28 January 2009. Last week’s PNAS online describes some new gross anatomical and electrophysiological changes that accompany Alzheimer disease (AD) and frontotemporal dementia (FTD). For one, researchers led by Klaus Linkenkaer-Hansen at VU University, Amsterdam, the Netherlands, report that α and ϑ brain waves in mild to moderate AD patients exhibit subtle changes in timing. In the authors’ view, the changes support the idea that default networks are compromised in AD, and they could also serve as a marker to monitor disease progression or treatment. For another, Maria Gorno-Tempini and colleagues in the U.S. and Italy used MRI scans to examine the relationship between ApoE status and brain atrophy in Alzheimer’s and behavioral variant FTD (bvFTD). While there is an established link between the ε4 variant of ApoE and brain atrophy in AD, the researchers now extend this link to bvFTD as well, supporting the idea that ApoE4 may be a risk factor for multiple neurodegenerative diseases.
The Dutch brain wave study employed magnetoencephalography (MEG) rather than the more common electroencephalography (EEG). “Electric fields can give rise to a potential on the scalp that makes it difficult to determine where the signals come from,” Linkenkaer-Hansen told ARF. With MEG, the source of the signal can be more accurately pinpointed, indeed closely enough to allow this technology to guide neurosurgical treatment of intractable epilepsy and brain tumors. MEG is also relatively unobtrusive and fast. It does not require a multitude of electrodes taped to the scalp; instead, the magnetic field is measured by a helmet-type device that the participant can slip on and off in seconds. A typical MEG recording takes three minutes compared to the 15 minutes required for an EEG. “From the time the patient walks into the room to the time they leave is about 10 minutes,” said Linkenkaer-Hansen. Speed is clearly an advantage when dealing with AD patients, who can get agitated during testing conditions.
The researchers took MEG recordings of 19 people with mild to moderate AD and 16 age-matched controls, and assessed temporal changes in different brain waves. It is established that amplitudes of different brain waves, including α, γ, and ϑ bands, are different in AD patients compared to controls (see recent review by Jackson and Snyder, 2008). What joint first authors Teresa Montez, Simon-Schlomo Poil, and colleagues investigated was not simply the amplitude in such bands, but how they are modulated temporally. “Normal EEG and MEG analysis throw out all temporal information in the signal,” explained Linkenkaer-Hansen. By contrast, he showed that normal volunteers generate oscillatory activity that has refractal character in time. This essentially means the oscillation can somehow carry a memory of its own dynamic for several tens of seconds (see Linkenkaer-Hansen et al., 2001). “I suspected that it is important for memory that you have this coordination of brain activity over time,” he said.
In this study, the researchers show that this temporal dynamic breaks down in AD patients. For example, α band (in this case 6-13 Hz) oscillations in the parietal region normally bias activity in the same region several tens of seconds later in normal people, but this bias is significantly reduced in AD. The authors suggest that the “temporal structure is at least as important as the magnitude of the oscillations as a marker of pathophysiology and, possibly, mnemonic operations.” In contrast, the authors found that temporal bias was significantly and greatly strengthened among ϑ frequency (4-5 Hz) oscillations emanating from the medial prefrontal cortex in AD patients compared to controls. “Our interpretation is that this might reflect some sort of compensatory mechanism,” said Linkenkaer-Hansen. There is growing evidence for compensatory mechanisms in Alzheimer’s, including hippocampal hyperactivation (see ARF related news story) and increased frontal activity (see ARF related news story).
Finally, the authors suggest that these MEG recordings support the concept that default networks—a baseline neural activity that occurs while people do not focus on a given mental task—is gone awry in people with dementia (see ARF related news story). ϑ oscillations are part and parcel of this default network activity (see Gusnard and Raichle, 2001).
Previous EEG studies have found differences in brain wave amplitudes between people with dementia and controls (see, for example, Moretti et al., 2008), and even correlated those differences with hippocampal atrophy (see Babiloni et al., 2009) and ApoE genotype (see Kramer et al., 2008). Several magnetic resonance imaging studies, as well, have linked ApoE status with rates of brain atrophy in AD patients (see, for example, van de Pol et al., 2007 and Hämäläinen et al., 2008); however, only one small study has examined the relationship between ApoE status and atrophy in FTD (see Boccardi et al., 2004). Now, researchers led by Maria Gorno-Tempini at the University of California at San Francisco report analysis of a larger FTD imaging study focusing on patients with behavioral variant FTD (bvFTD), also called Pick’s disease. This is the most common form of FTD and is characterized by altered social behavior, emotions, and self-awareness. The study indicates that bvFTD patients who also carry the ApoE4 allele have greater brain atrophy in select regions of the brain than bvFTD patients who do not carry that particular isoform of the apolipoprotein. ApoE4 is already a known risk factor for this type of FTD (see Engelborghs et al., 2006).
First author Federica Agosta and colleagues used voxel-based morphometric (VBM) analysis to measure brain atrophy in 51 people with AD, 31 with bvFTD, and 51 controls. Consistent with previous imaging studies, they found greater atrophy in hippocampus and parietal cortex in ApoE4-positive AD patients. In the bvFTD group, Agosta and colleagues found that ApoE4-positive patients had greater atrophy in regions of the brain that typically degenerate in this disease, most notably both sides of the anterior cingulate cortex, and a broad region of only the right frontal cortex. Other small areas that appeared to atrophy more in ApoE4 carriers than non-carriers include the right caudate, superior temporal gyri, and left frontal gyri. The results suggest that ApoE4 somehow influences the underlying pathology of FTD. According to the authors, that might explain some curious observations. For example, one concerned a pathological dichotomy between two first-degree relatives who both had FTD—the brother who was homozygous for ApoE4 had more profound behavioral and cognitive problems than his sibling, who carried two copies of ApoE3.
Whether ApoE affects the progression of bvFTD is unknown. In AD, it is generally accepted that E4 brings on the disease earlier and speeds it up. The authors had not set out to address this question in this study, but while they saw no correlation between cognition and ApoE status, they do write that “Certainly, the atrophy patterns in our VBM study suggest that the FTD ε4 carriers may be at higher risk for rapid clinical decline.” This question requires a longitudinal study.—Tom Fagan.
Montez T, Poil S-S, Jones BF, Manshanden I, Verbunt JPA, van Dijk BW, Brussaard AB, van Ooyen A, Stam CJ, Scheltens P, Linkenkaer-Hansen K. Altered temporal correlations in parietal α and prefrontal ϑ oscillations in early-stage Alzheimer disease. PNAS online. 2009, January 19. Abstract
Agosta F, Vossel KA, Miller BL, Migliaccio R, Bonasera SJ, Filippi M, Boxer AL, Karydas A, Possin KL, Gorno-Tempini ML. Apolipoprotein E4: disease-specific effects on brain atrophy in Alzheimer’s disease and frontotemporal dementia. PNAS online. 2009, January 19. Abstract