Category Archives: Research News (General)

Doctors who work with individuals at risk of developing dementia have long suspected that patients who do not realize they experience memory problems are at greater risk of seeing their condition worsen in a short time frame, a suspicion that now has been confirmed in a new study.

Some brain conditions can interfere with a patient’s ability to understand they have a medical problem, a neurological disorder known as anosognosia often associated with Alzheimer’s disease. A study published in Neurology shows that individuals who experience this lack of awareness present a nearly threefold increase in likelihood of developing dementia within two years.

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. When a patient reported having no cognitive problems but the family member reported significant difficulties, he was considered to have poor awareness of illness.

Researchers then compared the poor awareness group to the ones showing no awareness problems and found that those suffering from anosognosia had impaired brain metabolic function and higher rates of amyloid deposition, a protein known to accumulate in the brains of Alzheimer’s disease patients.

A follow up two years later showed that patients who were unaware of their memory problems were more likely to have developed dementia, even when taking into account other factors like genetic risk, age, gender and education. The increased progression to dementia was mirrored by increased brain metabolic dysfunction in regions vulnerable to Alzheimer’s disease.

Article: “Anosognosia predicts default mode network hypometabolism and clinical progression to dementia”
Reprinted from materials provided by McGill University.

Amyloid beta pathology might have been transmitted by contaminated neurosurgical instruments, a new study published in Acta Neuropathologica suggests.

Researchers studied the medical records of four people who had brain bleeds caused by amyloid beta build-up in the blood vessels of the brain. They found that all four people had undergone neurosurgery two or three decades earlier as children or teenagers, raising the possibility that amyloid beta deposition may be transmissible through neurosurgical instruments in a similar way to prion proteins which are implicated in prion dementias such as Creutzfeldt-Jakob disease.

Amyloid beta is best known for being one of the hallmark proteins of Alzheimer’s disease, but the researchers did not find evidence of Alzheimer’s in this study.

A separate review of the medical literature supported the discovery by identifying four other case studies with similar pathology and past surgical history. As these patients were all men with a history of head trauma, research teams had previously speculated that those were correlated.

The new study suggests otherwise, as all patients had a history of childhood neurosurgery, three were women and only one had a history of head trauma.

In a comparison group of 50 people of similar ages from the same archives, the researchers did not find any amyloid beta pathology and only three had a recorded history of childhood neurosurgery.

Previous work in laboratory animals has shown that tiny amounts of abnormal amyloid beta protein can stick to steel wires and transmit pathology into the animals’ brains, but this paper is the first to suggest the same may be possible in humans.

Paper: “Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery”
Reprinted from materials provided by UCL.

Researchers have 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. This is the first time it’s been shown that calcium influences the way alpha-synuclein behaves.

The study, published in Nature Communications, 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.

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. Thanks to super-resolution microscopy techniques, it is now possible to look inside cells to observe the behaviour of alpha-synuclein. To do so, the researchers isolated synaptic vesicles, part of the nerve cells that store the neurotransmitters that 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.

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, the researchers said.

Article: “C-terminal calcium binding of α-synuclein modulates synaptic vesicle interaction”
Reprinted from materials provided by Cambridge University.

For couples with decades of shared memories, a partner’s decline in the ability to communicate is one of the most frightening and frustrating consequences of Alzheimer’s disease and related dementias. Impaired communication leads to misunderstandings, conflict, and isolation.

A new study published in the International Journal of Geriatric Psychiatry demonstrates how creative ways of working with these couples change their communication behaviors in just 10 weeks.

CARE (Caring About Relationships and Emotions) was designed to increase facilitative communication in the caregiver and sociable communication in the care receiver. The relationship-focused intervention also was designed to reduce disabling behavior (such as criticizing or quizzing their partner’s memory) in caregivers and unsociable behavior (such as not making eye contact) in care receivers.

A key finding from the study showed that care receivers actually improved more than the caregivers following the intervention. Care receivers, who had moderate dementia, demonstrated statistically significant improvements in their social communication both verbally and non-verbally. They were more interested and engaged, maintained eye contact, responded to questions, stayed on topic, and even joked with and teased their partners.

Caregivers’ communication also showed a statistically significant improvement in their facilitative communication and a statistically significant decrease in their disabling communication.

Paper: “Preliminary study of a communication intervention for family caregivers and spouses with dementia”
Reprinted from materials provided by Florida Atlantic University.

The selective demise of motor neurons is the hallmark of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. Yet neurologists have suspected there are other types of brain cells involved in the progression of this disorder and perhaps also protection from it.

To get to the bottom of this question, researchers engineered mice in which the damage caused by a mutant human TDP-43 protein could be reversed by one type of brain immune cell. TDP-43 is a protein that misfolds and accumulates in the motor areas of the brains of ALS patients.

The study, published in Nature Neuroscience, found that microglia, the first and primary immune response cells in the brain and spinal cord, are essential for dealing with TDP-43-associated neuron death. It is the first study to demonstrate how healthy microglia respond to pathological TDP-43 in a living animal.

The number of microglia cells remained stable in mice with ALS symptoms. However, after the researchers chemically suppressed expression of pathological human TDP-43 in the mice, microglia dramatically proliferated and changed their shape and what genes they expressed.

The normally branched microglia retracted their extensions and expanded the size of their main cell bodies. The now abundant, remade microglia multiplied by 70 percent after one week and selectively cleared accumulated human TDP-43 from motor neurons. Microglia surrounded TDP-43-filled neurons and turned on genes to make proteins that helped them attach to the sick cells and induce a process called phagocytosis that envelops the mutant proteins for disposal. After the mop up, mice stopped exhibiting motor dysfunction symptoms such as leg clasping and tremors, and they regained their ability to walk and gain weight.

Paper: “Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy”
Reprinted from materials provided by the University of Pennsylvania.

Alcohol use disorders are the most important preventable risk factors for the onset of all types of dementia, especially early-onset dementia, according to a nationwide observational study of over one million adults diagnosed with dementia in France.

The study, published in The Lancet Public Health, looked specifically at the effect of alcohol use disorders, and included people who had been diagnosed with mental and behavioural disorders or chronic diseases that were attributable to chronic harmful use of alcohol.

Of the 57,000 cases of early-onset dementia (before the age of 65), the majority (57%) were related to chronic heavy drinking.

The World Health Organization (WHO) defines chronic heavy drinking as consuming more than 60 grams pure alcohol on average per day for men (4-5 standard drinks) and 40 grams (about 3 standard drinks) per day for women.

As a result of the strong association found in this study, the authors suggest that screening, brief interventions for heavy drinking, and treatment for alcohol use disorders should be implemented to reduce the alcohol-attributable burden of dementia.

The authors noted that only the most severe cases of alcohol use disorder – ones involving hospitalization – were included in the study.  This could mean that, because of ongoing stigma regarding the reporting of alcohol-use disorders, the association between chronic heavy drinking and dementia may be even stronger.

Paper: “Contribution of alcohol use disorders to the burden of dementia in France 2008–13: a nationwide retrospective cohort study”
Reprinted from materials provided by The Centre for Addiction and Mental Health (CAMH).

Researchers have found that disconnections of brain areas involved in attention and visual processing may contribute to visual hallucinations in individuals with Parkinson’s disease, according to a new study published online in the journal Radiology. The disconnected brain areas seen on functional MRI (fMRI) may be valuable in predicting the development of visual hallucinations in patients with Parkinson’s disease.

Studies using fMRI to investigate visual hallucinations in patients with Parkinson’s disease are rare and have been mainly limited to task-based methods using activities that involve visual stimulation or cognitive tasks. However, the authors note that the presence of visual hallucinations is strongly linked to the development of cognitive decline in patients with Parkinson’s disease. Cognitive deficits may influence a patient’s ability to perform specific tasks during an fMRI exam.

For this study, researchers used resting-state fMRI to examine the connectivity, or communication, between brain areas. The connectivity was measured in 15 patients with visual hallucinations, 40 patients without visual hallucinations, and 15 healthy controls by calculating the level of synchronization between activation patterns of different brain areas.

The results showed that in all the patients with Parkinson’s disease, multiple brain areas communicated less with the rest of the brain as compared to the control group. However, in patients suffering from visual hallucinations, several additional brain areas showed this decreased connectivity with the rest of the brain, especially those important in maintaining attention and processing of visual information.

While there are no direct therapeutic implications for patient care based on the research, the authors note that future studies could indicate whether techniques that could stimulate the areas with decreased connectivity could be helpful to treat visual hallucinations in people with Parkinson’s disease.

Paper: “Loss of Functional Connectivity in Patients with Parkinson Disease and Visual Hallucinations”

Reprinted from materials provided by the Radiological Society of North America.

Researchers have discovered a new class of molecules in the brain that synchronize cell-to-cell communication and neuroinflammation/immune activity in response to injury or diseases. Elovanoids (ELVs) are bioactive chemical messengers made from omega-3 very long chain polyunsaturated fatty acids (VLC-PUFAs,n-3). They are released on demand when cells are damaged or stressed.

Working in neuronal cell cultures from the cerebral cortex and from the hippocampus and a model of ischemic stroke, the researchers found that elovanoids not only protected neuronal cells and promoted their survival, but helped maintain their integrity and stability. The work is published in Science Advances.

Although the occurrence of very long chain polyunsaturated fatty acids has been well documented, what has not been known is their significance and potential to be converted into biochemical triggers to resolve injury, inflammation and other threats to neuronal communication and cell survival.

The researchers discovered the structure and characteristics of two elovanoids – ELV-N32 and ELV-N34 – in the brain. Starting with neuron cell cultures and then an experimental model of stroke, they found that elovanoids were activated when cells underwent either oxygen/glucose deprivation or excitotoxicity – early events associated with stroke, epilepsy, Parkinson’s, traumatic brain injury and other neurodegenerative diseases. They determined the concentrations and therapeutic windows at which elovanoids conferred neuroprotection. The team found that elovanoids overcame the damaging effects and toxicity of these early events. In the stroke model, elovanoids reduced the size of the damaged brain area, initiated repair mechanisms and improved neurological/behavioral recovery.

Paper: “Elovanoids are a novel class of homeostatic lipid mediators that protect neural cell integrity upon injury”
Reprinted from materials provided by the Louisiana State University Health Sciences Center.

The first symptom of Parkinson’s disease is often an impaired sense of smell. This neurodegenerative disease primarily causes irreparable damage to nerve cells in a brain area involved in movement control. Until now, how it affects the olfactory system has been unclear. Researchers have now carried out a study comparing the olfactory bulbs of individuals with and without Parkinson’s disease. The researchers found that the total volume occupied by the functional units in the olfactory bulb — the so-called glomeruli — is in Parkinson’s cases only half of that in normal individuals. Moreover, the distribution of the glomeruli within the olfactory bulb is altered in Parkinson’s cases.

Nine out of ten patients with Parkinson’s disease suffer from defects of the sense of smell in the early stages of the disease — often years before the appearance of the motor symptoms that are characteristic of the disease. The motor symptoms are caused by a loss of nerve cells in the region of the substantia nigra in the brain that is responsible for controlling movement. What causes this cell death has not yet been fully clarified, but a key role appears to be played by Lewy bodies. These are inclusions, inside the cells, that contain a misfolded, defective version of the alpha-synuclein protein. Lewy bodies are found in the olfactory bulb before they appear in the substantia nigra.

The so-called olfactory vector hypothesis for Parkinson’s disease proposes that environmental factors, such as viruses, heavy metals or pesticides, are risk factors or even causes of the condition. No other sensory system than the olfactory system is in such close contact with the external environment — the inhaled air. The hypothesis posits that the disease-causing agent is introduced from the nasal cavity into the olfactory bulb, where Parkinson’s disease is triggered and gradually spreads through other parts of the brain.

The human olfactory bulb remains poorly studied. Research on this brain structure depends critically on the availability of pristine samples, which are typically procured post mortem, from brain donors. The precarious location of the olfactory bulb below the bulk of the brain and the many axons that connect it to the olfactory mucosa mean that special efforts must be made to protect the morphology of the olfactory bulb when collecting the samples.

The researchers were able to collect olfactory bulbs fit for an in-depth quantitative study. In a globe-spanning project, the researchers processed the post mortem olfactory bulbs chemically, cut ten-micrometer thin sections throughout its entire length, and stained the sections with fluorescently labeled antibodies. The labeled sections were then scanned, and the images reconstructed in 3D allowing for quantitative whole-olfactory bulb analyses.

As glomeruli of the human olfactory bulb are difficult to count unambiguously, the researchers came up with a new, quantitative parameter: the global glomerular voxel volume. Having defined this new parameter, the researchers compared the values between olfactory bulbs from normal and Parkinson’s disease cases, and found that it was reduced by more than half. Whether the decrease is the result of Parkinson’s disease cases having fewer or smaller glomeruli, or is due to a combination of these two effects, remains to be seen.

In addition, the distribution of the glomeruli was altered. The olfactory bulbs of normal cases had 70 percent of their glomerular component in the bottom half of the olfactory bulb, but the olfactory bulbs of Parkinson’s disease cases contained only 44 percent in the bottom half. The scientists also discovered that the greater the number of Lewy bodies with aggregated alpha synuclein, the smaller the glomerular component of the olfactory bulb.

The question now is which type of neurons in the olfactory bulb is affected first or foremost in Parkinson’s disease. Next, the researchers would like to identify the neurons in the olfactory bulb that are the most vulnerable.

Paper: “A ventral glomerular deficit in Parkinson’s disease revealed by whole olfactory bulb reconstruction”
Reprinted from materials provided by Max-Planck-Gesellschaft.

New research has proven the existence of an important interaction between the molecules involved in the two types of pathologies.

Parkinson’s disease and prion diseases are very different from each other in regards to both origins and course. A group of researchers has discovered an unexpected and important link between the two pathologies.

According to the study recently published Scientific Reports, the link is a result the complex interaction between two different proteins present in our nerve cells: α-synuclein, in its aggregated form, and the prion protein PrPC, the molecule which is responsible for Creuzfeldt Jacob disease.

The presence of α-synuclein deposits in brain cells is typical of diseases technically called synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy. However, the modalities according to which these aggregates form and spread were unknown. The study reports α-synuclein actually makes use of the action of the prion protein to spread and deposit in the brain. This seems to favour the formation of these deposits and their spreading among brain cells.

But that’s not all. While the activity of the prion protein seems to support the development of synucleopathies, α-synuclein deposits seem to slacken the course of prion diseases. The research has proven that α-synuclein fibrils block the deposit of prions in nerve cells, thus preventing their replication. This surprising effect is corroborated by further evidence already found in the pathology: the course of the disease progression is slower in patients affected by prion diseases presenting α-synuclein deposits in nerve cells.

Paper: “α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication”

Reprinted from materials provided by SISSA.