Category Archives: Research News (General)

Researchers report that intermittent electrical stimulation of an area deep inside the brain that degenerates in Alzheimer’s appears to improve working memory. Conversely, continuous deep brain stimulation, like the type used for Parkinson’s impairs memory, according to study results in adult non-human primates reported in the journal Current Biology. Intermittent stimulation helped the monkeys to remember things up to five times longer in a standard test of working memory.

In the new studies, scientists used the technique of placing hair-thin electrodes into the brain to deliver electricity and increase the activity of the nucleus basalis of Meynert, a small area in the forebrain that is inexplicably degenerated in both Parkinson’s and Alzheimer’s.

Their goals included making more of the chemical messenger acetylcholine available in the region. The nucleus basalis has a large concentration of neurons that are connected to brain areas critical for memory and cognition, and under healthy conditions have a ready supply of acetylcholine that enables the important communication between them.

As we age, acetylcholine levels in the brain naturally decrease, but Alzheimer’s causes a dramatic multiplier effect, resulting in a shortage.

The researchers started with continuous stimulation, like the clinical approaches, and saw an unexpected decline in performance. Equally surprising, they found intermittent stimulation resulted in more available acetylcholine in the region and better performance.

In fact, use of the cholinesterase inhibitor donepezil restored memory performance in animals that received constant stimulation but had no impact on those whose memory was already enhanced by intermittent stimulation.

The scientists suspect the benefit resulted from the impact of increased levels of acetylcholine directly on neurons and their supportive cells in that region. However it may also result from a slight increase in blood flow to the brain region, they write. Cholinesterase inhibitors, drugs used to treat Alzheimer’s, are known to increase blood flow to the brain about 10-15 percent in humans. Blood flow is typically reduced in Alzheimer’s.

After months of intermittent stimulation, the monkeys got more adept at the memory test even without the stimulation. The reason for the enduring effect is not 100 percent clear: it could be the brain cells make more connections, it could be more acetylcholine keeps getting released, it could be both, the scientists note.

Paper: “Intermittent Stimulation of the Nucleus Basalis of Meynert Improves Working Memory in Adult Monkeys”

Reprinted from materials provided by the Medical College of Georgia at Augusta University.

Scientists have published a proof-of-concept study in the journal Neurobiology of Disease demonstrating that an antidepressant drug which has been on the market for more than 50 years could slow the progression of Parkinson’s.

The drug nortriptyline, which has been used to treat depression and nerve pain, stopped the growth of abnormal proteins that can build up in the brain and lead to the development of the disease.

Researchers began by examining previous patient data to see if individuals who were on antidepressants started a standard Parkinson’s therapy called levodopa later than those not taking the antidepressant. Levodopa increases levels of dopamine, a natural chemical in the body that sends signals to other nerve cells, which is usually significantly decreased in people with Parkinson’s. The medication also alleviates symptoms of the disease such as tremors and poor muscle control.

The researchers observed that people on tricyclic antidepressants did not need levodopa until much later, compared to patients not taking a tricyclic for depression.

Researchers then began testing rats with the tricyclic antidepressant nortriptyline and observed that it decreased the amount of alpha-synuclein, an abnormal protein that can build up in the brain and cause nerve cells to die. Alpha-synuclein buildup is a hallmark of Parkinson’s diease.

Finally, the scientists added nortriptyline to alpha-synuclein proteins in a test tube model and observed that the addition of the antidepressant caused the proteins to move and change shape more rapidly, preventing them from clumping together.

To further back up his research, he enlisted the help of his colleague and co-author Lisa Lapidus, who in previous studies had already detected whether certain compounds could bind to alpha-synuclein and stop it from accumulating.

Understanding how these proteins can clump together could point researchers in new directions and help them find other possible drugs that could potentially treat Parkinson’s. One such new drug that can affect both Parkinsons, depression, and anxiety is CBD, which Daily CBD has a list of working products you can learn more about.

Paper: “Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form”

Reprinted from materials provided by Michigan State University.

The protein amyloid beta is believed to be a major cause of Alzheimer’s disease. BACE inhibitors, which reduce the production of amyloid beta are therefore promising candidates for new drug treatments. A research team has recently demonstrated that one such BACE inhibitor reduces the amount of amyloid beta in the brain, restoring the normal function of nerve cells and improving memory performance. The team’s findings were published in the journal PNAS.

Using a mouse model of Alzheimer’s, the researchers tested a substance that inhibits beta secretase. In mice, as in humans, the disease causes amyloid beta plaques in the brain, which cause memory loss. In the study, mice were examined after having received the inhibitor in their food for up to eight weeks. Researchers observed individual nerve cells in the brain using an imaging technique called two-photon microscopy.

After the course of treatment, the mice had less amyloid beta in their brain, an unsurprising finding as its production was inhibited. However, their brain functions also normalised, with fewer hyperactive nerve cells and slow-wave brain patterns that were similar to those in healthy mice. Researchers also observed that the animals’ memory improved, with the treated mice finding a hidden platform in a water-filled maze as quickly as their healthy counterparts.

The scientists’ findings will soon find its way into clinical practice: a large-scale clinical trial is planned with around 1000 participants to test a slightly modified form of the BACE inhibitor.

Paper:“BACE inhibition-dependent repair of Alzheimer’s pathophysiology”

Reprinted from materials provided by TUM.

While memory and learning as people age have been intensively studied, changes in how people map their surroundings and construct and follow directions are not well understood.  Now a review published in the journal Neuron discusses the possibility that age-related declines in navigational ability could contribute to tools for the early diagnosis of Alzheimer’s disease.

Today, Alzheimer’s disease is diagnosed using factors such as medical history, genetic risk factors and performance on tests that measure memory, language and reasoning impairments. However the research team suggests that navigational impairments are among the earliest signs of the Alzheimer’s progression. According to the scientists, abnormal results on standard cognitive tests may only show up 10 years after the onset of Alzheimer’s. A navigation-based diagnostic test could reduce that window.

Navigational testing is held back by the lack of standard tests for navigational tasks and population norms with which to evaluate results. Now, more-affordable and portable virtual reality technology means it is possible to develop standardised tests. The second challenge is that navigational abilities vary greatly between individuals, meaning an effective diagnostic tool would need to track an individual’s navigational capabilities over the course of their life to identify signs of early or accelerated decline.

With such data and the improved virtual reality setups, the researchers conclude that a navigational test battery analogous to those used for memory and learning will be feasible.

Paper: “The Aging Navigational System”.

Reprinted from materials provided by Cell Press.

A gene called ” triggering receptor expressed on myeloid cells 2”, or TREM2, has been associated with a variety of neurodegenerative diseases, such as Alzheimer’s disease, Frontotemporal lobar degeneration, Parkinson’s disease, and Nasu-Hakola disease. Recently, a rare mutation in the gene has been shown to increase the risk for developing Alzheimer’s disease.

Independently from each other, two research groups have now revealed the molecular mechanism behind this mutation. Their research, published in EMBO Molecular Medicine, sheds light on the role of TREM2 in normal brain function and suggests a new therapeutic target in Alzheimer’s disease treatment.

Alzheimer’s disease, like other neurodegenerative diseases, is characterized by the accumulation of specific protein aggregates in the brain. Specialized brain immune cells called microglia strive to counter this process by engulfing the toxic buildup. But as the brain ages, microglia eventually fail to eliminate all the damaging material.

TREM2 is active on microglia and enables them to carry out their protective function. The protein spans the microglia cell membrane and uses its external region to detect dying cells or lipids associated with toxic protein aggregates. Subsequently, TREM2 is cut in two. The external part is shed from the protein and released, while the remaining part still present in the cell membrane is degraded. To better understand TREM2 function, the two research groups took a closer look at its cleavage.

Using different approaches, both groups first determined the exact site of protein shedding and found it to be at amino acid 157. Amino acid 157 was recently found to be the position of a mutation which increases the risk of Alzheimer’s disease. These observations indicate that protein cleavage is perturbed in the p.H157 mutant and that this alteration promotes disease development.

Next, each group investigated the biochemical properties of the p.H157Y mutant protein more closely. They found that the mutant was cleaved more rapidly than a healthy version of the protein.

While most TREM2 mutations affect protein production, the mechanism behind p.H157Y is somewhat different. The p.H157Y mutation allows the protein to be correctly manufactured and transported to the microglia cell surface, but then it is cleaved too quickly. As a result, there is too little full-length TREM protein on microglia, which suggests that stabilising TREM2 to make it less susceptible to cleavage may be a viable therapeutic strategy.

Papers: “TREM2 shedding by cleavage at the H157‐S158 bond is accelerated for the Alzheimer’s disease‐associated H157Y variant” and “An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function”

Reprinted from materials provided by EMBO.

Scientists are reporting that monkeys with Parkinson’s disease symptoms show significant improvement over two years after being transplanted neurons prepared from human iPS cells. The study, published in Nature, is an expected final step before the first iPS cell-based therapy for neurodegenerative diseases.

Parkinson’s disease damages a specific type of cell in the brain known as dopaminergic (DA) neurons. It is known that by the time symptoms are first detected, a patient will have already lost more than half of his or her DA neurons. Several studies have shown the transplantation of DA neurons made from fetal cells can mitigate the disease. The use of fetal tissues is controversial, however. On the other hand, iPS cells can be made from blood or skin.

To test the safety and effectiveness of DA neurons made from human iPS cells, researchers transplanted the cells into the brains of monkeys.

It is generally assumed that the outcome of a cell therapy will depend on the number of transplanted cells that survive, but the scientists found this was not the case. More important than the number of cells was the quality of the cells.

To understand why, the team looked for genes that showed different expression levels, finding 11 genes that could mark the quality of the progenitors.

Another feature of the study that is expected to extend to clinical study is the method used to evaluate cell survival in the host brains. The study demonstrated that magnetic resonance imaging (MRI) and position electron tomography (PET) are options for evaluating the patient post-surgery.

Paper: “Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model”

Reprinted from materials provided by the Center for iPS Cell Research and Application – Kyoto University.

New research suggests serotonin loss may be a key player in cognitive decline, rather than a side-effect of Alzheimer’s disease.

In a study examining the brain scans of people with mild loss of thought and memory ability, researchers report evidence of lower levels of the serotonin transporter — a natural brain chemical that regulates mood, sleep and appetite. Previous studies have shown that people with Alzheimer’s disease and severe cognitive decline also have severe loss of serotonin neurons, but the studies did not show whether those reductions were a cause or effect of the disease. Results of the new study of people with very early signs of memory decline, the researchers say, suggest that lower serotonin transporters may be drivers of the disease rather than a byproduct.

A report on the study, published in Neurobiology of Disease, also suggest that finding ways to prevent the loss of serotonin or introducing a substitute neurotransmitter could slow or stop the progression of Alzheimer’s disease and perhaps other dementias.

To further study serotonin’s role in cognition and neurodegenerative disease, the research team used brain positron emission tomography (PET) scans to look at levels of serotonin in the brains of people with mild cognitive problems, which may be a precursor of Alzheimer’s disease or other dementias.

The study paired 28 participants with mild cognitive impairment with 28 healthy matched controls. Participants were an average age of 66 and about 45 percent were women. Each participant underwent an MRI and PET scan to measure brain structures and levels of the serotonin transporter SERT.  The researchers found that people with mild cognitive impairment had up to 38 percent less SERT detected in their brains compared to each of their age-matched healthy controls. And not a single person with mild cognitive impairment had higher levels of SERT compared to their healthy control.

Each participant also underwent learning and memory tests. On a scale of 0 to 80, with 80 reflecting the best memory, the healthy participants had an average score of 55.8, whereas those with mild cognitive impairment scored an average of 40.5.

With the Brief Visuospatial Memory Test, participants were shown a series of shapes to remember and draw later. From a scale of 0 to 36, with 36 being the top score, healthy people scored an average of 20.0 and those with mild cognitive problems scored an average of 12.6.

The researchers then compared the results from the brain imaging tests for the serotonin transporter to those two memory tests, and found that the lower serotonin transporters correlated with lower scores. For example, those people with mild cognitive impairment had 37 percent lower verbal memory scores and 18 percent lower levels of SERT in the brain’s hippocampus compared to healthy controls.

Paper: “Molecular imaging of serotonin degeneration in mild cognitive impairment”

Reprinted from materials provided by Johns Hopkins University.

A new kind of antibody targets a feature shared by proteins thought to cause the most damage in Alzheimer’s disease, Parkinson’s disease, and related conditions, creating potential for a unified treatment approach. The findings are part of a study published online in Scientific Reports.

The new study builds on decades of work arguing that the contribution to disease of key proteins — amyloid beta and tau in Alzheimer’s, alpha-synuclein in Parkinson’s, and prion proteins in conditions like mad cow disease — is driven by certain, toxic forms dominated by a common structure: bundles of “beta sheets” in clumped proteins.

In tissues from autopsied patients with these diseases and in live mice, experiments demonstrated how the study’s antibodies target and remove only these toxic forms without triggering the immune toxicity that has stymied treatment development efforts to date.

The study focuses on proteins that form important structures in the brain. The instant they form as chains of amino acids, proteins fold into complex shapes needed to do their jobs. However proteins can also “misfold” and eventually cause disease. Cells and tissues die as misshapen proteins stop working and build up, but the field has struggled to pinpoint which of these shifting forms to target as the key drivers.

The researchers designed their antibodies to target the “oligomers” formed as several misfolded monomers associate and acquire the “beta-sheet” shape, but before they are large enough to fibrilize. These intermediate forms may be uniquely toxic because, unlike fibrils, they can dissolve and move in and out of cells, and from one cell to another. This mobility may explain the “prion-like” progression seen in misfolding diseases where abnormal proteins cause normal ones to misfold in a domino effect that damages nerve cells and their connections in the brain.

Importantly, growing toxic oligomers of amyloid beta, tau, alpha synuclein, and prion protein become increasingly dominated by twisted strands of amino acids, the beta sheet spatial arrangements that let the strands stack up.

To design new kinds of antibodies, the research team zeroed in on a small 13-amino-acid peptide, derived from the extremely rare genetic disease called British amyloidosis, but not present in the rest of the human population. They converted it into large, stable oligomer with more than 90 percent “beta-sheet” structure (the p13Bri immunogen) that could now be “seen” by the mammalian immune system. It also triggered a specific antibody response that solved problems encountered with standard approaches. By immunizing mice with p13Bri at high doses, they forced the production of extremely rare antibodies against beta sheets in toxic oligomers.

The researchers say that their rare antibodies, activated by protein fragments seen only in a rare disease, have almost zero chance of triggering unwanted immune responses to normal proteins with similar sequences (autotoxicity), the downfall of many previous attempts. Finally, the team screened their lead antibodies against tissues taken from the brains of human patients with Alzheimer’s, Parkinson’s and prion diseases. Only the six monoclonal antibodies that reacted to toxic oligomers from at least two misfolded proteins from two diseases were selected for further study.

Paper: “Production of Monoclonal Antibodies to Pathologic β-sheet Oligomeric Conformers in Neurodegenerative Diseases”

Reprinted from materials provided by NYU Langone Health / NYU School of Medicine.

New artificial intelligence research has demonstrated the predictive capability of AI to determine in advance who is likely to develop dementia.

Scientists used artificial intelligence techniques and big data to develop an algorithm capable of recognizing the signatures of dementia two years before its onset, using a single amyloid PET scan of the brain of patients at risk of developing Alzheimer’s disease. Their findings appear in a new study published in the journal Neurobiology of Aging.

Scientists have long known that a protein known as amyloid accumulates in the brain of patients with mild cognitive impairment (MCI), a condition that often leads to dementia. Though the accumulation of amyloid begins decades before the symptoms of dementia occur, this protein couldn’t be used reliably as a predictive biomarker because not all MCI patients develop Alzheimer’s disease.

To conduct their study, the researchers drew on data available through the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a global research effort in which participating patients agree to complete a variety of imaging and clinical assessments.

The researchers used hundreds of amyloid PET scans of MCI patients from the ADNI database to train the team’s algorithm to identify which patients would develop dementia, with an accuracy of 84%, before symptom onset.

While new software has been made available online to scientists and students, physicians won’t be able to use this tool in clinical practice before certification by health authorities.

Paper: “Identifying incipient dementia individuals using machine learning and amyloid imaging”

Reprinted from materials provided by McGill University.

Alzheimer’s disease manifest itself with widely divergent symptoms and, so far, its various expressions have mainly been observed through the behaviour and actions of patients. Researchers have now produced images showing the changes in the brain associated with these symptoms — a development which increases knowledge and could facilitate diagnosis and treatment in the future.

Symptoms vary in cases of Alzheimer’s disease and often relate to the phase of life in which the disease first occurs. People who become ill before the age of 65 often suffer early on from diminished spatial perception and impaired orientation. Elderly patients more often suffer the symptoms traditionally associated with the disease: above all, memory impairment.

Diagnostics could be facilitated, mainly among younger patients in whom it is particularly difficult to arrive at a correct diagnosis.

The findings, published in the journal Brain, are based on studies of around 60 Alzheimer’s patients and a control group consisting of 30 people with no cognitive impairment.

This new imaging method can clearly detect clumps of the tau protein, which forms lumps and destroys the transport route of the neurons once Alzheimer’s disease has taken hold.

The method uses a device known as a PET camera and a trace substance, a particular molecule, which binds to tau. The imaging method is currently only used in research, where the current study is one of several contributing to increased knowledge about the disease.

Paper: “Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer’s disease”

Reprinted from materials provided by Lund University.