Molecular Differences Between Clusters Can Be Linked To Known Disease Mechanisms
We next explored GO terms and KEGG pathways that were enriched in the difference between one cluster to all others. In other words, we looked into differential expression and differential methylation between cluster 1 and all others, cluster 2 and all others, and so on. For each of these comparisons a larger number of biological processes and pathways could be identified in both AD and PD . In agreement to the findings in the last Section, significant differences between clusters in methylation could only be found in PD patients, but not in AD. Transcriptome differences between clusters were observed in both diseases.
In the following, we highlight only selected examples : As explained previously, cluster 1 is strongly associated with the genetic burden on AKT signaling. At the transcriptional level we observed significant downregulation of genes in the cell cycle process in AD patients . Both can be linked together, as shown in Fig. A. AKT signaling influences acetylcholinesterase , which is thought to play a role in apoptotic processes and amyloid-beta formation. Amyloid-beta increases NAE1 via APP and influences the entire cell cycle process.
Figure 6
Studies used for discovery
ADNI
PPMI
Studies used for validation
Integrated AETIONOMY AD
-
clinical characteristics: e.g. post-mortem diagnosis, age at death, gender
-
genome-wide transcriptome and methylome data from post-mortem brain tissue
Integrated AETIONOMY PD
Lewy Bodies: More Than Lbd
LBD is characterized by the presence of Lewy bodies in the nerve cells of the brain, meaning that LBD patients have Lewy bodies in the brain.2 However, Lewy bodies are also common with other conditions, such as Alzheimer’s and Parkinsons disease. In fact, most people with PD also have Lewy bodies in their brain. However, even if they have Lewy bodies, not all Parkinsons patients will also develop LBD.2
Living With Parkinsons Disease
Depending on severity, life can look very different for a person coping with Parkinsons Disease. As a loved one, your top priority will be their comfort, peace of mind and safety. Dr. Shprecher offered some advice, regardless of the diseases progression. Besides movement issues Parkinsons Disease can cause a wide variety of symptoms including drooling, constipation, low blood pressure when standing up, voice problems, depression, anxiety, sleep problems, hallucinations and dementia. Therefore, regular visits with a neurologist experienced with Parkinsons are important to make sure the diagnosis is on target, and the symptoms are monitored and addressed. Because changes in your other medications can affect your Parkinsons symptoms, you should remind each member of your healthcare team to send a copy of your clinic note after every appointment.
Dr. Shprecher also added that maintaining a healthy diet and getting regular exercise can help improve quality of life. Physical and speech therapists are welcome additions to any caregiving team.
Also Check: Is Reading Good For Dementia
Don’t Smoke Lessen Alcohol Intake & Do Not Take Drugs
Even if you don’t drink a lot, alcohol has a cumulative effect on your brain. One blackout after a drinking binge can induce life long memory loss. Over time, smaller amounts of alcohol will lead to blackouts and soon you’ll have a ton of lost time even though you barely drank one bottle of beer.
Smoking negatively affects memory by reducing the amount of oxygen that reaches the brain while repeated drug use kills your neurons and the rushes of dopamine reinforce drug dependence.
Parkinsons Doesnt Always Cause Dementia
While cognitive decline is common in both Alzheimers and Parkinsons, it is less likely to occur in Parkinsons patients. According to studies, only half of those with Parkinsons develop cognitive difficulties. This can range from mild forgetfulness to full-blown dementia.
When dementia does manifest itself with Parkinson, it occurs in the subcortical area of the brain. Alzheimers dementia occurs in the cortical area of the brain. As a result of this, the clinical symptoms of these two dementias can be somewhat different.
Read Also: What Effects Does Alzheimer’s Have On The Brain
Thanks For Signing Up
We are proud to have you as a part of our community. To ensure you receive the latest Parkinsons news, research updates and more, please check your email for a message from us. If you do not see our email, it may be in your spam folder. Just mark as not spam and you should receive our emails as expected.
Lrrk2 Phosphorylates Tau Protein
Parkinsons patients can develop tangles of the tau protein as a result of a mutated enzyme called LRRK2, the researchers say.
From conducting a series of mammalian studies, the researchers discovered that standard LRRK2 adds groups of phosphate to tau protein, while mutated LRRK2 adds significantly more phosphates to tau protein.
Using these findings, the research team were able to uncover two sites on the tau protein T149 and T153 where the mutated LRRK2 was able to add phosphate groups, which they linked to tangle formations.
The researchers then went on to test their findings on human brain tissue. From this, they discovered that the two sites previously identified on the tau protein that were targeted by LRRK2, were altered the same way in human tissue with LRRK2 mutation.
When testing this finding on human brain tissue that was affected by Alzheimers disease, and other neurodegenerative diseases that form tangles, they found these alterations were the same.
Explaining their findings, the researchers say:
Our data, in aggregate, demonstrate that LRRK2 directly phosphorylates tau at T149 and T153 in vitro and the ability of LRRK2 to phosphorylate tau at these sites may underlie its ability to promote tauopathy in our novel mouse model.
Our current in vivo studies are the first of their kind and provide compelling evidence that LRRK2 and tau interact in a disease-relevant manner.
Recommended Reading: Does Alzheimer Disease Run In The Family
Finding Suggests That Treatment For One Disease Could Work For The Other Two
- Date:
- Loyola University Health System
- Summary:
- A study has found that abnormal proteins found in Alzheimer’s, Parkinson’s and Huntington’s diseases share a similar ability to cause damage when they invade brain cells. The finding suggests that an effective treatment for one neurodegenerative disease might work for other neurodegenerative diseases as well.
A Loyola University Chicago study has found that abnormal proteins found in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease all share a similar ability to cause damage when they invade brain cells.
The finding potentially could explain the mechanism by which Alzheimer’s, Parkinson’s, Huntington’s, and other neurodegenerative diseases spread within the brain and disrupt normal brain functions.
The finding also suggests that an effective treatment for one neurodegenerative disease might work for other neurodegenerative diseases as well.
The study by senior author Edward Campbell, PhD, first author William Flavin, PhD, and colleagues is published in the journal Acta Neuropathologica.
“A possible therapy would involve boosting a brain cell’s ability to degrade a clump of proteins and damaged vesicles,” Campbell said. “If we could do this in one disease, it’s a good bet the therapy would be effective in the other two diseases.”
Campbell stressed the study’s findings need to be followed up and confirmed in future studies.
Story Source:
How Is Parkinsons Dementia Different From Alzheimers Disease
The advanced cognitive changes that impact daily living in Alzheimers and Parkinsons disease are both types of dementia.
Parkinsons disease dementia can occur as Parkinsons advances, after several years of motor symptoms. Dementia with Lewy Bodies is diagnosed when cognitive decline happens first, or when Parkinsons motor symptoms and cognitive decline occur and progress closely together. Cognitive impairments in PDD, combined with the movement symptoms of the disease, produce a greater impact on social and occupational functioning than Alzheimers.
Alzheimers, a fatal brain disease, causes declines in memory, thinking and reasoning skills. Physicians can diagnose Alzheimers. Visit the Alzheimers Association to learn the 10 signs Alzheimers disease.
Fortunately for people with PD, Parkinsons disease dementia is less disabling than Alzheimers disease. People with Alzheimers have language difficulties earlier than people with Parkinsons, and no new memories are formed. People with PD also have more ability to compensate and adjust based on cues.
Read Also: How To Treat Agitation In Dementia Patients
Treating Alzheimers Disease Vs Other Types Of Dementia
Neither Alzheimerâs nor most other types of dementia have a cure. Doctors focus treatments on managing symptoms and keeping the disease from getting worse.
Some of the treatments for dementia and Alzheimerâs overlap.
- Cholinesterase inhibitors can help with memory loss in certain types of dementia and Alzheimerâs.
- Glutamate inhibitors help with learning and memory in both dementia and Alzheimerâs.
- Sleep medications may help with sleep changes.
- Antidepressants can help with depression symptoms.
- Antipsychotic medications may help with behavior changes.
Some types of dementia respond to treatment, depending on what is causing it. Your doctor may recommend:
- Stopping the use of drugs and alcohol
- Tumor removal
Symptoms Of Parkinsons Disease
- Apathy
- Feeling, seeing, smelling, hearing and tasting things that arent there
- Hallucinations and delusions
Parkinsons disease is usually expressed through the following five stages:
- Stage one Mild symptoms dont interfere with daily tasks, tremors occur on one side of the body, and posture, gait and facial expression changes may happen.
- Stage two Symptoms worsen, tremors and stiffness affect the entire body and walking and standing are more difficult. At this stage, people may have some trouble performing daily activities.
- Stage three Trouble moving quickly, and balance issues can make it hard to eat or get dresses. Patients may be more likely to fall.
- Stage four Patients may need a walker to move around. Most people are unable to live alone at this stage because they need help with daily activities.
- Stage five It may be impossible to stand or walk. A wheelchair may help with mobility. A caregiver should be present at all times during this stage.
Recommended Reading: When A Loved One Has Dementia
Caring For Someone With Parkinsons
Practice patience and understanding when dealing with Parkinsons. You may be very frustrated and challenged as a caregiver, but those with Parkinsons are just as frustrated. Their physical and mental conditions can be debilitating, depressing, and humiliating.
Diet and nutrition can have a huge impact on the health and comfort of a Parkinson patient. Eating well, getting more rest, sleeping well, fresh air, and exercise can make a difference. Getting the right medication and complementary therapies is also important.
As Parkinsons impacts a patients motor skills, modifications to the living environment may have to be made to accommodate wheelchairs and limited mobility issues. Professional in-home assistance for Parkinsons can allow Parkinson patients to remain independent and can enhance quality of life.
Most importantly, seek help and support from family, friends, and caregiving support groups. Take advantage of the resources in your community. Shouldering all the burden can take a toll on a caregiver.
Take care of yourself or you wont be able to take care of your loved one. Follow the preventive advice provided above for yourself as well, and take deep breaths!
Resources
Number Of People Affected
Parkinsons disease is thought to affect about 2 percent of Americans over 65. Of those, about 50 to 80 percent will go on to develop Parkinsons-related dementia.1 The Parkinsons Foundation estimates that nearly 1 million Americans will be living with Parkinsons by 2020. The disease affects 1.5 times more men than women.7
Approximately 5.8 million Americans are currently living with Alzheimers disease. That number is expected to increase to 14 million by 2050.8 There is little difference between numbers of men and women who develop Alzheimers, but there are more women with the disease, because women tend to live longer than men.3
Read Also: Can Vascular Dementia Be Prevented
Validation Of Patient Subtypes Via Independent Studies
Figure gives an overview of our overall validation strategy, which consists of two parts: In the first part we re-clustered patients in our merged AD/PD validation cohort using the same workflow that we had established for our discovery cohort, which re-confirmed the possible existence of 4 clusters in AD and PD .
Figure 7
After classifier development, we were able to assign patients from independent studies to the clusters discovered in our discovery cohort . The in-group proportion measure proposed by Kapp and Tibshirani then measured the proportion of patients in the validation study, whose nearest neighbors in the discovery cohort had the same cluster label. An IGP closer to 1 indicates a stronger coherence of the statistical distribution of data in the validation cohort with the clustering of the discovery cohort. An IGP closer to zero indicates disagreement.
To further assess the statistical significance of observed IGP values we performed a permutation test, in which we randomly permuted the cluster assignment of patients and re-calculated the IGP. This was done for 1000 times. None of the randomly permuted cluster assignments exceeded the IGP of the original clustering, i.e. our obtained results were highly significant.
Lewy Body Dementia: A Common Yet Underdiagnosed Dementia
While its not a household word yet, Lewy body dementia is not a rare disease. It affects an estimated 1.4 million individuals and their families in the United States. Because LBD symptoms can closely resemble other more commonly known disorders like Alzheimers disease and Parkinsons, it is often underdiagnosed or misdiagnosed. In fact, many doctors or other medical professionals still are not familiar with LBD.
Recommended Reading: What Are The Last Stages Of Vascular Dementia
Potential For Therapeutic Targets
The researchers add that their findings have the potential to provide new therapeutic targets for both Alzheimers and Parkinsons disease.
Until now, nobody has really understood what the overlap between Alzheimers and Parkinsons disease was, or if it were important, says Jada Lewis, associate professor of neuroscience at the Centre for Translational Research in Neurodegenerative Disease at the University of Florida. Our study ties these diseases together in a unique way.
The researchers conclude that their findings show that LRRK2 genetic studies in human tauopathies may be warranted.
Symptoms Of Alzheimers Disease
The most common symptoms of Alzheimers disease are associated with memory loss. However, the way that memories are stored and recalled is distinct in people with Alzheimers than other forms of dementia. Patients with this disease usually have strong recollections of deeply seated memories.
However, they have trouble regurgitating information that they learned recently. Thats because Alzheimers changes the regions of the brain that are associated with learning.
Some of the symptoms of Alzheimers disease include:
- Trouble remembering new information
- Confusion about time, places and events
- Suspicions toward loved ones and caregivers
- Difficulty speaking, walking or swallowing
Alzheimers disease presents itself in different stages. Symptoms may vary, and the stages dont always correspond exactly with these, but understanding them may help you identify the condition in yourself or a loved one.
The stages of Alzheimers disease include:
Don’t Miss: How Do You Treat Someone With Dementia
Things You Should Know About The Link Between Parkinsons And Dementia
Both Parkinsons disease and dementia were ravaging the brain and behavior of actor Robin Williams before his death, but at the time, he didnt realize he had the latter.
Despite the fact that the signs of this combination can be confusing, the double diagnosis of Parkinsons and dementia impacts a large number of people. Of the one million people who have Parkinsons in the U.S., 50 to 80 percent may have dementiaeither as a result of Parkinsons pathology, or separately.
Robin Williams widow, Susan, wrote an editorial published in Neurology that was addressed to neurologists after his death. In it, she shared what it was like seeing her husband experience both Parkinsons disease and Lewy body dementia firsthand.
My hope is that it will help you understand your patients along with their spouses and caregivers a little more, Susan wrote.
Williams was first diagnosed with Parkinsons disease, which at first seemed to provide some answers for his out-of-character symptoms.
But it wasnt until after his death that an autopsy revealed he had been in the later stages of Lewy body dementiaa common form of dementia characterized by deposits of Lewy body proteins in the brain, which can impact physical movement, mood, memory and behavior.
I will never know the true depth of his suffering, nor just how hard he was fighting, Susan wrote. But from where I stood, I saw the bravest man in the world playing the hardest role of his life.
The Differences Between Alzheimer’s And Parkinson’s
16 October, 2020
Do you know the differences between Alzheimers and Parkinsons? First of all, we must say that both diseases constitute two of the causes of dementia. Now, lets be a bit more specific. According to data from the WHO , dementia due to Alzheimers disease represents 60-70% of all cases of dementia in the world.
However, its important to keep in mind that theyre very different diseases. Additionally, we must make clear that having either condition doesnt always lead to the development of dementia . In this sense, we know that between 20-60% of people with Parkinsons disease end up developing dementia.
Buter et al. conducted a study that was published in the journal Neurology. It was conducted with 233 patients with Parkinsons disease. The researchers were able to observe that about 60% of them developed Parkinsons dementia in a period of 12 years.
So whats dementia? It refers to the set of symptoms that arise as a consequence of neurological damage or disease. These symptoms involve the loss or weakening of the mental faculties and mainly affect three different areas: cognitive , behavioral , and personality .
Don’t Miss: How Many Caregivers Are Caring For Parents With Dementia
Identification Of Common Molecular Mechanisms
Common molecular mechanisms between AD and PD were identified with the help of a systematic literature mining approach with post-hoc manual curation. More specifically, the text mining engine SCAIView was used to construct cause-effect relationships between molecules, pathways, biological processes and imaging features in both, AD and PD, see Domingo-Fernandez et al. and Kodamullil et al. for details, for details. After manual curation, two computable disease maps, one for AD and one PD were created. Finally, we have also made them interactively usable via a dedicated web application .
Calculation of the intersection of cause-effect relationships described in the AD and PD disease maps resulted into 27 genes grouped into 15 cause-effect relationship sub-graphs, called mechanisms from now on . While some of these mechanisms describe only posttranslational modifications of a single protein, others reflect more complex proteinprotein interactions and signaling cascades . Key proteins described in both diseases include e.g. APOE, TAU, SNCA and TOMM40. These proteins are involved into several known disease relevant processes that we have made computationally accessible via our earlier developed NeuroMMSig database.
We mapped 148 genetic variants measured in ADNI1, ADNI2/GO as well as PPMI to the 27 common AD/PD disease genes via a combination of two strategies: a) proximity ; and b) eQTL mapping, see details in Supplements on page 2.
Is There A Test To Diagnose Pd Dementia
There is no single test for PDD. The diagnosis is made clinically. If you or someone you spend time with notices cognitive changes, it is important to discuss them with your care team. If you dont have a care team in place, its important to find a specialist or physician familiar with dementia or geriatric medicine. Call the Parkinson’s Foundation Helpline 1-800-4PD-INFO for a referral.
Don’t Miss: How Do You Know If You Have Dementia
Association With Brain Imaging Derived Features In Ad And Pd
In ADNI, AD patients demonstrated highly significant pairwise differences when comparing 193 intracranial volume normalized subcortical brain structures of those patients which had a recent AD diagnosis at study baseline and correcting statistical differences for the confounding effects of age and sex. We found significant differences in several brain regions, such as the calcarine sulcus, the cuneus gyrus and the medial occipitotemporal gyrus .
Figure 5
Example of significant differences between clusters with respect to brain imaging derived features at study baseline/time of first disease diagnosis . left calcarine sulcus in AD patients; left cuneus gyrus in AD patients; volume of right medial occipitotemporal gyrus in AD patients; DaTSCAN left Putamenratio to age expected value in healthy controls; DaTSCAN Count Density Ratio: Caudate/Putamen; DaTSCAN Count Density Ratio : Caudate contralateral/Putamen contralateral. The Figures shows statistical distributions as violin plots , and individual data points are shown as superimposed dots.
In PPMI, pairwise differences between the clusters were significant for in presynaptic dopaminergic imaging were identified in caudate and putamen . Also, the dopamine receptor density ratio of caudate versus putamen differed significantly between clusters.
Altogether, we concluded that our genetically derived clusters are associated with significant pathophysiological differences in the brain.
The Difference Between Parkinson’s Disease And Lewy Body Dementia
One of the most confusing concepts to explain in the clinic is the difference between Parkinson’s Disease, Parkinson’s Disease Dementia and Lewy Body Dementia. Ultimately people with Parkinson’s can look very similar with motor and non-motor problems. This is particularly tricky when PwP first present but the easiest way to consider Lewy Body Dementia is like having a very aggressive progression of Parkinson’s where patients are dementing in the first year of their condition whereas this process is much slower when patients develop Parkinson’s Disease Dementia. Indeed, clinically Lewy Body Dementia patients look like they have a cross between Parkinson’s and Alzheimer’s, which is actually close to what is seen down the microscope when researchers study the brain. Understanding the differences between Parkinson’s Disease and Lewy Body Dementia is not only difficult for patients and their families but has led some professional groups to try and lump all of these patients together under one umbrella, which probably does little to help individual families appreciate what the future holds.
Hopefully this video will help you to gain a more complete understanding of the differences between Parkinson’s Disease, Parkinson’s Disease Dementia and Lewy Body Dementia.
_____________________________________________________________________________________
Also Check: Is Weight Loss A Symptom Of Dementia
Visions Of The Future
Alzheimers and Parkinsons cause sweeping changes to the landscape of the brain before there are any behavioral shifts blood vessels atrophy, neurons die prematurely and snarls of misfolded proteins disrupt communication between surviving neurons. Current techniques for detecting these shifts, including PET imaging at $3,000 to $6,000, can identify Parkinsons and Alzheimers pathology in the brain before symptoms begin, but theyre too invasive and costly for widespread use. But identifying parallel changes in the retina is a different story.
Maya Koronyo-Hamaoui, a neuroscientist and professor of neurosurgery, studies early Alzheimers intervention and treatment at Cedars-Sinai. She and her team have pioneered a technique to visualize the plaques associated with Alzheimers in the retinal neurons of live patients with mild cognitive impairments, at a cost of about $285 a scan. All it requires is modified ophthalmological equipment and a lot of curry flavoring.
If Koronyo-Hamaouis imaging system seems low-tech to neuroscientists accustomed to PETs radioactive tracers and million-dollar scanners, Ruogu Fangs technique for Parkinsons screening is downright stone age.
Initial results suggest that computer algorithms are able to use these fundus images to distinguish Parkinsons patients from healthy controls with an accuracy upward of 70 percent.
Strategy For Identifying Mechanism Based Ad/pd Subtypes
Before going into more detail, we briefly outline our general approach for identifying subtypes of sporadic AD and PD idiopathic patients : Following Tan et al. it is largely driven by the idea of a genetic sub-classification followed by a clinical, imaging based and biological characterization of patients in each cluster to test disease relevance.
Figure 1
Genetic commonalities between AD and PD can only be expected at the biological function level. Hence, the starting point of our work was a comprehensive mapping of the molecular disease landscape of AD and PD based on the scientific literature . The result was a set of 15 molecular mechanisms comprising 27 proteins that have been implicated in both diseases . We mapped 148 SNPs to these genes based on proximity as well as eQTL analysis, see details in Supplements. Using ADNI and PPMI as discovery cohorts , we calculated for each of the 15 molecular mechanism an aggregate burden score via sparse autoencoders and then used sparse non-negative matrix factorization to identify 4 distinct patient subgroups in AD and PD, see section. These subgroups were found independently in both diseases as well as in a merger of ADNI and PPMI patients .
Figure 2
Also Check: How To Deal With Someone With Dementia