Abstract
Protein changes identified in early-onset Alzheimer's
Discovery may lead to better understanding of the disease, possible therapies
With a lack of effective treatments for Alzheimer's, most of us would think long and hard about whether we wanted to know years in advance if we were genetically predisposed to develop the disease. For researchers, however, such knowledge is a window into Alzheimer's disease's evolution.
Understanding the biological changes that occur during the clinically “silent” stage — the years before symptoms appear — provides clues about the causes of the disease and may offer potential targets for drugs that will stop it from progressing.
In a new study, researchers at UCLA have identified chemical changes taking place in the brains of people destined to develop familial Alzheimer's disease at least 10 years before symptoms or diagnoses occur. Reporting in the current online edition of the journal Archives of Neurology, John Ringman, a UCLA associate professor of neurology, and colleagues identified changes in 56 proteins, including increases in the amyloid protein long associated with Alzheimer's, inflammatory markers and other proteins related to the brain's synapses, the connections between neurons through which these brain cells communicate with each other.
Familial Alzheimer's and sporadic, late-onset Alzheimer's are distinct forms of what many consider a single disease. The majority of Alzheimer's cases are sporadic and late-onset, developing after age 65; the causes of this disease type are not completely understood but are at least partly genetic. Familial Alzheimer's (FAD), a rare form of the disease caused by certain gene mutations, affects less than 2 percent of patients. It is typically early-onset, developing before age 65, and it is inherited — all offspring in the same generation have a 50 ∼ chance of developing FAD if one of their parents had it.
For this study, researchers developed protein profiles drawn from the cerebrospinal fluid of 14 FAD mutation carriers and compared them with five related non-carriers. In all, they identified 56 proteins that showed significant differences between carriers and non-carriers. Fourteen of these proteins had been reported in prior studies on late-onset Alzheimer's (including APP, transferrin and other inflammatory markers), but many others were unique to this study, including calsyntenin 3, AMPA 4 glutamate receptor and osteopontin. Normally, these proteins are thought to play a role in the growth and remodeling of synapses, and their alteration in pre-symptomatic Alzheimer's may represent an early manifestation of the loss of these critical structures.
“Unfortunately, we do not yet have effective medications to stop the progression of Alzheimer's,” said Ringman, who works at UCLA's Mary S. Easton Center for Alzheimer's Disease Research. “In this study, we've identified chemical changes occurring in the brains of persons destined to develop Alzheimer's disease 10 years or more prior to the expression of symptoms. By studying the cerebrospinal fluid of persons developing Alzheimer's disease at a relatively young age with cutting-edge protein chemical techniques, we found changes in markers reflecting inflammation as well as the breakdown of synapses.
“This provides potential new targets for drug interventions, and it helps elucidate the degree to which FAD and late-onset Alzheimer's are similar and to what degree they are distinct. Such knowledge may ultimately allow us to tailor our treatments to individuals, depending on the ‘type' of Alzheimer's they have.”
The study, funded in part by the pharmaceutical company Pfizer Inc., a grant from the state of California and other sources, was performed at UCLA's Easton Center, one of 10 centers currently receiving funding from the state. State funding helps these centers provide specialized care for patients with Alzheimer's disease and other forms of dementia and their families, and it enables the centers to provide training for those engaged in the diagnosis and care of patients with dementia in California. (Source: EurekAlert! A service of AAAS and the University of California – Los Angeles).
A decade of research proves PET effectively detects dementia
Reston, Va. (December 28, 2011) – In a new review of imaging studies spanning more than ten years, scientists find that a method of positron emission tomography (PET) safely and accurately detects dementia, including the most common and devastating form among the elderly, Alzheimer's disease. This research is featured in the January issue of the Journal of Nuclear Medicine.
Researchers reviewed numerous PET studies to evaluate a molecular imaging technique that combines PET, which provides functional images of biological processes, with an injected biomarker called 18F-FDG to pinpoint key areas of metabolic decline in the brain indicating dementia. Having physiological evidence of neurodegenerative disease by imaging patients with PET could give clinicians the information they need to make more accurate diagnoses earlier than ever before.
“The new data support the role of 18F-FDG PET as an effective addition to other diagnostic methods used to assess patients with symptoms of dementia,” says Nicolaas Bohnen, MD, PhD, lead author of the study and professor of radiology and neurology at the University of Michigan, Ann Arbor, Mich. “The review also identified new literature showing the benefit of this imaging technique for not only helping to diagnose dementia but also for improving physician confidence when diagnosing a patient with dementia. This process can be difficult for physicians, especially when evaluating younger patients or those who have subtle signs of disease.”
Dementia is not a specific illness but a pattern of symptoms characterized by a loss of cognitive ability. These disorders can be caused by injury or progressive disease affecting areas of the brain that control attention, memory, language and mobility. While Alzheimer's is most commonly associated with progressive memory impairment, dementia with Lewy bodies, another form of the disease, can be associated with symptoms of Parkinson's and prominent hallucinations, while another disorder, called frontotemporal dementia, can be seen in patients showing uncharacteristic personality changes and difficulties in relating and communicating. Physicians can use FDG-PET with high accuracy to not only help diagnose dementia but also differentiate between the individual disorders. The role molecular imaging plays in the diagnosis of dementia has expanded enough that the official criteria physicians use to diagnose patients now includes evidence from molecular imaging studies.
“For the first time, imaging biomarkers of Alzheimer's disease are included in the newly revised clinical diagnostic criteria for the disease,” says Bohnen. “This is a major shift in disease definition, as previously an Alzheimer's diagnosis was based mainly on a process of evaluating patients to exclude possible trauma, hemorrhage, tumor or metabolic disorder. Now it is becoming a process of inclusion based on biomarker evidence from molecular imaging.”
The PET biomarker 18F-FDG comprises a radionuclide combined with fluorodeoxyglucose (FDG), which mimics glucose in the body. Cells metabolize FDG as fuel, and the variation in this uptake by cells throughout the body can then be imaged to detect a range of abnormalities. In the case of dementia, marked reductions in the metabolism of different lobes of the cerebral cortex can confirm a patient's disorder. Physicians can tell Alzheimer's disease apart from other dementias, depending on the specific cortices affected.
This review presents the most up-to-date and salient evidence of FDG-PET's usefulness for the evaluation of patients with suspected dementia. The objective of the study was to replace prior retrospective reviews that were performed as the technique was just emerging and that suggested methodological improvements. The new review includes studies with better methodology, including confirmation of diagnoses with autopsy, more expansive recruitment of subjects and use of multi-center studies. After reviewing 11 studies that occurred since the year 2000 and that met more stringent study review standards, researchers conclude that 18F-FDG is highly effective for detecting the presence and type of dementia.
“Using 18F-FDG PET in the evaluation of patients with dementia can improve diagnostic accuracy and lead to earlier treatment and better patient care,” says Bohnen. “The earlier we make a diagnosis, the more we can alleviate uncertainty and suffering for patients and their families.”
The biomarker 18F-FDG is among a variety of imaging agents being investigated for its efficacy in Alzheimer's imaging. As treatments for dementia become available for clinical use, PET will no doubt play an important role in not only the diagnosis of these diseases, but also the assessment and monitoring of future therapies.
According to the World Health Organization, an estimated 18 million people worldwide are currently living with Alzheimer disease. That number is projected to almost double by 2025. (Source: EurekAlert! A service of AAAS and the Society of Nuclear Medicine).
‘Exergames' may provide cognitive benefit for older adults
San Diego, CA, January 17, 2012 – Virtual reality-enhanced exercise, or “exergames,” combining physical exercise with computer-simulated environments and interactive videogame features, can yield a greater cognitive benefit for older adults than traditional exercise alone, according to a new study published in the February issue of the American Journal of Preventive Medicine.
“We found that for older adults, virtual-reality enhanced interactive exercise, or ‘cybercycling' two to three times per week for 3 months, yielded greater cognitive benefit, and perhaps added protection against mild cognitive impairment (MCI), than a similar dose of traditional exercise,” explains lead investigator Cay Anderson-Hanley, PhD, from the Healthy Aging and Neuropsychology Lab and Department of Psychology at Union College, Schenectady, NY.
Research shows that exercise may prevent or delay dementia and improve cognitive functioning in normal aging. However, only 14% of adults aged 65-74 years old, and only 7% of those over 75 report regular exercise. Exergames have the potential to increase exercise by shifting attention from aversive aspects toward motivating features such as competition and three-dimensional scenery, leading to greater frequency and intensity, and enhanced health outcomes.
The Cybercycle Study enrolled 101 volunteers, ranging in age from 58 to 99 years, from independent living facilities with indoor access to an exercise bike. 79 participants completed initial evaluations and training, and rode identical recumbent stationary bikes, except the experimental bike was equipped with a virtual reality display. Cybercycle participants experienced 3D tours and raced against a “ghost rider,” an avatar based on their last best ride. 63 adults completed the study, averaging three rides per week. Cognitive assessment to evaluate executive functions such as planning, working memory, attention, and problem solving was conducted at enrollment, 1 month later (pre-intervention) and 3 months after (post-intervention). Blood plasma was tested to measure whether a change in brain-derived neurotrophic growth factor (BDNF) indicated possible neuroplasticity, a mechanism of change that could link exercise to cognition.
The cybercycle riders had significantly better executive function than those who rode a traditional stationary bike, and cybercyclists experienced a 23% reduction in progression to MCI compared to traditional exercisers. Co-principal investigator on the project, Paul Arciero, PhD, professor of health and exercise sciences at Skidmore College, comments, “No difference in exercise frequency, intensity, or duration was found between the two groups, indicating that factors other than effort and fitness were responsible for the cognitive benefit.”
“Navigating a 3D landscape, anticipating turns, and competing with others require additional focus, expanded divided attention, and enhanced decision making. These activities depend in part on executive function, which was significantly affected,” notes Dr. Anderson-Hanley.
The study also found a significantly greater increase of BDNF in cybercyclists than in traditional riders, suggesting that interactive/combined mental and physical exercise may lead to cognitive benefits by way of biomarkers linked to neurotrophic effects.
“Further research will be needed to tease apart the contributions of a variety of factors in the cybercycling condition,” says Dr. Anderson-Hanley. “Consistency across conditions for goal setting and competition suggests virtual reality imagery and interactive decision-making might be potent factors of the cybercycle.” Exit interviews provided anecdotal evidence of the value of these unique features. Participants commented on their enjoyment of visual stimulation and the challenge of outpacing avatars.
“The implication of our study is that older adults who choose exergaming with interactive physical and cognitive exercise over traditional exercise may garner added cognitive benefit, and perhaps prevent decline, all for the same exercise effort,” concludes Dr. Anderson-Hanley. (Source: EurekAlert! A service of AAAS and Elsevier Health Sciences).
Defective cell ‘battery' plays central role in neurodegenerative disease
A devastating neurodegenerative disease that first appears in toddlers just as they are beginning to walk has been traced to defects in mitochondria, the ‘batteries' or energy-producing power plants of cells. This finding by a team of researchers, led by investigators from the Montreal Neurological Institute and Hospital – The Neuro- at McGill University, was published in this week's issue of the Proceedings of the National Academy of Sciences of the USA (PNAS). The research, which was highlighted as “Novel & Newsworthy” by the American Society for Cell Biology (ASCB), significantly increases understanding of the disease and reveals an important common link with other neurodegenerative diseases, providing renewed hope and potential new therapeutic strategies for those affected around the world.
The disorder, Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), primarily affects the cerebellum, a centre for movement coordination in the brain. ARSACS was first identified in the late 1970s in a large group of patients from the Charlevoix and Saguenay regions of Quebec. The incidence of ARSACS in this ‘founder' population is 1 in 1,500-2,000 births, with a high carrier rate of 1 in 23. ARSACS strikes at an early age. Symptoms, which worsen over time, include poor motor coordination, spastic stiffness, muscle wasting, uncoordinated eye movements and slurred speech. Most patients with the disease are wheelchair-bound by their early 40s and have a reduced life expectancy. ARSACS is not unique to French-Canada as scientists have now found over 100 separate mutations in people worldwide including Japan, Turkey and across Western Europe.
“This finding is the first important advancement in the 10 years since the identification of the mutated gene because it gives an indication of the underlying cellular mechanism of the disease,” says Dr. Bernard Brais, neurologist at The Neuro, “and is a vital first step towards developing therapeutic strategies for ARSACS.” In 2000, scientists identified the gene associated with the disease, called SACS, which produces a massive 4,579 amino acid protein called sacsin, but until now the role or the function of the sacsin protein has been unknown. The multi-institutional collaborative research led by Dr. Brais and Dr. Peter McPherson at The Neuro as well as Dr. Paul Chapple at Queen Mary, University of London indicates that that the sacsin protein has a mitochondrial function, and that mutations causing ARSACS are linked to a dysfunction of mitochondria in neurons.
“By studying neurons in culture as well as in knockout mice (which do not produce sacsin), the team found that loss of the sacsin protein results in abnormally shaped and poorly functioning mitochondria,” says Dr. Peter McPherson, researcher at The Neuro. This disruption led to defective changes in the neurons and eventual death of the neurons. In the knockout mice, these disruptions led to neuron death specifically in the cerebellum, suggesting that this is the basis for the neurodegenerative impairments suffered by ARSACS patients.
“Mitochondrial dysfunction has also been identified in major neurodegenerative diseases such as Parkinson, Alzheimer, and Huntington diseases,” says Dr. McPherson. “This common link means that research being done on a large-scale on these other diseases may prove critically informative to rarer neurological diseases such as ARSACS, and the inverse may be true, our findings may be fundamental to the study and treatment of other neurodegenerative diseases.” (Source: EurekAlert! A service of AAAS and McGill University).
MAKS: Drug-free prevention of dementia decline
There are many different causes of dementia and, although its progression can be fast or slow, it is always degenerative. Symptoms of dementia include confusion, loss of memory, and problems with speech and understanding. It can be upsetting for both the affected person and their relatives and carers. New research published in BioMed Central's open access journal BMC Medicine shows that a regime of behavioral and mental exercises was able to halt the progression of dementia.
Researchers led by Prof. Graessel, from Friedrich-Alexander-Universität Erlangen, included in their study patients with dementia from five nursing homes in Bavaria. After random selection, half the patients were included on the year-long MAKS ‘intervention' consisting of two hours of group therapy, six days a week. In addition all patients maintained their normal treatment and regular activities provided by the nursing home.
The MAKS system consists of motor stimulation(M), including games such as bowling, croquet, and balancing exercises; cognitive stimulation (K), in the form of individual and group puzzles; and practicing ‘daily living' activities (A), including preparing snacks, gardening and crafts. The therapy session began with a ten minute introduction, which the researchers termed a ‘spiritual element' (S), where the participants discussed topics like ‘happiness', or sang a song or hymn.
After 12 months of therapy the MAKS group maintained their level on the Alzheimer's Disease Assessment Scale (ADAS) and, even more importantly maintained their ability to carry out activities of daily living, while the control group all showed a decrease in cognitive and functional ability.
Prof. Graessel explained, “While we observed a better result for patients with mild to moderate dementia, the result of MAKS therapy on ADAS (cognitive function) was at least as good as treatment with cholinesterase inhibitors. Additionally we found that the effect on the patients' ability to perform daily living tasks (as measured by the Erlanger Test of Daily Living (E-ADL)) was twice as high as achieved by medication. This means that MAKS therapy is able to extend the quality of, and participation in, life for people with dementia within a nursing home environment. We are currently in the process of extending these preliminary results to see if this prevention of dementia decline can be maintained over a longer time period.” (Source: EurekAlert! A service of AAAS and BioMed Central).
Brain size may predict risk for early Alzheimer's disease
ST. PAUL, Minn. – New research suggests that, in people who don't currently have memory problems, those with smaller regions of the brain's cortex may be more likely to develop symptoms consistent with very early Alzheimer's disease. The study is published in the December 21, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology.
“The ability to identify people who are not showing memory problems and other symptoms but may be at a higher risk for cognitive decline is a very important step toward developing new ways for doctors to detect Alzheimer's disease,” said Susan Resnick, PhD, with the National Institute on Aging in Baltimore, who wrote an accompanying editorial.
For the study, researchers used brain scans to measure the thickness of regions of the brain's cortex in 159 people free of dementia with an average age of 76. The brain regions were chosen based on prior studies showing that they shrink in patients with Alzheimer's dementia. Of the 159 people, 19 were classified as at high risk for having early Alzheimer's disease due to smaller size of particular regions known to be vulnerable to Alzheimer's in the brain's cortex, 116 were classified as average risk and 24 as low risk. At the beginning of the study and over the next three years, participants were also given tests that measured memory, problem solving and ability to plan and pay attention.
The study found that 21 percent of those at high risk experienced cognitive decline during three years of follow-up after the MRI scan, compared to seven percent of those at average risk and none of those at low risk.
“Further research is needed on how using MRI scans to measure the size of different brain regions in combination with other tests may help identify people at the greatest risk of developing early Alzheimer's as early as possible,” said study author Bradford Dickerson, MD, of Massachusetts General Hospital in Boston and a member of the American Academy of Neurology.
The study also found 60 percent of the group considered most at risk for early Alzheimer's disease had abnormal levels of proteins associated with the disease in cerebrospinal fluid, which is another marker for the disease, compared to 36 percent of those at average risk and 19 percent of those at low risk. (Source: EurekAlert! A service of AAAS and the American Academy of Neurology).
New research reveals how alpha-synuclein interacts with cell membranes in Parkinson's disease
Amsterdam, NL, January 18, 2012 – The accumulation of α-synuclein, a small, negatively charged protein, in neural cells, is one of the hallmarks of Parkinson's disease. It has been suggested that oligomeric α-synuclein causes membranes to become permeable, or to form channels on the outer cell membrane. Now, a group of scientists from Sweden has found a way to reliably replicate α-synuclein aggregation on cell membranes to investigate how different forms of α-synuclein interact with membranes under different conditions and to learn if any of the α-synuclein species can penetrate these membranes. Their results are published in the current issue of the Journal of Parkinson's Disease.
“We found that on-pathway oligomers and α-synuclein fibrils associate with negatively charged model membranes. Furthermore, when investigating seeded α-synuclein aggregation in the presence of giant unilamellar vesicles (GUVs), we find lipid and α-synuclein co-localized in the GUV membrane,” explains lead author Marie Grey, of Lund University and the Wallenberg Neuroscience Center in Lund, Sweden. “Importantly, no transport of α-synuclein was seen, indicating that the ability of α-synuclein to enter cells is more complex than diffusive transport over cell membranes.”
The scientists generated GUVs containing a small amount of a lipid-conjugated red emitting dye (rhodamine B) and varied the membrane charge by using different molecular ratios of phosphatidyl choline (DOPC), a common phospholipid in human cell membranes with a neutral charge, with the negatively charged lipids phosphatidyl serine (DOPS), a major component of the plasma membrane in human cells, or cardiolipin (CL), abundant in mitochondrial membranes. They then used confocal fluorescence microcopy to examine how monomer, fibril, and on-pathway α-synuclein species labeled with a green emitting fluorophore interacted with phospholipid bilayers of the GUV. The study achieved unique, reproducible aggregation without addition of stirring bars, chemicals, and vigorous shaking as had been used in previous studies. These gentler methods make the results more physiologically relevant while still yielding the desired reproducibility.
“On-pathway oligomers are difficult to isolate and enrich due to their dynamic nature. Using our reproducible protocol, we could compare the outcome when adding the different species of α-synuclein to the GUVs,” notes Dr. Grey.
The researchers found that on-pathway and aggregated forms of α-synuclein species bound to lipid membranes, but α-synuclein monomers did not. α-synuclein was particularly strongly associated with GUVs containing the negatively charged anionic lipids CL or DOPS, but did not associate with GUVs containing only the neutrally charged DOPC. α-synuclein progressively accumulated at the surface of the GUVs, typically in distinct areas rather than uniformly covering the membrane. They did not observe transport of α-synuclein over the GUV bilayer.
“Our results indicate that alpha-synuclein does not readily traverse any biological lipid membrane, but that there most likely are required proteins that regulate the transport, possibly with some degree of specificity. This is good news for future attempts to develop treatments that prevent transport of synuclein across membranes, as proteins provide better drug targets than do lipid membrane constituents,” concludes Dr. Grey. (Source: EurekAlert! A service of AAAS and IOS Press).
Test for Alzheimer's disease predicts cognitive decline in Parkinson's disease
Intertwined diseases may both contribute to cognitive decline in Parkinson's
PHILADELPHIA – A method of classifying brain atrophy patterns in Alzheimer's disease patients using MRIs can also detect cognitive decline in Parkinson's disease, according to a new study by researchers from the Perelman School of Medicine at the University of Pennsylvania. Researchers also found that higher baseline Alzheimer's patterns of atrophy predicted long-term cognitive decline in cognitively normal Parkinson's patients. The study is published online in Brain.
“On the basis of a simple neuroimaging study, we can now predict which patients with Parkinson's disease will experience long-term cognitive decline or develop dementia in the future,” said the study's lead author, Daniel Weintraub, MD, associate professor of Geriatric Psychiatry with Penn's Perelman School of Medicine and the Philadelphia Veterans Affairs Medical Center. “Diagnostic tests like this can help us determine which patients would benefit from future clinical trials of medications aiming to stave off or prevent dementia progression in Parkinson's disease.”
This research raises the possibility that both Alzheimer's disease and Parkinson's disease pathology contribute to cognitive decline in Parkinson's disease. Researchers are still uncertain whether the neurodegeneration seen in these patients is caused by primary Parkinson's disease pathology, Alzheimer's pathology, a combination of the two, or is a form of compensation.
As biomarkers for Alzheimer's and Parkinson's disease continue to emerge, the researchers suggest at least an overlap in regions undergoing neurodegeneration with cognitive decline, and point to the Spatial Pattern of Abnormalities for Recognition of Alzheimer's disease (SPARE-AD) classification system to detect brain atrophy in Parkinson's disease, to detect patients at imminent risk of cognitive decline before clinically identifiable symptoms emerge.
Around 80 percent of Parkinson's patients become demented over the course of the illness. Some patients experience cognitive impairment relatively soon after the disease strikes, while others won't experience dementia until the very end of their disease. Duration and severity of the disease and advanced age are risk factors for dementia, while nearly 20 percent of patients never have dementia. Over half of Parkinson's patients with dementia have significant signs of Alzheimer's disease-related plaques and neurofribrillary tangles on autopsy, and similar brain regions, such as the hippocampus and medial temporal lobe, have been reported to be affected in both diseases.
The Penn research team applied a pattern classification individual-based score, the SPARE-AD score, to a cross-sectional cohort of 84 Parkinson's patients including patients with dementia, mild cognitive impairment and no dementia. In the cross-sectional analyses, the SPARE-AD score correlated to cognitive impairment across all groups. From this group, 59 Parkinson's patients without dementia were followed for an additional two years. Researchers determined that a higher baseline SPARE-AD score predicted worsening cognitive performance over time, even in those patients with normal cognition at baseline. (Source: EurekAlert! A service of AAAS and the University of Pennsylvania School of Medicine).