Clinic-led collaboration with VA Puget Sound in Seattle and University of California San Diego. The sites are currently recruiting a total of 108 participants, aged 50 to 90 years, evenly divided between patients with biomarker-confirmed Alzheimer’s disease and biomarker-confirmed DLB. All sites are conducting cognitive and physiological testing. In addition, University of Washington is contributing advanced data analytics.

Participants are being tracked for up to four years and will undergo annual informant-based questionnaires and neurocognitive measurements of CF. These will be compared with a variety of real-time tools, including:

• Actigraphy
• At-home iPad-administered neuropsychological tests
• Resting and sleep EEG
• Resting-state functional MRI

“We anticipate that the real-time tools will help identify objective biomarkers reflecting the presence, frequency and stability of CF,” Dr. Pillai says. “We expect them to be more reliable than informant-based questionnaires, which are currently used to capture the presence of CFs.”

Potential implications

Dr. Pillai highlights several ways this research can contribute to the understanding of Alzheimer’s disease:

1. Shedding light on underlying causes. CFs have been hypothesized to be caused by disruptions in neural pathways that regulate attention and wakefulness or by changes in blood pressure. Multimodal tools will help detect correlations between underlying physiology and functional states, and resting-state functional MRI is expected to bring to light specific brain regions where disturbances may be occurring. The research may also help elucidate whether CFs in DLB and Alzheimer’s disease are fundamentally related or are distinct phenomena.
2. Understanding clinical implications of CFs. The longitudinal study design will contribute to understanding how the presence of CFs affects disease course, and whether this differs between Alzheimer’s disease and DLB.
3. Diagnosis and treatment monitoring. Biomarkers for CFs could become important for earlier and more accurate detection of Alzheimer’s disease as well as for monitoring treatment effectiveness.
4. Strengthening research. Dr. Pillai emphasizes that the development of effective medications depends on better objective disease measures. Having reliable markers of CFs may facilitate formation of more uniform patient cohorts and provide new metrics for detecting clinical improvement from experimental therapeutics.

Dr. Pillai notes that this research involves the most comprehensive investigation to date focused on CFs, using the largest cohort of patients over the longest period of time.

“This novel tack in studying cognitive fluctuation in DLB and Alzheimer’s disease shows great promise by providing real-time physiological information for a poorly understood but potentially important phenomenon,” Dr. Pillai says. “I expect it will help move the field forward in innovative and significant new directions.”

Image at top: Brain images showing differences in connectivity between CF-positive and CF-negative groups.