ARTICLE IN BRIEF
Using a novel 3-D visualization technique, researchers discovered a unique signature in dendritic spines that may help explain cognitive resilience and offer a novel strategy to protect against cognitive decline.
Two decades ago, scientists discovered that as much as 30 percent of postmortem tissue from people older than 80 years old has the classic signs of Alzheimer's disease (AD) – amyloid plaques and tau tangles. It was a puzzle: How could they have the pathological signs of AD without any clinical symptoms?
Now, scientists from the University of Alabama at Birmingham (UAB) have discovered a unique signature: elongated dendritic spines that were not present in people with a clinical diagnosis of AD. They believe that these elongated spines may help explain cognitive resilience and offer a novel strategy to protect against cognitive decline.
“We think that the shape of these spines allows older people to maintain or create new synapses in the presence of Alzheimer's pathology,” said Jeremy H. Herskowitz, PhD, assistant professor of neurology at the Center for Neurodegeneration and Experimental Therapeutics at UAB, and corresponding author of the study published in the September 16 online editition of Annals of Neurology. The scientists study proteins that regulate spine morphology and are now trying to create a model where spines are elongated in the presence of AD pathology.
The technique to visualize the dendrites and the shape of their spines was developed by Benjamin D. Boros, a UAB undergraduate who is the first author of the paper. Dr. Herskowitz said that the novel technique allowed them to study the morphology of the spines and identify their subtle but important differences. Synapse strength and activity is linked to spine morphology, he said.
STUDY METHODS, FINDINGS
The team compared dendritic spines within layers II and III pyramidal neuron dendrites in the dorsolateral prefrontal cortex (Brodmann Area 46) — a region often associated with executive function. Dr. Herskowitz said they analyzed thousands of spines from fixed brain tissue samples from eight people with AD pathology and no clinical history — which they referred to as CAD cases — a dozen age-matched pathology-free controls, and 21 AD cases. They traced the dendrites from microscopy images and created a three-dimensional digital reconstruction of dendritic structure for morphologic analyses.
An examiner blinded to the identity of the samples analyzed the samples. At first, each tissue slice was viewed under low 4X magnification to select a region of interest. Then, a pyramidal cell dendrite was viewed at 60X magnification to determine if the dendrite fulfilled the morphological criteria. Photos were taken and fed into sophisticated software that created a three-dimensional reconstruction of the dendrite and spines.
They ended up with about 118 spines per control cases, 109 spines per CAD cases, and 95 spines per AD cases. They then calculated the mean spine density per patient and per condition.
The research team found a substantial reduction in the number of spines in the samples from AD patients compared to the other groups. They compared samples from cognitively normal people with and without AD pathology, finding the elongated dendrites in the samples that came from people with AD pathology and no clinical history of AD.
They observed three different shapes of the dendritic spines: thin and mushroom-type spines, which were reduced in AD compared to the CAD brains; stubby spines, whose density was decreased significantly in CAD and AD samples compared to controls; and elongated spines that were only present in the CAD brains.
An analysis of all the samples suggested that spine density was not associated with amyloid burden. The spine density was negatively correlated with tau deposition and Braak staging for neurofibrillary pathology. (Recent studies have also shown that tau burden is a better marker for cognitive disease progression than amyloid.)
“These observations provide cellular evidence to support the hypothesis that dendritic spine plasticity is a mechanism of cognitive resilience that protects older individuals with AD pathology from developing dementia,” Dr. Herskowitz and his colleagues concluded in the paper.
Some scientists suspect that environmental factors like education and lifestyle factors and genetics shape a person's cognitive resilience as the brain ages. It is possible that the CAD brains were in some preclinical state when they came to autopsy; if the owners of those brains lived longer they may have developed clinical signs of AD. Another explanation is that these people were somehow protected against the AD pathology and they would never have developed AD.
Dr. Herskowitz said that they did not have information on the education and socioeconomic status of those who came to autopsy and were selected to be part of the study.
“Understanding these factors will help us figure out how to move forward,” he added.
The UAB scientists plans to use Rho-kinase inhibitors, which change dendritic morphology, in animal models to see if they elongate spines in the presence of AD pathology and how that might alter cognition and behavior. Dr. Herskowitz contends that it may be possible someday to use a cocktail of medicines to lengthen dendritic spines and strengthen the synaptic signals and enhance cognitive resilience. “Neuronal synapse loss correlates more strongly with cognitive impairment than classical pathologic markers of AD,” he added. “Our findings argue that the dendritic spines are what we need to fix.”
EXPERTS WEIGH IN
“The study is important and novel (it uses 3-D digital reconstruction) and adds support to the idea first reported several decades ago that the cognitive symptoms of Alzheimer's disease correlate best with neuronal and especially synaptic integrity,” said John C. Morris, MD, FAAN, the Harvey A. and Dorismae Friedman Distinguished Professor of Neurology and director of the Knight Alzheimer Disease Research Center at Washington University School of Medicine.
“The investigators suggest that individuals with the neuropathology of Alzheimer's disease who maintain synaptic integrity — with preserved dendritic spines — are able to tolerate the neuropathology without developing AD symptoms (resilience), whereas individuals who are symptomatic for AD demonstrate loss of those dendritic spines, that is, they have experienced loss of synaptic integrity.”
The caveat to the study is that it is difficult to know whether there is a direct connection between maintenance of dendritic spines and the clinical status of the individuals, Dr. Morris said. Also, it is unknown what would happen to the CAD group had they lived longer – perhaps over time they also would have a loss of synaptic integrity and become symptomatic.
Dr. Morris added: “The big question remains as to which factors do or do not confer resilience.”
Dr. Morris's team has reported that the asymptomatic (preclinical) phase of Alzheimer disease has several stages; in stage 2 and 3, the percentage of individuals who become symptomatic within a five-year period of follow-up is somewhere between 25 to 50 percent. That means that any one of the people who came to donate their brains might have someday developed clinical signs as well, he said.
“The most compelling evidence is compensation,” added Juan C. Troncoso, MD, professor of pathology and neurology at Johns Hopkins University School of Medicine. Dr. Troncoso and his colleagues analyzed the pathology on samples from the Baltimore Longitudinal Study that showed a high percentage of people with AD pathology but no evidence of a clinical disease. His group and others have also reported that people with preclinical AD seem to have larger nerve cells in some brain regions, specifically in the anterior cingulate cortex and the hippocampus. The thought is that this is the brain's compensatory mechanism – the brain reacting to injury. This hypertrophy disappears as the clinical disease progresses.
Or, as Dr. Troncoso explained, “they may have a brain that developed with more synapses or spines. Perhaps they had more nerve cells to start with so that they can withstand more injury.”
“The amount of work this group did is exceptional,” he added. “It is a beautiful study.”
David T. Jones, MD, assistant professor of neurology at the Mayo Clinic in Rochester, MD, agreed. He thinks that the different morphology of the dendritic spines in CAD patients is a marker of cognitive reserve, and it “may be the cellular analogue” of increased functional connectivity frequently observed in functional MRI studies.
“This could be a phase that everyone goes through before they get clinical disease,” he said. “Based on our model of a cascading network failure, we should see changes in dendrites or synapses in preclinical AD during the period of time that we observe high functional connectivity in the frontal lobe, and that's what makes this study very interesting to me.”
Prashanthi Vemuri, PhD, associate professor of radiology at the Mayo Clinic, who has done research on lifestyle changes that may prevent people who have pathology but no clinical symptoms from developing AD, said: “This is important because we can now image the brain and identify pathology in living people. How do some people escape cognitive problems? This study is exciting, but it is small and needs replicating. Synaptic plasticity is very important and could be the way to protect individuals from cognitive decline.”
Yaakov Stern, PhD, a professor of neuropsychology in the departments of neurology and psychiatry at Gertrude H. Sergievsky Center and in the Taub Institute at Columbia University Medical Center, said, however, that it is hard to say that “this represents cognitive resilience.”
“I think they have identified an aspect of brain morphology that is sensitive to the neurodegeneration that is taking place. The increasing tau deposition could make the spines more vulnerable to morphological change,” he said, adding that it would be interesting to show that this is the case.
When asked about that, Dr. Herskowitz noted that they compared people with the same tau burden, and the dendritic spines were different (elongated) in only those with CAD.
EXPERTS: ON A UNIQUE DENDRITIC SIGNATURE FOR COGNITIVE RESILIENCE
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© 2017 American Academy of Neurology
•. Boros BD, Greathouse KM, Gentry EG, et al Dendritic spines provide cognitive resilience against Alzheimer's disease http://onlinelibrary.wiley.com/doi/10.1002/ana.25049/full. Ann Neurol
2017; Epub 2017 Sept 16.
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