Immune Biomarkers May Better Classify Patients, Direct Therapy, Study Says

biomarkers, brain inflammation

Biomarkers of brain inflammation could provide a useful means for classifying Parkinson’s and Alzheimer’s patients and defining the mechanisms underpinning each person’s disease.

Testing for these biomarkers could support clinicians in providing precision medicine, by helping people with the progressive neurodegenerative disorders to choose treatments with a greater chance of benefiting them, based on their individual characteristics.

The study, “Multicenter Alzheimer’s and Parkinson’s disease immune biomarker verification study,” was published in the journal Alzheimer’s & Dementia.

Typically, diseases such as Parkinson’s are defined largely on the basis of patients’ symptoms. But while individuals share the same diagnosis, the underlying molecular and cellular causes of their illness may differ.

This also could explain why treatments do not work equally for all patients. Using these individual differences to identify patient groups may help clinicians choose more tailored treatment choices.

Many researchers propose that neurodegenerative illnesses could be defined on the basis of their molecular features, before evident symptoms occur in later stages of the disease.

To address this hypothesis, the AETIONOMY project, an European public-private partnership funded by the Innovative Medicines Initiative, is exploring potential molecular classifiers for Alzheimer’s and Parkinson’s.

Candidate markers include tracers of neuroinflammation, meaning trackers of the inflammatory reactions occurring in the brain and spinal cord, which comprise the central nervous system, or CNS.

Neuroinflammation probably begins early in neurodegenerative diseases, when the immune system senses the presence of misshaped or aggregated proteins — including beta-amyloid in Alzheimer’s, or alpha‐synuclein in Parkinson’s.

The formation of abnormal clumps of each of these proteins in the brain is believed to be at the root cause of each disease. In Parkinson’s, alpha-synuclein proteins clump together in aberrant aggregates termed protofibrils, which are toxic and thought to play an important role in the death of nerve cells (neurodegeneration).

In the first stages of the disease, these aggregates are known to activate immune cells called microglia and other supportive cells in the brain, known as astroglia. Later, immune reactivity — in which the body mistakenly attacks its own healthy cells — propagates in response to nerve cell death, with immune signals released as a consequence of the damage.

A team of researchers involved in the AETIONOMY project now sought to identify neuroinflammation-specific biomarkers. They screened 227 samples of cerebrospinal fluid or CSF, the fluid that surrounds the brain and spinal cord, collected from Alzheimer’s and Parkinson’s patients.

The goal was to look for relationships between the levels of these markers and patients’ characteristics — for example, age and sex — as well as their link with markers of neurodegeneration, such as tau, and measures of disease progression, like the Hoehn and Yahr scale for Parkinson’s.

People without dementia and patients diagnosed with mild cognitive impairment also were included for comparison.

The researchers specifically focused on 21 selected immunity markers. These included chemical messengers known as cytokines or chemokines, namely YKL‐40, TGF‐beta1, IP‐10, MCP‐1, MIF, and MIP‐1beta. The immune receptors sIl‐1RAcP, sAXL, sTyro3, sTREM2, sTNF‐RI/II, and sICAM‐1 also were targeted, as well as other complement and innate immune factors, including C-reactive protein and C1q, C3, C3b, C4, B, H, and properdin.

The findings were highly reproducible and consistent with previous findings. However, they revealed that immune markers were more tightly related to neurodegeneration — reflected by the levels of the protein tau — than having a diagnosis of Alzheimer’s, Parkinson’s, or mild cognitive impairment.

This suggests that such biomarkers may work better to discriminate the mechanisms underlying each patient’s illness.

Age was the “most striking covariate” with a “strong influence” on immunity markers. Older patients had increased levels of most immune proteins, and also tended to have more advanced disease.

The individual’s sex also influenced marker levels, as did APOE genetic variants — one of the strongest genetic risk factors for Alzheimer’s and a proposed risk factor for Parkinson’s — and center‐specific factors, or variations from the different centers from which patient data was obtained.

“These results are supportive of the use of mechanism‐based disease taxonomies [classifications] in addition to clinical features,” the researchers said.

Ageing seems to have a strong link with increased neuroinflammation; thus it should be taken into account when translating marker results to clinical practice or studies, the team said.

“Immunity biomarker levels in CSF reflect molecular and cellular pathology [disease characteristics] rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration,” the researchers concluded.

Looking ahead, the researchers reaffirm the need to characterize patients not only by symptoms but also by molecular markers that reflect their complex neurodegenerative disorders.

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Certain Compounds in Coffee, But Not Caffeine, Seen to Prevent Protein Buildup Linked to Parkinson’s in Early Study

coffee consumption

Chemical compounds in coffee — especially phenylindanes that form during the roasting of coffee beans — appear to prevent the damaging aggregation of amyloid-beta and tau known to play key roles in Parkinson’s and Alzheimer’s disease, researchers report.

Caffeine, in contrast, had no effect on protein buildup in this early lab study, and researchers saw coffee consumption to offer no protection against alpha-synuclein aggregation.

The study, “Phenylindanes in Brewed Coffee Inhibit Amyloid-Beta and Tau Aggregation,” was published in Frontiers in Neuroscience.

Coffee consumption has been suggested to reduce the risk of developing diabetes, various cancers, and neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease. Despite the available evidence, however, it’s unclear what how exactly coffee can help to prevent age-related cognitive decline.

Past studies have reported that caffeine, the main bioactive compound of coffee, can reduce the risk of Parkinson’s both in men and in women who were not taking hormone replacement therapy. It has also been seen to reduce nerve cell death in the substantia nigra – the brain area most affected in Parkinson’s – in mouse models of the disease.

However, recent data also suggests that long-term consumption of caffeine may exacerbate anxiety-related behavioral and psychological symptoms in patients with dementia, counteracting its potential beneficial effects.

These contrasting findings highlight the need to identify those coffee components that may be neuroprotective.

Researchers led by Donald Weaver, MD, PhD, co-director of the Krembil Brain Institute, evaluated the potential of chemical components of coffee to inhibit the buildup of proteins that can drive neurodegenerative diseases like Alzheimer’s and Parkinson’s, in particular: amyloid-beta, tau, and alpha-synuclein.

The team started by examining three types of instant coffees — light roast, dark roast, and decaffeinated dark roast — in terms of their ability to prevent protein aggregates. They tested the instant coffees by adding them to one of these three proteins in an in vitro (laboratory dish) context.

“The effect of caffeine content would be assessed by comparing the activity of caffeinated and decaffeinated dark roast coffee extracts. Further, since it is known that different levels of roasting affect the composition of the coffee brew, comparison of light versus dark roast coffee extracts was also performed,” the researchers wrote.

Dark roast coffee showed the greatest inhibitory effect against tau protein buildup. Interestingly, the level of caffeine in each type of coffee had no impact on tau, amyloid-beta, and alpha-synuclein’s ability to aggregate.

“We were surprised to find that caffeine content did not influence aggregation inhibition, and thus performed a post-hoc analysis of pure caffeine,” the researchers said in the study. “No effect on fibril growth was observed relative to the vehicle control, consistent with the results for caffeinated versus decaffeinated coffee extracts.”

Further experiments found that all coffee extracts could prevent amyloid-beta and tau protein aggregation at 200 μg/mL concentration. Dark roast coffee (with or without caffeine) was seen as more potent in preventing the oligomerization — a chemical form that proteins can take — of amyloid-beta than the light roast extract.

All types of coffee as an instant mix, however, showed an ability to promote alpha-synuclein aggregation at amounts above 100 mg/mL.

To better understand these findings, the team then explored the activity of the six main chemical components of coffee — caffeine, chlorogenic acid, quinic acid, caffeic acid, quercetin, and phenylindane.

Researchers found that most of these compounds — with exception of caffeine and quinic acid for amyloid-beta, and caffeine and caffeic acid for tau — prevented protein aggregation.

Phenylindane was found to hold the strongest inhibitory activity, working as a dual-inhibitor to prevent the formation of amyloid-beta aggregates by 99% and those of tau tangles by 95.2%. Importantly, in later experiments, phenylindanes did not show “pro-aggregation behavior” toward alpha-synuclein, the study reported.

Phenylindanes are formed during the roasting of coffee beans and are found in higher concentrations in dark roast coffees, which have longer roasting times.

“It’s the first time anybody’s investigated how phenylindanes interact with the proteins that are responsible for Alzheimer’s and Parkinson’s,” Ross Mancini, a research fellow in medicinal chemistry at the Krembil institute and the study’s first author, said in a news release.  “The next step would be to investigate how beneficial these compounds are, and whether they have the ability to enter the bloodstream, or cross the blood-brain barrier.”

The team is now investigating if phenylindanes can reduce amyloid-beta, tau and alpha-synuclein loads in cell and animal models of Alzheimer’s and Parkinson’s disease.

Researchers caution that their findings are not recommendation for excessive coffee consumption.

“What this study does is take the epidemiological evidence and try to refine it and to demonstrate that there are indeed components within coffee that are beneficial to warding off cognitive decline,” Weaver said. “It’s interesting, but are we suggesting that coffee is a cure? Absolutely not.”

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Alpha-Synuclein Could Be Biomarker for Non-Motor Symptoms in Parkinson’s, Study Suggests

Alpha-synuclein biomarker

Reduced alpha-synuclein levels in the cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord — are associated with more severe non-motor symptoms in Parkinson’s patients, according to a study.

The study, “CSF α-synuclein inversely correlates with non-motor symptoms in a cohort of PD patients,” published in the journal Parkinsonism and Related Disorders, suggests that measurements of alpha-synuclein could be used as a biomarker for non-motor symptoms in Parkinson’s disease.

Unlike its characteristic motor symptoms, Parkinson’s non-motor symptoms — which include emotional and mood changes, cognitive changes or dementia, fatigue, or hallucinations — still lack reliable predictors.

While motor manifestations are due to degeneration of dopamine-producing neurons in a brain area called the substantia nigra, non-motor complications may be caused by more diverse and non-dopaminergic neurodegenerative processes.

Assessing CSF proteins enables the study of disease-related changes in the brain that occur in neurodegenerative diseases. Such an analysis, along with the identification of biomarkers, are key to developing effective treatments.

Italian researchers in this study hypothesized that widespread degeneration underlying non-motor symptoms may mirror the CSF protein profile, which could be used as a biomarker for these symptoms.

They evaluated the association between non-motor symptom severity and CSF levels of alpha-synuclein — the main component of clumps known as Lewy bodies in the brain of Parkinson’s patients; total tau and one of its altered (phosphorylated) versions that form tangles inside neurons in Parkinson’s disease; and a form of amyloid-beta called 42-amyloid-beta, which is also relevant in Alzheimer’s disease.

A total of 83 individuals were included, 46 with Parkinson’s (24 men, mean age 57.4 years) and 37 controls (22 men, mean age 60.9 years). The control group included participants with non-neurodegenerative conditions receiving a spinal tap for diagnostic purposes, but without signs of motor and cognitive impairment.

Standard clinical scores were used to assess Parkinson’s patients: Non-motor symptoms were measured using the Non Motor Symptoms Scale (NMSS) total and single-item scores, motor symptoms with the Unified Parkinson Disease Rating Scale part 2 and 3 (UPDRS 2-3), and cognition with the Mini Mental State Examination. Evaluations were conducted while patients were on standard antiparkinsonian medications.

The results showed that Parkinson’s patients had lower alpha-synuclein and total tau levels than controls. According to the authors, the reduced amount of alpha-synuclein in the CSF could be attributed to its accumulation in Lewy bodies.

Additionally, the phosphorylated/total tau ratio was significantly higher in Parkinson’s patients than in controls. However, the total tau/alpha-synuclein + 42-amyloid-beta ratio was lower in people with Parkinson’s. Alpha-synuclein at a cut-off value of 1,143 pg/ml showed the highest sensitivity (86%) and specificity (77%) for diagnostic accuracy.

Researchers also found that the lower the alpha-synuclein level, the higher (worse) the NMSS total score and single-item 3 scores, which refer to mood/cognition, and item 9 scores, referencing pain/smell/weight/sweating. This association was independent of age, disease duration, motor impairment severity and dopaminergic treatment, and indicates prominent dysfunction of brain networks controlling these functions, the scientists observed.

A similar inverse association was found between phosphorylated tau level and NMSS total score and item 3 score, though in this case it was not statistically significant. Alpha-synuclein level was not significantly associated with motor symptoms assessed with the UPDRS 2-3.

“We suggest that the decrease of CSF a-syn levels mirrors a widespread degenerative process involving non-dopaminergic networks,” the researchers wrote.

Although cautioning that the results are preliminary and need validation in longer studies, the team believes that “measurement of total CSF [alpha-synuclein] may represent a biomarker for NMS [non-motor symptoms], supporting the assessment of frailty in PD [Parkinson’s disease] patients.”

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Specific Biomarkers May Help to Distinguish Parkinson’s Dementia from Dementia with Lewy Bodies

biomarkers, dementia study

The levels of specific protein biomarkers in the cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord — can distinguish patients with Parkinson’s disease dementia (PDD) from those with dementia with Lewy bodies (DLB) regardless of dementia stage, according to a new study.

The research, “Cerebrospinal fluid markers analysis in the differential diagnosis of dementia with Lewy bodies and Parkinson’s disease dementia,” appeared in the journal European Archives of Psychiatry and Clinical Neuroscience.

Brain protein clumps known as Lewy bodies are characteristic of both Parkinson’s and DLB.

Current practice gives a DLB diagnosis if dementia occurs before or during the first year of parkinsonism, a general term for neurological disorders that cause movement problems similar to those of Parkinson’s patients.

As such, a follow-up is essential to differentiate between PDD and DLB. However, the overlap of clinical symptoms and the difficulty in establishing when specific symptoms start make this distinction challenging and impacts treatment.

A percentage of DLB cases share a varying extent of pathological features with Alzheimer’s. But, unlike in that disease, no specific CSF biomarkers  have been validated for DLB and PDD. Researchers, for this reason, assessed the diagnostic potential of widely accepted CSF biomarkers across dementia stages to differentiate between DLB and PDD.

A total of 136 patients, all being treated at University Medical Center, Göttingen, Germany, underwent routine laboratory testing and a spinal tap to collect CSF. Cognitive examinations were preformed using the Mini-Mental State Exam (MMSE), and 65% of these patients were also tested with the Montreal Cognitive Assessment (MoCA), and the Clinical Dementia Rating (CDR).

The group included 51 people (31 men) with a diagnosis of probable DLB — 6 later confirmed — 53 with Parkinson’s, and 32 who were cognitively intact. Thirty-one of the Parkinson’s patients met the criteria for PDD (16 women and 15 men). Patients exhibiting dementia were classified as mild, moderate or severe.

CSF samples were tested for the proteins amyloid-beta1–42, tau, phoshorylated tau (a modified form of the tau protein), neuron-specific enolase (NSE) — a predictor of severity and neurobehavioral outcome after acute stroke, and implicated in Alzheimer’s — and S100B, a marker of brain damage. Of note, both amyloid-beta and phoshorylated tau form clumps in the brains of Alzheimer’s and Parkinson’s patients.

Levels of tau and amyloid-beta1–42, as well as the phosphorylated tau/total tau ratio were helpful in distinguishing between DLB and Parkinson’s patients with or without dementia.

Specifically, tau levels were higher in DLB than in Parkinson’s patients regardless of cognitive status, and were also higher in Parkinson’s patients with dementia than those without it.

DLB patients had lower levels of both amyloid-beta1–42 and phosphorylated tau/total tau ratio than did Parkinson’s dementia patients. This ratio was lower in DLB patients with mild and moderate dementia.

Levels of tau and phosphorylated tau protein in patients’ CSF reflected the severity of dementia in both DLB and PDD patients. Tau ratio enabled a distinction between Parkinson’s patients with mild and moderate dementia, and was lower in those with severe dementia than those with mild dementia.

Lower levels of amyloid-beta1–42 correlated with a rapid disease course in DLB but not in PDD. Both DLB and Parkinson’s patients with dementia showed elevated levels of S100B in comparison to healthy controls — indicating brain damage.

For both DLB and PDD, patients with less than a year of disease duration showed a trend toward higher tau, phosphorylated tau and NSE as opposed to lower amyloid-beta1–42  when compared to those whose disease had been diagnosed earlier.

Nevertheless, only values for amyloid-beta1–42 were lower in DLB patients whose dementia was confirmed less than one year after their primary diagnosis, compared to those diagnosed with PDD.

“These results have clinical relevance by suggesting that the descent of CSF [amyloid-beta1–42] values mainly in rapid disease course might have a prognostic significance,” the researchers wrote.

“[W]e conclude that CSF profile with the appropriate clinical context could be effective in distinguishing DLB from PDD patients, regardless of the severity of dementia,” they added.

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Source: Parkinson's News Today

Cell Surface Molecule Seen as Player in Spread of Protein Clumps That Compose Lewy Bodies

Parkinson's and HSPG

How cell surface proteins participate in spreading, from one cell to another, misfolded proteins related to neurodegenerative diseases like Parkinson’s and Alzheimer’s, possibly aiding in the progression of these disorders, was seen in early research.

The study, “Specific glycosaminoglycan chain length and sulfation patterns are required for cell uptake of tau versus α-synuclein and β-amyloid aggregates,” was published in The Journal of Biological Chemistry.

Parkinson’s and like diseases are marked by an accumulation of misfolded protein aggregates that contain α-synuclein, β-amyloid, or tau. Studies suggest that these proteins spread from cell to cell — or “seed” cells — turning normal proteins into disease-promoting ones.

Researchers at UT Southwestern discovered in 2013 that these abnormal proteins bind to heparan sulfate proteoglycan (HSPG) — a specific type of sugar-protein molecule found on a cell’s surface — in order to enter a cell and seed it with misfolded proteins that then aggregate.

But they did not know if specific HSPG features were necessary for binding to take place.

HSPGs can have distinct patterns of sugars, which themselves can hold specific patterns of sulfur-containing groups called sulfate moieties.

Using lab-grown brain cells, the researchers tested the binding and cell-uptake behavior of α-synuclein, β-amyloid, and tau based on the sulfate moieties in the HSPGs on the cells’ surface. [Lewy bodies that characterize Parkinson’s contain α-synuclein protein clumps in abundance.]

They found that abnormal tau only entered cells when an extremely specific sulfur-modified HSPG was evident. But the other two proteins were more adaptable as to the kinds of sulfate moieties that triggered their uptake, or entrance into a cell.

“Tau aggregates required a precise … architecture with defined sulfate moieties… whereas the binding of α-synuclein and  Aβ [β-amyloid] aggregates was less stringent,” the researchers wrote.

Enzymes that generate HSPGs’ distinct patterns of sulfur-containing groups were also identified. In the absence of these enzymes, the researchers found, abnormal tau and α-synuclein could not get inside a cell, as if they lacked the key.

“There’s something very remarkable about how efficiently a cell will take up these aggregates, bring them inside and use them to make more,” Barbara Stopschinski, MD, the study’s first author, said in a press release. “This knowledge has important implications for our understanding how neurodegenerative diseases get worse over time. Because we have identified specific enzymes that can be inhibited to block this process, this could lead to new therapies.”

A next step, the team added, is to understand if the molecular processes observed in these lab-grown cells also take place in a living brain.

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Source: Parkinson's News Today