13 Mar 2020

Brain rhythms change their tune in people with Alzheimer’s disease, and they do so to the beat of Aβ and tau, according to a study published in Science Translational Medicine on March 11. Researchers led by Keith Vossel and Srikantan Nagarajan at the University of California, San Francisco, reported that while alpha wave synchrony collapses in certain regions of the brain, delta-theta waves synchronize more tightly in others. Where in the brain the alpha synchrony fell apart correlated with where tau tangles were. It also differed among clinical subtypes of AD. In contrast, heightened delta-theta synchrony occurred in regions burdened by either Aβ or tau. The findings show that Aβ and tau degrade the function of the brain’s circuitry in different ways in AD, and suggest that the electrical readouts might serve as functional biomarkers.

In people with Alzheimer’s, alpha rhythms fell out of step, whereas delta-theta rhythms became more synchronous.

Regional alpha hyposynchrony mapped to tangles, differed among AD clinical subtypes.

Delta-theta hypersynchrony aligned with Aβ and tau pathology.

“[The findings] provide further support for the notion that the cellular and molecular changes in AD converge at the level of circuits,” wrote Samuel Harris and Marc Aurel Busche of University College London in a joint comment to Alzforum. The study also points to novel diagnostic and therapeutic approaches, they added.

“This study adds to the literature on the value of neurophysiological biomarkers on top of other more established biomarkers, e.g. Aβ, tau, and neurodegeneration markers, in better diagnosing, classifying, and predicting trajectories in Alzheimer’s disease,” wrote Tarek Rajji, University of Toronto, to Alzforum.

Far from a mass of neurons firing at random, the brain is an exquisitely organized mesh of functional circuitry. The coordinated firing of clusters of neurons throughout the brain yields electrical pulses of different frequencies, ranging from slow delta-theta rhythms that beat at 2 to 8 Hz, to moderate 8 to 12 Hz alpha waves, to the rapid gamma waves that flutter at 30 to 100 Hz.

Using electroencephalography (EEG) or magnetoencephalography (MEG) to detect these rhythms through the scalp, researchers have reported changes in people with AD—alpha waves weaken, delta-theta waves swell (Osipova et al., 2005; Stam et al., 2006; Lizio et al., 2011). Functional MRI studies, which gauge neuronal activity indirectly by measuring local blood oxygen levels, also point to disturbances in the brain networks of people with AD (Mar 2004 news; Aug 2009 news). However, exactly where these electrical disturbances arise, and how they relate to the regional distribution and severity of AD pathology in the brain, remain tough questions to answer.

First author Kamalini Ranasinghe and colleagues combined electrical recordings with multimodal brain imaging. First, they charted patterns of neuronal synchrony, using magnetoencephalography imaging, MEGI for short. This technique combines MEG readings from 275 scalp sensors with individualized structural MRI scans to measure brain rhythms with improved spatial and temporal resolution. Essentially, for each of about 2,000 voxels in the brain, an algorithm calculates how closely brain rhythms sync up with those in the rest of the brain.

Compared with 20 healthy controls, 60 people diagnosed with probable AD or MCI due to AD had less synchronous alpha rhythms and hypersynchronous delta-theta waves. Alpha hyposynchrony predominated in the left inferior temporal, left posterior parietal, and bilateral occipital regions, while delta-theta hypersynchrony occurred in more anterior regions, including the frontal and parietal cortices and the right temporal cortex.

Curiously, regions with most alpha hyposynchrony differed among people with distinct clinical subtypes of AD. Among 30 people with the typical amnestic, dysexecutive type of AD, alpha waves fell most out of step in the posterior parietal and occipital cortices, while among 15 participants with the logopenic variant of primary progressive aphasia, the left posterior temporal cortex was most affected. People with the posterior cortical atrophy variant of AD had the poorest alpha synchrony in the occipital cortices, with their right hemispheres doing worst.

In contrast with alpha synchrony, regional patterns of delta-theta hypersynchrony did not differ among clinical AD subtypes.

Synchrony subtypes. Patterns of alpha hyposynchrony (left) differed significantly among clinical subtypes of AD, whereas the distribution of delta-theta hypersynchrony (right) did not. [Courtesy of Ranasinghe et al., Science Translational Medicine, 2020.]

In a subset of 12 AD patients who had tau-PET scans, waning alpha synchrony also appeared to coincide with tangles. Regions most afflicted by tau pathology—the posterior and inferior temporal cortices and left posterior parietal cortex—also emitted alpha waves most out of sync with the rest of the brain. Alpha hyposynchrony did not align with patterns of Aβ deposition (see image above). In contrast, delta-theta hypersynchrony co-localized with Aβ deposition as well as tau tangles. Either pathology alone boosted it, but in regions heavily burdened by Aβ and tau, the net effect was a lowering of delta-theta synchrony.

“This suggests that delta/theta synchrony reflects an interaction between Aβ and tau pathologies, and it will thus be fascinating to confirm in longitudinal studies whether delta/theta hypersynchrony at early stages of AD, transitions to hyposynchrony in late stages, and may be a biomarker of disease progression,” wrote Harris and Busche. This would dovetail with data from mouse models reported by Busche and others, in which Aβ triggered an uptick in neuronal signaling, while tau silenced it. When put together, tau’s silencing effect won out (Dec 2018 conference news).

In Sync with Aβ, Tau. Alpha hyposynchrony (left) more closely aligned with tau PET (top) than with Aβ PET (bottom). Delta-theta hypersynchrony (right) correlated with both tangles and plaques. [Courtesy of Ranasinghe et al., Science Translational Medicine, 2020.]

Ranasinghe noted that while delta-theta rhythms associate with excitatory neurons, alpha rhythms reflect inhibitory circuits. Essentially, alpha rhythms gate the flow of information in the brain, she said. Alpha hyposynchrony could release the brakes on excitatory circuits, leading to hyperactivity. That alpha synchrony slips in people with AD meshes with previous reports of hyperactivity in their default mode network, she added.

Finally, Ranasinghe and colleagues reported that alpha hyposynchrony, but not delta-theta hypersynchrony, associated with poorer cognition, as assessed by MMSE scores. Together, the findings place alpha hyposynchrony most proximal to the business end of AD, i.e., tau pathology and cognitive decline. Ranasinghe noted that while only three to four people with each clinical subtype of AD underwent tau-PET scans, the results suggest that differences in the distribution of alpha hyposynchrony among the clinical subtypes could be dictated by tau deposition patterns.

“The results confirm previous findings that AD has clinical variations and that these are linked to concordant anatomical differences in the distribution of neurofibrillary tauopathy,” wrote Marsel Mesulam and Emily Rogalski of Northwestern University, Chicago, in a comment to Alzforum. They added that the MEGI findings mesh with those of their recent resting-state fMRI study, in which unique perturbations in network connectivity cropped up in people with amnestic versus aphasic symptoms (Martersteck et al., 2020).

The study adds to mounting evidence implicating offbeat brain rhythms in cognitive decline. While animal studies suggest that stimulating the brain with gamma waves can help mop up Aβ plaques and boost memory, a recent study in humans found that getting theta rhythms back on track improved working memory (Dec 2016 news; Mar 2019 news; Apr 2019 news).

Ranasinghe did not measure fast gamma waves in this study because these waves are not detected in the resting state; they only pop up during tasks. However, she noted that slower alpha and theta waves are clearly tied to gamma waves through a phenomenon called phase-amplitude coupling, in which the amplitude of gamma waves ebb and flow with the phase of slower theta or alpha waves.

In a joint comment to Alzforum, Li-Huei Tsai and Chinnakkaruppan Adaikkan of Massachusetts Institute of Technology noted that the changes in theta and alpha coherence in people with AD fit nicely with previous studies in rodents, which reported that theta/alpha coherence is enhanced during spatial memory tasks (Jones and Wilson, 2005).

“Future longitudinal studies may reveal how and why disruptions in network synchrony evolve as AD pathogenesis progress,” they added. “Overall, these findings point to the idea that targeting network synchrony early on in the disease progression may offer benefits.”

Future studies will track changes in brain rhythms along the spectrum of AD, Ranasinghe said. With a better understanding of how brain rhythms change throughout the course of the disease, these electrical signals may one day serve as sensitive markers of progression or for specific subtypes of AD. This would help researchers track specific cognitive deficits, such as memory or language, in the course of a clinical trial.

Rajji agreed. “The findings support the potential use of these neurophysiological markers in identifying different aspects of the AD syndromes for clinical classification and treatment interventions,” he wrote.—Jessica Shugart