In the October 31 Nature Communications, researchers led by Oskar Hansson of Lund University in Sweden reported that in cognitively normal people, parts of the default mode network (DMN) were among the first regions to accumulate Aβ deposits detected by PET imaging. The longitudinal study followed people who had abnormally low Aβ42 in their cerebrospinal fluid (CSF), but were deemed amyloid-negative on global PET scans. While these earliest deposits did not correlate with neurodegeneration, they did correlate with a loss of connectivity within and beyond the DMN.
- In people with abnormal CSF Aβ42, PET first detects Aβ in and around the default mode network.
- Early amyloid accumulation correlated with weak connectivity in and between the DMN and other regions.
- There were no signs of neurodegeneration, cognitive decline, or changing brain metabolism.
“These results support the idea that synaptic dysfunction caused by amyloid aggregation is a very early event in Alzheimer’s disease,” commented Betty Tijms of VU University in Amsterdam (see full comment below). They also add more evidence that measures of brain connectivity are particularly sensitive at picking up subtle brain alterations associated with amyloid accumulation, she wrote.
Deposits of Aβ start forming in the brain decades before the cognitive symptoms of AD emerge, but where do they first take hold? Postmortem neuropathological studies indicated neocortical regions, but these are cross-sectional studies, limited to examining single points in time (Price and Morris, 1999; Thal et al., 2002). Similarly, a recent cross-sectional study led by Michel Grothe of the German Center for Neurodegenerative Diseases in Rostock used florbetapir-PET data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to conclude that Aβ deposits crop up earliest in the temporobasal and frontomedial regions, and that CSF concentrations of Aβ42 nudge downward even in the nascent stages of deposition (Oct 2017 news). The authors borrowed from neuropathological staging methods to develop a four-stage scheme of regional Aβ progression. However, without longitudinal data, the authors could not definitively conclude where Aβ deposition first started.
Aβ’s First Strike. Tracking the annual deposition rate of Aβ revealed a distinctive accumulation pattern in early accumulators (a) compared to non-accumulators (b), and late accumulators (c). [Courtesy of Palmqvist et al., Nature Communications, 2017.]
For the current study, co-first authors Sebastian Palmqvist and Michael Schöll and colleagues used longitudinal data from ADNI to address the question. Previously, the authors had leveraged this data to confirm what others had reported: Among cognitively normal people, CSF Aβ42 concentrations become abnormal before global amyloid-PET scans do (Palmqvist et al., 2016). Using this finding as a foundation, the researchers divided ADNI participants into three categories. They dubbed 218 people who tested negative on both CSF and PET as “non-accumulators,” 59 participants with abnormal CSF Aβ42 but normal amyloid-PET scans as “early accumulators,” and 191 people who tested positive for both as “late accumulators.”
At baseline, early accumulators had slightly higher neocortical standardized uptake value ratios (SUVRs) on florbetapir-PET scans than did non-accumulators, although uptake was still within the normal range. The two groups had similar baseline cognition, hippocampal volume, and CSF tau concentrations. By contrast, late accumulators had Aβ throughout the brain, which was accompanied by hippocampal atrophy, and they performed worse on cognitive tests than did early or non-accumulators.
To search for the earliest regions to develop Aβ deposits, the researchers tracked regional amyloid-PET signals in early versus non-accumulators over two years. They found that tracer uptake increased in the medial orbitofrontal cortex; anterior, posterior, and isthmus cingulate cortices; and precuneus in the early accumulators, but not in non-accumulators. In these brain regions, the average annual growth rate of Aβ in early accumulators was quadruple that of non-accumulators.
The regions roughly matched those reported by Grothe and colleagues. Grothe pointed out that compared to his study, Palmqvist found relatively less Aβ deposition in the inferior temporal lobe and more in the posterior medial cortex. “Although their methodological approaches are very different, both studies agree that that amyloid-PET scans considered ‘amyloid-negative’ by commonly used criteria can harbor notable regional amyloid signal,” Grothe wrote to Alzforum.
These early Aβ deposits did not appear to cause neurodegeneration or reduce glucose metabolism in the brain, as longitudinal measures of both showed no difference between early and non-accumulators. Late accumulators, however, did have distinct loss of gray-matter volume and waning brain metabolism over the two-year follow up.
In an attempt to glimpse even earlier Aβ deposition, the researchers next scrutinized PET scans of “CSF converters.” These are people who had normal CSF Aβ42 concentrations at baseline, which then dipped into the abnormal range during the two-year follow-up. Eleven people fit the bill. All developed Aβ plaques in the same locations—the left posterior cingulate and right medial orbitofrontal cortex. The statistically underpowered findings did not survive correction for multiple comparisons. Still, the researchers noted that the localization of deposits in CSF converters aligned well with a subset of affected regions in the early accumulators.
By aligning their amyloid-PET data with a brain network atlas, the researchers determined that several of the early Aβ-accumulating regions—the posterior cingulate cortex, precuneus, and medial orbitofrontal cortex in particular—overlapped with certain parts of the DMN. The frontoparietal network (FPN) also aligned with some affected regions, although to a lesser extent.
Would these findings replicate outside of the ADNI cohort? To find out, the researchers looked to the Swedish BioFINDER study. This longitudinal biomarker study collects CSF and conducts brain scans and cognitive tests on its participants, but so far only baseline data is available for analysis. The study also uses a different PET ligand (18F-flutemetamol ) and CSF Aβ immunoassay than does ADNI. Despite the differences in study methodology, the results were roughly the same: Compared to 219 people with normal CSF and normal PET readings, the 30 people with abnormal CSF but normal amyloid-PET accumulated Aβ in the same regions as did early accumulators in ADNI.
The researchers next asked whether these early deposits of Aβ affected connectivity in the brain. Drawing on BioFINDER resting-state functional MRI, the researchers found that in people with abnormal, i.e. low, CSF Aβ42, network connections flagged both within the DMN and between the DMN and the FPN. Surprisingly, in a subset of 80 participants whose Aβ42 CSF concentrations were in the normal range but close to the abnormal threshold, the reverse was true: Lower CSF Aβ42 correlated with higher connectivity.
The researchers offered several explanations for this unexpected correlation. For one, when cortical hubs such as the medial frontal lobe and posterior cingulate cortex are more active, they produce more Aβ, and that would start to drive accumulation in the brain, reducing it slightly in the CSF. Hypoconnectivity would ensue later on, as the accumulating Aβ starts to take a toll on synapses. Alternatively, it could be that Aβ accumulation in the parenchyma, though insufficient to lower CSF levels into the abnormal range, boosts neuronal activity, they proposed. Again, this uptick would ultimately wane as Aβ accumulates further.
Rachel Buckley and Aaron Schultz of Massachusetts General Hospital in Boston commented that while this period of hyperconnectivity has been documented in other studies, none have demonstrated it so early in the AD cascade. “Further investigation of this phenomena is clearly warranted and may have important implications for understanding both the consequences and the drivers of Aβ pathology,” they wrote to Alzforum.
What makes regions in the DMN particularly vulnerable to Aβ deposition? Hansson speculated that increased activity of the DMN—perhaps exacerbated by lack of cognitive or social interactions—might slightly enhance Aβ production in these regions over decades. This hypothesis is in line with what others in the field have proposed (May 2011 news). The DMN has long been known to harbor a particularly heavy burden of Aβ pathology, along with metabolic and functional deficits in people with AD (Mar 2004 news; Sep 2005 news; Aug 2009 news).
Tijms was fascinated by one part of the DMN in particular. Her lab has tied loss of connectivity in the precuneus to lower CSF Aβ42 concentrations. From its position at the back of the parietal lobe, the precuneus is functionally and anatomically connected to many other regions of the brain. “This puts the precuneus in an ideal position to link early pathological alterations in terms of amyloid deposition and later atrophy in other distant areas, like the medial temporal lobe,” she wrote to Alzforum.
“The study by Palmqvist et al. represents an important step toward a better characterization of the earliest amyloid-accumulating regions in the human brain,” commented Grothe. He added that future studies should investigate the mechanisms that underlie selective vulnerability of some regions to Aβ accumulation. “This may provide interesting new insights into the complex pathophysiologic mechanisms of Alzheimer's disease.”—Jessica Shugart
- PET Staging Charts Gradual Course of Amyloid Deposition in Alzheimer’s
- Do Overactive Brain Networks Broadcast Alzheimer’s Pathology?
- Network Diagnostics: "Default-Mode" Brain Areas Identify Early AD
- Tracing Alzheimer Disease Back to Source
- BOLD New Look—Aβ Linked to Default Network Dysfunction
- Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann Neurol. 1999 Mar;45(3):358-68. PubMed.
- Thal DR, Rüb U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002 Jun 25;58(12):1791-800. PubMed.
- Palmqvist S, Mattsson N, Hansson O, Alzheimer’s Disease Neuroimaging Initiative. Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography. Brain. 2016 Apr;139(Pt 4):1226-36. Epub 2016 Mar 2 PubMed.
No Available Further Reading
- Palmqvist S, Schöll M, Strandberg O, Mattsson N, Stomrud E, Zetterberg H, Blennow K, Landau S, Jagust W, Hansson O. Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nat Commun. 2017 Oct 31;8(1):1214. PubMed.