Category: Neurodegenerative Diseases

How Many Intervention Sessions to Prevent Cognitive Decline?

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Physical activity, diet and cognitive stimulation are all known to be good interventions for the prevention of Alzheimer’s disease and dementia. Now an international team of researchers has determined that only about a dozen intervention sessions are all that were needed to observe an improvement in cognition.

Until now, the number of sessions or “doses” needed for optimal effect has been unknown. Published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, the study led by Université de Montréal psychology professor Sylvie Belleville showed that between 12 and 14 sessions were all that were needed to boost cognitive ability, though the gain observed levelled off with more sessions.

“In pharmacological studies, every effort is made to define an optimal treatment dose needed to observe the expected effects, “ said Prof Belleville,  a neuropsychologist and researcher at the research centre of the UdeM-affiliated Institut universitaire de gériatrie de Montréal. “This is rarely done in non-pharmacological studies, especially those on the prevention of cognitive decline, where little information is available to identify this dose.

“Defining an optimal number of treatment sessions is therefore crucial.,” she continued. “Indeed, proposing too few sessions will produce no noticeable improvement effects, but too many sessions is also undesirable as these interventions are costly. They are costly both for the individual who follows the treatments, in terms of time and involvement, and for the organisation offering these treatments.”

The study is based on a secondary analysis of data from the three-year Multidomain Alzheimer Preventive Trial (MAPT) and examined 749 participants who received a range of interventions aimed at preventing cognitive decline. These interventions included dietary advice, physical activity and cognitive stimulation.

In their research, Prof Belleville’s team noted that people’s individuality should be considered when determining the optimal treatment dose.

In their study, the researchers gauged the effects of the sessions in terms of each participant’s age, gender, education level, and cognitive and physical condition. The relationship between the “dose” each received and their cognitive improvement was then analysed.

The findings revealed an increase with dose followed by a plateau effect after 12 to 14 sessions. However, participants with lower levels of education or more risk factors for frailty did benefit from more sessions.

The researchers concluded that it’s important to pinpoint an optimal dose and to customise the treatment for each individual. Not only is “dosage” an important component of behavioural interventions, it can also provide valuable information in resource-constrained settings, helping public-health agencies develop effective prevention programs and offer guidance to older adults and clinicians.

Source: University of Montreal

MS Likely Caused by Epstein-Barr Virus

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Multiple sclerosis (MS) is likely caused by infection with the Epstein-Barr virus (EBV), according to a new Harvard University study.

“The hypothesis that EBV causes MS has been investigated by our group and others for several years, but this is the first study providing compelling evidence of causality,” said senior author Professor Alberto Ascherio. “This is a big step because it suggests that most MS cases could be prevented by stopping EBV infection, and that targeting EBV could lead to the discovery of a cure for MS.” The findings were published in Science.

Currently incurable, MS is a chronic inflammatory disease of the central nervous system that attacks the myelin sheaths protecting neurons in the brain and spinal cord. One of the top suspects for its cause is EBV, a herpes virus that can cause infectious mononucleosis and establishes a latent, lifelong infection of the host. Establishing a causal relationship between the virus and the disease has been hard because EBV infects approximately 95% of adults, MS is relatively rare, and the onset of MS symptoms begins about ten years after EBV infection. To determine the connection between EBV and MS, the researchers conducted a study among over 10 million US military personnel, identifying 955 who were diagnosed with MS during their period of service.

The team analysed serum samples taken twice a year by the military and determined the soldiers’ EBV status at time of first sample and the relationship between EBV infection and MS onset during the period of active duty. In this cohort, the risk of MS increased 32-fold after infection with EBV but remained unchanged after infection with other viruses. Serum levels of neurofilament light chain, a biomarker of the nerve degeneration typical in MS, increased only after EBV infection. The findings cannot be explained by any known risk factor for MS and suggest EBV as the leading cause of MS.

The delay between EBV infection and the onset of MS may be partly a result of the disease’s symptoms being undetected early on and partly the evolving relationship between EBV and the host’s immune system, which is repeatedly stimulated whenever latent virus reactivates.

“Currently there is no way to effectively prevent or treat EBV infection, but an EBV vaccine or targeting the virus with EBV-specific antiviral drugs could ultimately prevent or cure MS,” Prof Ascherio said.

Source: Harvard University

Hydroxychloroquine Effective in Slowing MS

A healthy neuron.
A healthy neuron. Credit: NIH

Promising results for a generic antimalarial drug, hydroxychloroquine, have been seen when used to treat the evolution of disability of primary progressive multiple sclerosis (MS), the least treatable form of the autoimmune disease.

Research teams led by Dr Marcus Koch, MD, PhD, and Dr Wee Yong, PhD, found that hydroxychloroquine helped to slow the progression of disability during the 18-month study involving participants at the MS clinic in Calgary. The research was published in Annals of Neurology.

“With primary progressive MS, there is no good treatment to stop or reverse the progression of disease. The disability progressively worsens through time,” said Dr Koch. “Dr Yong’s research team, with whom we closely collaborate, has been screening a large number of generic drugs over several years and the results with hydroxychloroquine show some promise. Our trial is a preliminary success that needs further research. We hope sharing these results will help inspire that work, specifically larger scale clinical trials into the future.”

The experimental study followed 35 people, at least 40% of whom, or 14 participants, were expected to experience a significant worsening of their walking function, but at the end of the trial only eight participants had worsened.

Hydroxychloroquine is an anti-malaria medication more commonly used to manage the symptoms of rheumatoid arthritis and autoimmune conditions such as lupus. It was selected as it is use in rheumatological diseases is widespread and is generally well-tolerated.

“Based on research in our lab on models of MS, we predicted that hydroxychloroquine would reduce disability in people living with MS. Calgary has a vibrant bench-to-bedside MS program and the work from Dr Koch’s trial offers further evidence which we were pleased to see,” said Prof Yong.

To date, the cause of MS is unknown. This autoimmune disease generally long-lasting, often affecting the brain, spinal cord and the optic nerves in your eyes. It can cause problems with vision, balance and muscle control, although the effects are different for every patient with the disease.

Dr Koch and the research team have been studying the impact of hydroxychloroquine on primary progressive MS for several years and that work continues, including its potential to achieve even greater results as a therapy in combination with select other generic drugs.

Source: EurekAlert!

In Dementia, De-cluttering is of Little Value

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A new study has shown that a clutter-free environment may not help people living with dementia carry out daily tasks.

Researchers studied whether people with dementia were better able to carry out tasks, such as making a cup of tea, at home amidst their normal clutter or in a clutter-free environment. Surprisingly, participants with moderate dementia performed better when surrounded by their usual clutter. But the different environments made no difference to people with mild and severe dementia, who were able to perform at the same level in both settings. The findings were published in Alzheimer Disease & Associated Disorders.

Prof Eneida Mioshi, from the University of East Anglia. said: “As dementia progresses, people gradually lose their ability to carry out daily tasks due to changes in their cognitive, perceptual and physical abilities. Participation in daily tasks could then be improved by adapting the person’s environment.

“To this end, we wanted to investigate the role of clutter in activity participation, given the potential to use de-cluttering to support people with dementia to continue to be independent.

“Environmental clutter has been defined as the presence of an excessive number of objects on a surface or the presence of items that are not required for a task. It is generally assumed that a person with dementia will be better-able to carry out daily tasks when their home space is tidy and clutter free. However there has been very little research to really test this hypothesis.

“We wanted to see whether clutter was negatively affecting people with dementia. So we studied how people at different stages of dementia coped with carrying out daily tasks at home, surrounded by their usual clutter, compared to in a clutter-free setting – a specially designed home research lab.”

Occupational therapist and PhD student Julieta Camino carried out the study with 65 participants. They were grouped into those with mild, moderate and severe dementia, and were asked to carry out daily tasks including making a cup of tea and making a simple meal, both at their own home and at UEA’s specially designed NEAT research bungalow, a fully furnished research facility that feels just like a domestic bungalow. 

The researchers evaluated performance of activities in both settings, and also measured the amount of clutter in the participants’ homes. Meanwhile the NEAT home setting was completely clutter free.

Source: University of East Anglia

Deaths from Parkinson’s on the Rise

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Over the last two decades, the death rate from Parkinson’s disease has risen about 63% in the US, and the death rate was twice as high in men as in women, with a higher death rate in White people than other racial/ethnic groups.

“We know that people are living longer and the general population is getting older, but that doesn’t fully explain the increase we saw in the death rate in people with Parkinson’s,” study author Wei Bao, MD, PhD, who conducted the research at the University of Iowa in Iowa City. “Understanding why more people are dying from this disease is critical if we are going to reverse the trend.”

The study, published in Neurology, looked at a national death registry that included 479 059 people who died of Parkinson’s from 1999–2019.

After adjusting for age, researchers found that the number of people who died from the disease increased from 5.4 per 100,000 people in 1999 to 8.8 per 100 000 people in 2019. The average annual increase was 2.4%.

Mortality increased significantly across all age groups, both sexes, various racial and ethnic groups and different urban-rural classifications. However, death rates were twice as high in men as in women. According to Dr Bao, a possible explanation for this sex difference is that oestrogen, which leads to higher dopamine levels in parts of the brain that control motor responses, may protect women from developing Parkinson’s.

White people were more likely to die from Parkinson’s than other racial and ethnic groups. In 2019, the death rate for White people was 9.7 per 100 000, followed by Hispanic people, at 6.5 per 100 000, and non-Hispanic Black people, at 4.7 per 100 000. In previous studies, compared to White people, Black and Hispanic people are less likely to see an outpatient neurologist, due to socioeconomic barriers, suggesting that White people may have a higher chance of receiving a Parkinson’s diagnosis.

“It’s important to continue to evaluate long-term trends in Parkinson’s death rates,” Dr Bao said. “This can inform future research that may help pinpoint why more people are dying of the disease. Also, updating vital statistics about Parkinson’s death rates may be used for priority setting and financing of health care and policy.”

A limitation of the study is that only one underlying cause of death was recorded on each death certificate, so only people who were recorded as having died of Parkinson’s were included in the study. This may not accurately reflect the prevalence of the disease as a cause of death.

Source: American Academy of Neurology

No Overall Link of Concussions to Cognitive Decline in Older Ex-rugby Players

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Elite ex-rugby players aged 50+ who suffered three or more rugby-related concussions in their career have similar cognitive function to those who had experienced fewer concussions, according to a new study in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

The BRAIN study worked with nearly 150 retired elite male players now aged 50+ who played for either England, Oxford University or Cambridge University in the pre-professional era.

While no worsening of cognitive function was seen in the group overall and in the under 75s, the study did find that over 75s with three or more rugby-related concussions during their career (14/48) had significantly worse cognitive function on average than those who had experienced fewer concussions, and may be at risk of future cognitive problems.

The findings have implications for the clinical management of older ex-rugby players, and possibly ex-players of other contact sports who may be at risk of impaired cognition, the team noted.

Given the age of the 75+ participants, these findings therefore primarily relate to the pre-professional era in rugby. Additional work is needed for younger players, particularly when reaching older ages when more cognitive problems manifest.

This study marks the first to attempt to measure cognitive function in a large number of former players and to link this to their concussion and playing history. Previous studies which have focussed on younger players have found little or no association between concussions and reduced cognitive function.

The study’s last author, Professor Neil Pearce from the London School of Hygiene & Tropical Medicine, said: “Evidence is accumulating on the possible long-term health risks in former contact sport athletes. However, each sport is different and there is currently little evidence from rugby players. This study adds to this knowledge gap, and shows that playing elite rugby may affect cognitive function in older age. It’s important more research is conducted to confirm this, and on those who played in the early years of professional rugby.”

One partial explanation for the reduced cognition in the 75+ groups could be that the former elite rugby players in this study were mostly highly educated, therefore having a higher average cognitive function at the start of their playing careers.

Dr Valentina Gallo, from the University of Groningen in the Netherlands (formerly at Queen Mary University of London), another of the Principal Investigators of the BRAIN study, and study first author, said: “Our findings are in line with those of previous studies, and perhaps highlight that the high cognitive reserve in this study group may have masked the initial phases of any cognitive problems they experience. We’ll be following up on this group of players to shed further light on our findings.”

Participants took part in an extensive set of tests capturing physical and cognitive capabilities. with cognitive function measured using the Pre-clinical Alzheimer Cognitive Composite (PACC) score, which combines tests that assess episodic memory, timed executive function, and global cognition.

After adjusting for possible confounding factors including age, smoking and player playing position, participants over 75 with three or more concussions scored about two points lower on the PACC score. This indicates a difference in cognitive function that can only be detectable with this sort of detailed testing, but which may indicate an increased risk of developing neuro-degenerative conditions.

A total of 116 (80%) respondents reported at least one rugby-related concussion. Among the concussed, the number of rugby-related concussion ranged between one and 25, with a median of two. The number of rugby-related concussions was not associated with the position they played or with length of rugby career.

Dr Simon Kemp, RFU Medical Services Director, said: “This study, that started in 2017, adds to our developing understanding of the potential long term consequences of head impacts and concussions.  The agreed group of participants were aged 50+ principally because of the greater likelihood that we might detect any neurocognitive decline if present.  It is important to also conduct research with younger retired players.

Source: London School of Hygiene & Tropical Medicine

No Dementia Risk with Hormone Replacement Therapy

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A large UK study found that use of menopausal hormone therapy (MHT, also known as hormone replacement therapy, HRT) is not associated with increased dementia risk.

The study, published in the BMJ, found within the subgroup of women with a specific diagnosis for Alzheimer’s disease, a slight increasing risk association was found with use of oestrogen-progestogen treatments, but only seen for long-term usage (5 years or more).

This study “brings clarity to previously inconsistent findings and should reassure women in need of menopausal hormonal therapy,” said the researchers.

MHT relieves menopausal symptoms such as hot flushes, sleep disturbance, mood swings, memory losses and depression. Treatment includes oral tablets with oestrogen only, or oestrogen and progestogen combined, as well as patches, gels and creams.

Early signs of dementia are similar to some menopausal symptoms. Research has shown a beneficial link between oestrogen and age-related brain decline. However, in the largest trial of MHT, the Women’s Health Initiative Memory Study, an increased dementia risk was found among users of oestrogen-progestogen treatments. A recent study picked up a possible link to Alzheimer’s disease among users of both oestrogen-only and oestrogen-progestogen treatments, though the study has some issues.

To address this uncertainty, researchers set out to investigate the risks of developing dementia for women using commonly available menopausal hormone therapy treatments.

They used two UK primary care databases to analyse MHT prescriptions for the 118 501 women aged 55 and older diagnosed with dementia between 1998 and 2020 (cases), and 497 416 matched women without dementia (controls).

After adjusting for confounding factors, no overall associations were found between use of hormone therapy and risk of dementia, regardless of hormone type, application, dose, or duration of treatment. Only a slightly decreased risk of dementia was found in one subgroup: those under 80 years who had been taking oestrogen-only therapy for 10 years or more.
Analysis of cases with a specific diagnosis of Alzheimer’s disease showed a slight increase in risk associated with oestrogen-progestogen therapy. This rose gradually with each year of exposure, reaching an average 11% increased risk for use of between 5 and 9 years and an average 19% for use of 10 years or more, equivalent to, respectively, five and seven extra cases per 10 000 woman years.

As this is an observational study it cannot establish cause, and some limitations include incomplete recording of menopausal symptoms, particularly for women registered after their menopause. However, its large size counts in its favour.
According to the researchers, this study provides the most detailed estimates of risk for individual treatments, and their results are in line with existing concerns in guidelines about long term exposures to combined hormone therapy treatments.

“The findings will be helpful to policy makers, doctors, and patients when making choices about hormone therapy,” they concluded.

The findings do not change the recommendation that menopausal hormone therapy should not be used to prevent dementia, US researchers commented in a linked opinion article. However, it is helpful for providers to put dementia findings in context for patients, they added.

“The primary indication for hormone therapy continues to be the treatment of vasomotor symptoms, and the current study should provide reassurance for women and their providers when treatment is prescribed for that reason,” they concluded.

Source: News-Medical.Net

New Connection Found Between Diabetes and Alzheimer’s

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Researchers have added to the body of evidence linking Type 2 diabetes to Alzheimer’s disease.

In a study published in Communications Biology, researchers show that chronic hyperglycaemia impairs working memory performance and also alters key aspects of working memory networks. Insulin insensitivity has been linked to memory deficits, cognitive decline, and many of the characteristic symptoms that have been displayed in Alzheimer’s disease. At the same time, Type 2 diabetes has remained one of the most adjustable risk factors for the development of Alzheimer’s disease.

“Diabetes is a major risk factor for developing Alzheimer’s disease, but it is not clear why,” said James Hyman, study author and associate professor of psychology at UNLV. “We show that a central feature of diabetes, hyperglycaemia, impairs neural activity in ways that are similar to what is observed in preclinical Alzheimer’s disease models. This is the first evidence showing neural activity changes due to hyperglycemia overlap with what is observed in Alzheimer’s systems.”

“As the number of Alzheimer’s disease diagnoses rapidly rises and the incidence of diabetes and pre-diabetes has accelerated, it’s crucial that we understand what connects these two disorders,” said coauthor Jefferson Kinney, chair and professor in UNLV’s Department of Brain Health.

The researchers found that two parts of the brain crucial for memory, the hippocampus and the anterior cingulate cortex, were over-connected, or hyper-synchronised. When it came time to recall the information and complete a task, these two parts of the brain – which are affected early in Alzheimer’s progression – were over-communicating with each other, resulting in errors.

“We know synchrony is important for different parts of the brain to work together. But, we’re finding more and more these days, that the key with neural synchrony is it has to happen at the right time, and it has to happen with control,” Prof Hyman said. “Sometimes, there’s just too much ‘talking’ between certain areas and we think this leads to memory difficulties, among other things.”

Prof Hyman likens the situation to a CEO who hands over a majority of the company’s business operations to their son, who then decides to upend previous communication structures and become the sole gatekeeper of information.

“The only communication the CEO has is with one person, as opposed to talking with all of the other people in the office,” Prof Hyman explained. “It is possible that in Alzheimer’s patients there’s over-connection in certain areas where there should be flexibility. And in the models in our study, we’re seeing evidence of that in real-time at these crucial moments to do the task.”

This discovery not only provides new insights into brain activity in the hyperglycaemia model, it also provides an important new measure which can be used in future research.

“Our next step is to combine the biochemical markers and electrophysiology data to test specific mechanisms responsible and potential treatments,” said Prof Kinney. “This research will now be able to work towards understanding the risk as well as what may be able to be done to help.”

Source: University of Nevada, Las Vegas

New Drug Targets for Memory Loss

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Researchers have identified specific drug targets within memory-encoding neural circuits, opening up possibilities for new treatments of a range of brain disorders.

Memory loss is a main feature of a number of neurological and psychiatric disorders including Alzheimer’s disease and schizophrenia. Presently, there are few, very limited memory loss treatments and the search for safe and effective drug therapies has, until now, borne little fruit.

The research was done in collaboration with colleagues at the international biopharmaceutical company Sosei Heptares. The findings, published in Nature Communications, identify specific receptors for the neurotransmitter acetylcholine that re-route information flowing through memory circuits in the hippocampus. Acetylcholine is released in the brain during learning and is critical for the acquisition of new memories. Until now, the only effective treatment for the symptoms of cognitive or memory impairment seen in diseases such as Alzheimer’s is using drugs that broadly boost acetylcholine. However, this leads to multiple adverse side effects. The discovery of specific receptor targets that have the potential to provide the positive effects whilst avoiding the negative ones is promising.

Lead author Professor Jack Mellor from the University of Bristol’s Center for Synaptic Plasticity, said: “These findings are about the fundamental processes that occur in the brain during the encoding of memory and how they may be regulated by brain state or drugs targeting specific receptor proteins. In the long-term, the discovery of these specific targets opens up avenues and opportunities for the development of new treatments for the symptoms of Alzheimer’s disease and other conditions with prominent cognitive impairments. The academic-industry partnership is important for these discoveries and we hope to continue working together on these projects.”

Dr Miles Congreve, Chief Scientific Officer at Sosei Heptares, added: “These important studies have helped us to design and select new, exquisitely targeted therapeutic agents that mimic the effects of acetylcholine at specific muscarinic receptors, without triggering the unwanted side effects of earlier and less-well targeted treatments. This approach has the exciting potential to improve memory and cognitive function in patients with Alzheimer’s and other neurological diseases.”

“It is fascinating how the brain prioritises different bits of information, working out what is important to encode in memory and what can be discarded. We know there must be mechanisms to pull out the things that are important to us but we know very little about how these processes work. Our future program of work aims to reveal how the brain does this using acetylcholine in tandem with other neurotransmitters such as dopamine, serotonin and noradrenaline,” said Professor Mellor.

Source: University of Bristol

Antioxidant Trial for Parkinson’s Disease Flops

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Raising brain levels of the natural antioxidant urate through ionosine administration failed to slow the progression of Parkinson’s disease (PD), reported researchers at Massachusetts General Hospital (MGH).

Still, the rigor of the clinical study and some of its novel investigative approaches are seen as improving the prospects for future clinical trials to demonstrate the benefits of disease-modifying therapies for people with Parkinson’s disease. The results were published in JAMA.

“The convergence of epidemiological, biological, and clinical data from past research made a compelling argument that elevating urate, the main antioxidant circulating in the blood, could protect against the oxidative damage thought to play a role in Parkinson’s disease,” explained senior author Michael Schwarzschild, MD, PhD, a neurologist at MGH. “While our study did not rule out a protective effect of urate in Parkinson’s, it clearly showed that increasing urate did not slow disease progression based on clinical assessments and serial bran scan biomarkers of neurodegeneration.”

So far, no treatment has been shown to prevent or forestall progression of Parkinson’s disease, which affects the body’s motor system. The Phase III trial, SURE-PD3, enrolled 298 individuals recently diagnosed with early Parkinson’s disease based on MRI scans indicating loss of dopamine-producing brain cells characteristic of PD. In participants who received the metabolite inosine — which raises levels of urate in the brain and blood and has shown neuroprotective properties in preclinical models — there was no significant difference in the rate of disease progression compared to placebo. Additionally, there was an increased rate of kidney stones among those randomised to inosine treatment.

Despite the lack of evidence to support urate elevation, Dr Schwarzschild found the study successful in other ways. “The findings were very helpful in providing a reality check that now allows the field to move on to other therapeutic approaches,” he explained. “We also learned a lot in terms of clinical trials science for Parkinson’s, and ways to conduct future studies that will increase their chance of success.” One of those ways is to tailor treatment to subsets of patients who are most likely to benefit – a hallmark of the move to precision medicine in Parkinson’s research. In SURE-PD3, for example, only patients who had lower levels of urate were enrolled to increase the chance of benefit and reduce the chance of side effects.

Another innovative feature of the trial is that many participants gave blood samples for genotyping – a valuable source of genetic information that could figure in the hunt for clinical solutions in smaller subpopulations of PD patients. A significant number also volunteered for an extension of the study to help determine how monitoring at home could provide more efficient ways to conduct future clinical trials. “There were many positive results from SURE-PD3 which we believe will improve the prospects of researchers discovering a disease-modifying therapy which people with Parkinson’s have been desperately seeking,” Dr Schwarzschild concluded.

Source: Massachusetts General Hospital