Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease

Anne M. Fagan, et. al.

¹Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
²Knight Alzheimer’s Disease Research Center at Washington University School of Medicine, St. Louis, MO 63110, USA.
³Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁴Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁵Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁶Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA.
⁷WA Center for Alzheimer’s Research and Care, Edith Cowan University, Perth, Western Australia 6009, Australia.
⁸Mental Health Research Institute, University of Melbourne, Melbourne, Victoria 3052, Australia.
⁹Department of Neurology, The Taub Institute and the Sergievsky Center, Columbia University, New York, NY 10032, USA.
¹⁰Mary S. Easton Center for Alzheimer’s Disease Research, Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹Dementia Research Center, University College London, London WC1N 3BG, UK.
¹²Departments of Neurology and Psychiatry, Warren Alpert Medical School of Brown University, Butler Hospital, Providence, RI 02906, USA.
¹³Neuroscience Research Australia, Sydney, New South Wales 2031, Australia.
¹⁴School of Medical Sciences, University of New South Wales, Sydney, New South Wales 2031, Australia.
¹⁵Department of Neurology, Brigham and Women’s Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
¹⁶Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹⁷http://www.dian-info.org/personnel.htm

↵*Corresponding author. E-mail: fagana@neuro.wustl.edu

Abstract

Clinicopathological evidence suggests that the pathology of Alzheimer’s disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic (“preclinical”) stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-β_1–42 (Aβ_1–42) associated with the presence of Aβ plaques, and elevated concentrations of CSF tau, ptau₁₈₁ (phosphorylated tau₁₈₁), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.

Tuesday, March 4, 2014

But, It's Only a Dog...?

Feeling Simpatico with Your Dog? It May Be Based on Similar Human–Canine Brain Structures

New research shows that humans and dogs have very similar voice-sensitive brain regions, which may help explain our intense bonds with these furry, four-legged friends

Feb 20, 2014 |By Annie Sneed

Dog lies motionless in a MRI brain scanner — A dog lies motionless in an fMRI brain scanner at the MR Research Center in Budapest.
*Credit: Flickr/Eniko Kubinyi*

You may snicker when you see dog owners talk to their pets as though they were human or view YouTube videos of dogs supposedly speaking English back to their owners, saying words like “banana” and “I love you.” And with good reason: although dogs have the capacity to understand more than 100 words, studies have demonstrated Fido can’t really speak human languages or comprehend them with the same complexity that we do. Yet researchers have now discovered that dog and human brains process the vocalizations and emotions of others more similarly than previously thought. The findings suggest that although dogs cannot discuss relativity theory with us, they do seem to be wired in a way that helps them to grasp what we feel by attending to the sounds we make.

To compare active human and dog brains, postdoctoral researcher Attila Andics and his team from MTA-ELTE Comparative Ethology Research Group in Hungary trained 11 dogs to lie still in an fMRI brain scanner for several six minute intervals so that the researchers could perform the same experiment on both human and canine participants. Both groups listened to almost two hundred dog and human sounds—from whining and crying to laughter and playful barking—while the team scanned their brain activity.

The resulting study, published in Current Biology today, reveals both that dog brains have voice-sensitive regions and that these neurological areas resemble those of humans. Sharing similar locations in both species, they process voices and emotions of other individuals similarly. Both groups respond with greater neural activity when they listen to voices reflecting positive emotions such as laughing than to negative sounds that include crying or whining. Dogs and people, however, respond more strongly to the sounds made by their own species. “Dogs and humans meet in a very similar social environment but we didn’t know before just how similar the brain mechanisms are to process this social information,” Andics says.

These striking similarities help clarify the timeline and stages of mammalian evolutionary history. Until now researchers had identified voice-sensitive brain regions only in humans and macaque monkeys, whose last common ancestor lived 30 million years ago. The last common ancestor of humans and dogs—a mammalian carnivore with a brain the size of an egg—existed around 100 million years ago. The canine finding thus suggests that the voice-sensitive brain regions in both species evolved at least that long ago, if not earlier. Other mammals on the same evolutionary branch as humans and hounds that also arose from that last mutual ancestor likely share the same brain areas as well.

But dog owners might be most interested in what this study says about our special relationship with canine pets. Humans domesticated dogs somewhere between 18,000 and 32,000 years ago, and since then they have become people’s best friends, hunting partners, guards and even purse accessories. Andics thinks the parallel brain sensitivity to voices and emotions may account in part for our unique bond. “This similarity helps explain what makes vocal communication between dogs and humans so successful,” he says. “It’s why dogs can tune into their owners’ feelings so well.”

Turns out, people who talk to their poodles or golden retrievers aren’t so silly after all.