Early diagnosis of Alzheimer’s disease using artificial intelligence

According to a study published in the journal of radiology, research shows that artificial intelligence (AI) technology predict the development of Alzheimer’s disease early.

Early diagnosis of Alzheimer’s is important as treatments and interventions are more effective early in the course of the disease. However, early diagnosis has proven to be challenging. Research has linked the disease process to changes in metabolism, as shown by glucose uptake in certain regions of the brain, but these changes can be difficult to recognize.

Credit: Radiological Society of North America

“Differences in the pattern of glucose uptake in the brain are very subtle and diffuse,” said study co-author Jae Ho Sohn, M.D., from the Radiology & Biomedical Imaging Department at the University of California in San Francisco (UCSF). “People are good at finding specific biomarkers of disease, but metabolic changes represent a more global and subtle process.”

The researchers trained the deep learning algorithm on a special imaging technology known as 18-F-fluorodeoxyglucose positron emission tomography (FDG-PET). In an FDG-PET scan, FDG, a radioactive glucose compound, is injected into the blood. PET scans can then measure the uptake of FDG in brain cells, an indicator of metabolic activity.

The researchers had access to data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a major multi-site study focused on clinical trials to improve the prevention and treatment of this disease. The ADNI dataset included more than 2,100 FDG-PET brain images from 1,002 patients. Researchers trained the deep learning algorithm on 90 percent of the dataset and then tested it on the remaining 10 percent of the dataset. Through deep learning, the algorithm was able to teach itself metabolic patterns that corresponded to Alzheimer’s disease.

Finally, the researchers tested the algorithm on an independent set of 40 imaging exams from 40 patients that it had never studied. The algorithm achieved 100 percent sensitivity at detecting the disease an average of more than six years prior to the final diagnosis.

“We were very pleased with the algorithm’s performance,” Dr. Sohn said. “It was able to predict every single case that advanced to Alzheimer’s disease.”

Although he cautioned that their independent test set was small and needs further validation with a larger multi-institutional prospective study, Dr. Sohn said that the algorithm could be a useful tool to complement the work of radiologists especially in conjunction with other biochemical and imaging tests–in providing an opportunity for early therapeutic intervention.

Future research directions include training the deep learning algorithm to look for patterns associated with the accumulation of beta-amyloid and tau proteins, abnormal protein clumps and tangles in the brain that are markers specific to Alzheimer’s disease, according to UCSF’s Youngho Seo, Ph.D., who served as one of the faculty advisors of the study.

Citation: Yiming Ding, Jae Ho Sohn, Michael G. Kawczynski, Hari Trivedi, Roy Harnish, Nathaniel W. Jenkins, Dmytro Lituiev, Timothy P. Copeland, Mariam S. Aboian, Carina Mari Aparici, Spencer C. Behr, Robert R. Flavell, Shih-Ying Huang, Kelly A. Zalocusky, Lorenzo Nardo, Youngho Seo, Randall A. Hawkins, Miguel Hernandez Pampaloni, Dexter Hadley, and Benjamin L. Franc. “A Deep Learning Model to Predict a Diagnosis of Alzheimer Disease by Using 18F-FDG PET of the Brain.” Radiology, 2018, 180958.
doi:10.1148/radiol.2018180958.

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Preventing Alzheimer’s dementia with Ibuprofen

Researchers suggest that daily intake of nonsteroidal anti-inflammatory drugs like over the counter ibuprofen could prevent the onset of Alzheimer’s disease. This research is led by Dr. Patrick McGeer and is published in the Journal of Alzheimer’s Disease.

Alzheimer’s dementia affects those diagnosed and their family along with a significant financial burden on the society. It is estimated around 47 million people worldwide are affected by this and is the fifth leading cause of death in those aged 65 and above. The Alzheimer’s Association estimates that there are more than 5 million cases in the United States alone. The annual cost United States in 2017 is estimated to be around $259 billion and the projected for the costs go to 1.1 trillion by 2050.

According to the latest publication by Dr. Patrick McGeer diagnosis of people at risk of Alzheimer’s disease is possible with positron-electron microscopy for AD senile plaques, blood or saliva analysis for the elevation of the amyloid-β protein fragment terminating at position 42, and cerebrospinal fluid analysis showing a decrease in the content of this protein. The publication also suggests prevention strategies like self-treatment by consumption of non-steroidal anti-inflammatory drugs, adhering to a Mediterranean diet, and consuming antioxidants such as quercitin which is contained in coffee.

Reference: Mcgeer, Patrick L., and Edith Mcgeer. “Conquering Alzheimer’s Disease by Self Treatment.” Journal of Alzheimers Disease, 2018, 1-3. doi:10.3233/jad-179913.

Adapted from press release by IOS press.

Potential treatment for Alzheimer’s dementia using cell therapy

Researchers from Gladstone Institute uncovered the therapeutic benefits of genetically improving interneurons with a voltage-gated sodium channel Nav1.1 and transplanting them into the brain of a mouse model of Alzheimer’s disease. This study is led by Jorge Palop, Ph.D., an assistant investigator at the Gladstone Institutes. The study findings are published in journal Neuron.

Inhibitory interneurons are essential for managing brain rhythms.  They regulate the oscillatory rhythms and network synchrony that are required for cognitive functions. Network dysrhythmias in Alzheimer’s disease and multiple neuropsychiatric disorders are associated with hypofunction of Nav1.1, a voltage-gated sodium channel subunit predominantly expressed in interneurons in Alzheimer’s disease (AD).

Researchers found a way to re-engineer inhibitory interneurons genetically boosted by adding protein Nav1.1 to improve their function. They showed that these enhanced interneurons, when transplanted into the abnormal brain of Alzheimer mice, can properly control the activity of excitatory cells and restore brain rhythms.

The researchers then discovered that the interneurons with enhanced function were able to overcome the toxic disease environment and restore brain function. The findings could eventually lead to the development of new treatment options for patients with Alzheimer’s disease.

In addition to examining if the cell therapy could be translated from mice to humans, researchers are working on pharmaceutical drugs to enhance the function of inhibitory interneurons.

Citation: Martinez-Losa, Magdalena, Tara E. Tracy, Keran Ma, Laure Verret, Alexandra Clemente-Perez, Abdullah S. Khan, Inma Cobos, Kaitlyn Ho, Li Gan, Lennart Mucke, Manuel Alvarez-Dolado, and Jorge J. Palop. “Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer’s Disease.” Neuron, 2018. doi:10.1016/j.neuron.2018.02.029.

Research funding: National Institutes of Health, Alzheimer’s Association; S.D. Bechtel, Jr. Foundation.

Adapted from press release by Gladstone Institutes.

New biomarkers for assessing Alzheimers dementia risk and early diagnosis

Researchers from the University of Texas have analyzed biomarkers to predict future risk of dementia. Their findings are published in journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 

Dementia is a rising tidal wave of devastation for families and society. Age is the biggest risk factor. Alzheimer’s disease, which is the leading cause of dementia, is the sixth-leading cause of death in the United States, and more than 5 million Americans are currently living with Alzheimer’s. That figure is expected to triple by 2050.

Researchers analyzed metabolites in blood samples taken from 22,623 individuals, including 995 who went on to develop dementia. The participants were enrolled in eight research cohorts in five countries. They found that higher blood concentrations of branched-chain amino acids were associated with lower risk of future dementia. Another molecule, creatinine, and two very low-density lipoprotein (VLDL)specific lipoprotein lipid subclasses also were associated with lower risk of dementia. On the other hand, one high-density lipoprotein (HDL) and one VLDL lipoprotein subclass were associated with increased dementia risk.

These findings will broaden the search for drug targets in dementia caused by Alzheimer’s disease, vascular disease, and other subtypes, said Dr. Seshadri, professor of neurology at UT Health San Antonio. “It is now recognized that we need to look beyond the traditionally studied amyloid and tau pathways and understand the entire spectrum of pathology involved in persons who present with symptoms of Alzheimer’s disease and other dementias,” Dr. Seshadri said. “It is exciting to find new biomarkers that can help us identify persons who are at the highest risk of dementia.”

The study was in persons of European ancestry and was carried out in collaboration with researchers in Finland, the Netherlands, the United Kingdom and Estonia. Dr. Seshadri is eager to replicate it in South Texas. “The Glenn Biggs Institute at UT Health San Antonio will expand these studies to include the diverse racial and ethnic groups who live in South Texas,” she said.

Researchers feel that more studies are needed to clarify whether the branched-chain amino acids and other molecules play a causal role in the dementia disease process or are merely early markers of the disease.

Citation: Tynkkynen, Juho, Vincent Chouraki, Sven J. Van Der Lee, Jussi Hernesniemi, Qiong Yang, Shuo Li, Alexa Beiser, Martin G. Larson, Katri Sääksjärvi, Martin J. Shipley, Archana Singh-Manoux, Robert E. Gerszten, Thomas J. Wang, Aki S. Havulinna, Peter Würtz, Krista Fischer, Ayse Demirkan, M. Arfan Ikram, Najaf Amin, Terho Lehtimäki, Mika Kähönen, Markus Perola, Andres Metspalu, Antti J. Kangas, Pasi Soininen, Mika Ala-Korpela, Ramachandran S. Vasan, Mika Kivimäki, Cornelia M. Van Duijn, Sudha Seshadri, and Veikko Salomaa. “Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimers disease: A prospective study in eight cohorts.” Alzheimers & Dementia, 2018. doi:10.1016/j.jalz.2018.01.003.

Adapted from press release by the University of Texas Health Science Center at San Antonio.

Role of calcium in Parkinson’s disease

The international team, led by the University of Cambridge found that excess levels of calcium in brain cells may lead to the formation of toxic clusters that are the hallmark of Parkinson’s disease. Their research found that calcium can mediate the interaction between small membranous structures inside nerve endings, which are important for neuronal signalling in the brain, and alpha-synuclein, the protein associated with Parkinson’s disease. Excess levels of either calcium or alpha-synuclein may be what starts the chain reaction that leads to the death of brain cells.

Credit: Janin Lautenschläger

The findings, reported in the journal Nature Communications, represent another step towards understanding how and why people develop Parkinson’s. According to the charity Parkinson’s UK, one in every 350 adults in the UK currently has the condition. Parkinson’s disease is one of a number of neurodegenerative diseases caused  by amyloid deposits of aggregated alpha-synuclein. These deposits also known as Lewy bodies, are the sign of Parkinson’s disease.

Curiously, it hasn’t been clear until now what alpha-synuclein actually does in the cell: why it’s there and what it’s meant to do. It is implicated in various processes, such as the smooth flow of chemical signals in the brain and the movement of molecules in and out of nerve endings, but exactly how it does is unclear.

Thanks to super-resolution microscopy techniques, it is now possible to look inside cells to understand role of alpha-synuclein. To do so researchers isolated synaptic vesicles, part of the nerve cells that store the neurotransmitters which send signals from one nerve cell to another.

In neurons, calcium plays a role in the release of neurotransmitters. The researchers observed that when calcium levels in the nerve cell increase, such as upon neuronal signalling, the alpha-synuclein binds to synaptic vesicles at multiple points causing the vesicles to come together. This may indicate that the normal role of alpha-synuclein is to help the chemical transmission of information across nerve cells.

“This is the first time we’ve seen that calcium influences the way alpha-synuclein interacts with synaptic vesicles,” said Dr Janin Lautenschläger, the paper’s first author. “We think that alpha-synuclein is almost like a calcium sensor. In the presence of calcium, it changes its structure and how it interacts with its environment, which is likely very important for its normal function.”

“There is a fine balance of calcium and alpha-synuclein in the cell, and when there is too much of one or the other, the balance is tipped and aggregation begins, leading to Parkinson’s disease,” said co-first author Dr Amberley Stephens.

The imbalance can be caused by a genetic doubling of the amount of alpha-synuclein (gene duplication), by an age-related slowing of the breakdown of excess protein, by an increased level of calcium in neurons that are sensitive to Parkinson’s, or an associated lack of calcium buffering capacity in these neurons.

Understanding the role of alpha-synuclein in physiological or pathological processes may aid in the development of new treatments for Parkinson’s disease. One possibility is that drug candidates developed to block calcium, for use in heart disease for instance, might also have potential against Parkinson’s disease.

Citation: Lautenschläger, Janin, Amberley D. Stephens, Giuliana Fusco, Florian Ströhl, Nathan Curry, Maria Zacharopoulou, Claire H. Michel, Romain Laine, Nadezhda Nespovitaya, Marcus Fantham, Dorothea Pinotsi, Wagner Zago, Paul Fraser, Anurag Tandon, Peter St George-Hyslop, Eric Rees, Jonathan J. Phillips, Alfonso De Simone, Clemens F. Kaminski, and Gabriele S. Kaminski Schierle. “C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction.” Nature Communications 9, no. 1 (2018). doi:10.1038/s41467-018-03111-4.

Adapted from press release by University of Cambridge.

Brain changes in diabetic patients

A new study published in Diabetologia reveals that overweight and obese individuals with early stage type 2 diabetes (T2D) had more severe and progressive abnormalities in brain structure and cognition compared to normal-weight study participants.

The research conducted by Dr Sunjung Yoon and Dr In Kyoon Lyoo (Ewha Brain Institute, Ewha Womens University, Seoul, South Korea), Hanbyul Cho (The Brain Institute, University of Utah, Salt Lake City, UT, USA), and colleagues in Korea and the USA looked into the effects of being overweight or obese on the brains and cognitive functions of people with early stage type 2 diabetes.

The study found that grey matter was significantly thinner in clusters in the temporal, prefrontoparietal, motor and occipital cortices of the brains of diabetic study participants when compared to the non-diabetic control group. Further thinning of the temporal and motor cortices was also observed in the overweight/obese diabetic group, compared to normal-weight diabetics. The team also discovered region-specific changes which suggested that the temporal lobe has a particular vulnerability to the combined effects of having type 2 diabetes and being overweight or obese.

Citation: Yoon, Sujung, Hanbyul Cho, Jungyoon Kim, Do-Wan Lee, Geon Ha Kim, Young Sun Hong, Sohyeon Moon, Shinwon Park, Sunho Lee, Suji Lee, Sujin Bae, Donald C. Simonson, and In Kyoon Lyoo. “Brain changes in overweight/obese and normal-weight adults with type 2 diabetes mellitus.” Diabetologia, 2017.
doi:10.1007/s00125-017-4266-7.
Adapted from press release by Diabetologia.

New approach to treating dementia using antisense oligonucleotides

In a study of mice and monkeys, NIH funded researchers showed that they could prevent and reverse some of the brain injury caused by the toxic form of a protein called tau.

Scientists used a designer compound to prevent and reverse brain damage caused by tau in mice.
Credit: Miller lab, Washington University, St. Louis, MO

The results, published in Science Translational Medicine, suggest that the study of compounds, called tau antisense oligonucleotides, that are genetically engineered to block a cell’s assembly line production of tau, might be pursued as an effective treatment for a variety of disorders. Antisense oligonucleotides are short sequences of DNA or RNA that are programmed to turn genes on or off.

In several disorders, toxic forms of tau clump together inside dying brain cells and form neurofibrillary tangles, including Alzheimer’s disease, tau-associated frontotemporal dementia, chronic traumatic encephalopathy and progressive supranuclear palsy.

Researchers tested sequences designed to turn tau genes off in mice that are genetically engineered to produce abnormally high levels of a mutant form of the human protein. Tau clusters begin to appear in the brains of 6-month-old mice and accumulate with age. The mice develop neurologic problems and die earlier than control mice.

Injections of the tau antisense oligonucleotides into the fluid-filled spaces of the mice brains prevented tau clustering in 6-9-month-old mice and appeared to reverse clustering in older mice. The compound prevented the older mice from losing their ability to build nests. Further experiments on non-human primates suggested that the antisense oligonucleotides tested in mice could reach important areas of larger brains and turn off tau. In comparison with placebo, two spinal tap injections of the compound appeared to reduce tau protein levels in the brains and spinal cords of Cynomologus monkeys. As the researchers saw with the mice, injections of the compound caused almost no side effects.

Currently, researchers are conducting early phase clinical trials on the safety and effectiveness of antisense oligonucleotides designed to treat several neurological disorders, including Huntington’s disease and amyotrophic lateral sclerosis. The U.S. Food and Drug Administration recently approved the use of an antisense oligonucleotide for the treatment of spinal muscular atrophy, a hereditary disorder that weakens the muscles of infants and children.

Citation: DeVos, Sarah L., Rebecca L. Miller, Kathleen M. Schoch, Brandon B. Holmes, Carey S. Kebodeaux, Amy J. Wegener, Guo Chen et al. “Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy.” Science Translational Medicine 9, no. 374 (2017): eaag0481.
DOI: 10.1126/scitranslmed.aag0481
Research funding: National Institutes of Health, Tau Consortium, Cure PSP.
Adapted from press release by National Institute of Neurological Disorders and Stroke.

Concussion and Alzheimer’s disease link

New research has found concussions accelerate Alzheimer’s disease-related brain atrophy and cognitive decline in people who are at genetic risk for the condition. The findings, which appear in the journal Brain, show promise for detecting the influence of concussion on neurodegeneration.

Brain. Ashton University

Moderate-to-severe traumatic brain injury is one of the strongest environmental risk factors for developing neurodegenerative diseases such as late-onset Alzheimer’s disease, although it is unclear whether mild traumatic brain injury or concussion also increases this risk.

Researchers from Boston University School of Medicine (BUSM) studied 160 Iraq and Afghanistan war veterans, some who had suffered one or more concussions and some who had never had a concussion. Using MRI imaging, the thickness of their cerebral cortex was measured in seven regions that are the first to show atrophy in Alzheimer’s disease, as well as seven control regions.

We found that having a concussion was associated with lower cortical thickness in brain regions that are the first to be affected in Alzheimer’s disease,” explained corresponding author Jasmeet Hayes, PhD, assistant professor of psychiatry at BUSM and research psychologist at the National Center for PTSD, VA Boston Healthcare System. “Our results suggest that when combined with genetic factors, concussions may be associated with accelerated cortical thickness and memory decline in Alzheimer’s disease relevant areas.”

Of particular note was that these brain abnormalities were found in a relatively young group, with the average age being 32 years old. “These findings show promise for detecting the influence of concussion on neurodegeneration early in one’s lifetime, thus it is important to document the occurrence and subsequent symptoms of a concussion, even if the person reports only having their “bell rung” and is able to shake it off fairly quickly, given that when combined with factors such as genetics, the concussion may produce negative long-term health consequences,” said Hayes.

The researchers hope that others can build upon these findings to find the precise concussion-related mechanisms that accelerate the onset of neurodegenerative diseases such as Alzheimer’s disease, chronic traumatic encephalopathy, Parkinson’s and others. “Treatments may then one day be developed to target those mechanisms and delay the onset of neurodegenerative pathology,” she added.

Citation: Hayes, Jasmeet P., Mark W. Logue, Naomi Sadeh, Jeffrey M. Spielberg, Mieke Verfaellie, Scott M. Hayes, Andrew Reagan, David H. Salat, Erika J. Wolf, Regina E. McGlinchey, William P. Milberg, Annjanette Stone, Steven A. Schichman and Mark W. Miller. ” Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer’s disease.” Brain 2017 vol: 83 pp: aww344.
DOI: 10.1093/brain/aww344
Research funding: US Department of Veterans Affairs, NIH/National Institute of Mental Health.
Adapted from press release by Boston University School of Medicine.

Research shows musicians have faster reaction to sensory stimuli

According to a new study by Université de Montréal’s School of Speech-Language Pathology and Audiology, part of UdeM’s medical faculty learning to play musical instrument help elderly to react faster and to stay alerted. The study is published in journal Brain and Cognition.  The study shows that musicians have faster reaction times to sensory stimuli than non-musicians have.

Credit: Pexels/pixabay

According to lead researcher Simon Landry, this study has implications for preventing some effects of aging. “The more we know about the impact of music on really basic sensory processes, the more we can apply musical training to individuals who might have slower reaction times,” Landry said.

In his study, co-authored with his thesis advisor, audiology associate professor François Champoux, Landry compared the reaction times of 16 musicians and 19 non-musicians. Research subjects sat in a quiet, well-lit room with one hand on a computer mouse and the index finger of the other on a vibrotactile device, a small box that vibrated intermittently. They were told to click on the mouse when they heard a sound (a burst of white noise) from the speakers in front of them, or when the box vibrated, or when both happened.

Each of the three stimulations – audio, tactile and audio-tactile – was done 180 times. The subjects wore earplugs to mask any buzzing “audio clue” when the box vibrated. “We found significantly faster reaction times with musicians for auditory, tactile and audio-tactile stimulations,” Landry writes in his study.

“These results suggest for the first time that long-term musical training reduces simple non-musical auditory, tactile and multisensory reaction times.” The musicians were recruited from UdeM’s music faculty, started playing between ages 3 and 10, and had at least seven years of training. There were eight pianists, 3 violinists, two percussionists, one double bassist, one harpist and one viola player. All but one (a violinist) also mastered a second instrument or more. The non-musicians were students at the School of Speech-Language Pathology. As with the musicians, roughly half were undergraduates and half graduates.

Landry, whose research interest is in how sound and touch interact, said his study adds to previous ones that looked at how musicians’ brains process sensory illusions. “The idea is to better understand how playing a musical instrument affects the senses in a way that is not related to music,” he said of his study.

Citation: Landry, Simon P., and François Champoux. “Musicians react faster and are better multisensory integrators.” Brain and Cognition 111 (2017): 156-162.
DOI: 10.1016/j.bandc.2016.12.001
Research funding: Canadian Institutes of Health Research, Fonds de recherche Québec – Santé, and Natural Sciences and Engineering Research Council of Canada.
Adapted from press release by the Université de Montréal.

Early detection of Alzheimer’s disease using tau protein biomarker in platelets

Researchers have pioneered the technology that detects pathological oligomeric forms of brain tau protein levels in platelets to diagnose Alzheimer’s disease (AD) and other neurodegenerative disorders.  More importantly, the ratio between this anomalous tau and the normal tau protein can discriminate Alzheimer’s disease patients from normal controls, and are associated with decreased cognitive impairment. This discovery is published in Journal of Alzheimer’s Disease (JAD). The research findings stems from a fruitful collaboration between the neuroscience laboratory from the International Center for Biomedicine (ICC) under the leadership of Dr. Ricardo Maccioni and the research teams of Drs. Andrea Slachevsky, Faculty of Medicine, University of Chile, together with Drs. Oscar Lopez and James Becker from University of Pittsburgh, School of Medicine, USA.

Credit: IOS press.

These studies open a new avenue in the development of highly sensitive and efficient biomarkers for neurodegenerative disorders. The fact that pathological forms of tau proteins in platelets correlated with decreased brain volume in areas known to be associated with Alzheimer’s disease pathology in the brain is one step forward for the use of peripheral biomarkers, not only for clinical purposes, but also for research studies oriented to understand the complexity of Alzheimer’s disease pathology.

This article, highlighted by Journal of Alzheimer’s Disease, proved that the relationship between the pathological and normal variants of tau were associated with the reduction of cerebral volume in key structures linked with the disease. These structures included the left medial and right anterior cingulate gyri, right cerebellum, right thalamus (pulvinar), left frontal cortex, and right parahippocampal region, in agreement with MRI neuroimaging approaches.

In addition to the enormous utility of this non-invasive technology for the detection and progression of Alzheimer’s disease, the use of a tau biomarker could lead to the identification of Alzheimer’s disease pathology before the clinical symptoms are evident, and it could play an essential role in the development of preventive therapies. Moreover, the determination of peripheral tau markers in platelets can contribute to the understanding of the pathophysiology of multiple neurodegenerative processes where tau proteins play a critical role.

Citation: Slachevsky, Andrea, Leonardo Guzmán-Martínez, Carolina Delgado, Pablo Reyes, Gonzalo A. Farías, Carlos Muñoz-Neira, Eduardo Bravo et al. “Tau Platelets Correlate with Regional Brain Atrophy in Patients with Alzheimer’s Disease.” Journal of Alzheimer’s Disease vol. 55, no. 4, pp. 1595-1603, 2017.
DOI: 10.3233/JAD-160652
Adapted from press release by IOS press.