Alzheimer's: Inflammatory markers are conspicuous at an early stage
Evidence of damage and also neuroprotective processes long before
symptoms of dementia manifest

Date:
January 12, 2022
Source:
DZNE - German Center for Neurodegenerative Diseases
Summary:
Long before the onset of dementia, there is evidence for increased
activity of the brain's immune system. Researchers from DZNE and
the University Hospital Bonn (UKB) come to this conclusion based
on a study of more than 1,000 older adults. To this end, various
proteins were measured in the cerebrospinal fluid: They served as
so-called biomarkers that indicate inflammatory processes of the
nervous system. As it turned out, some of these molecules seem to
be part of a damage control program of the immune system, which
could be useful for the development of new drugs.



FULL STORY ==========================================================================
Long before the onset of dementia, there is evidence for increased
activity of the brain's immune system. Researchers from DZNE and the
University Hospital Bonn (UKB) come to this conclusion based on a study of
more than 1,000 older adults. To this end, various proteins were measured
in the cerebrospinal fluid: They served as so-called biomarkers that
indicate inflammatory processes of the nervous system. As it turned out,
some of these molecules seem to be part of a damage control program of the immune system, which could be useful for the development of new drugs. The study results have been published in the scientific journal Neuron.


==========================================================================
In recent years, it has become evident that the brain's immune system and related inflammatory processes -- also known as "neuroinflammation" - - significantly contribute to the development of Alzheimer's disease. In
view of this, the scientists analyzed various immunological biomarkers
that are characterized by good detectability in the cerebrospinal
fluid and reproducible results. "It was already known that these markers indicate immune processes in the context of Alzheimer's disease. However,
how these markers relate to brain volume, cognitive performance and
other parameters had not been studied as comprehensively as we have
now," explains Prof. Michael Heneka, who led the current study during
his long-time tenure at DZNE and UKB. Since the beginning of this year,
he has been director of the Luxembourg Centre for Systems Biomedicine.

"We have found that some of these inflammatory markers are conspicuous
even when there are no symptoms of dementia yet," Heneka says. "Based
on the data we have so far, we can't specify the lead time at this
point. But my estimate is that it is at least ten to twenty years."
Extensive Database The starting point for the investigations were data
from the so-called DELCODE study, in which the DZNE researches dementia
and its preliminary stage in collaboration with several university
hospitals across Germany. The current study project included findings from around 300 women and men, all over the age of 60. This group comprised cognitively normal adults, individuals with memory problems of varying
degrees of severity and also people with dementia of the Alzheimer's
type. Samples of cerebrospinal fluid and standardized memory tests were available from all study participants, and magnetic resonance images
of the brain were taken from most of them. For each study participant,
the data included the baseline examination and at least one follow-up
one year later.

For some subjects, findings spanned multiple follow-ups over a period
of up to five years.

Striking Even Without Dementia "There are established biomarkers
for amyloid and tau. These are proteins that accumulate in the brain
in Alzheimer's disease and can also be detected in the cerebrospinal
fluid. Their levels usually change even before symptoms of dementia arise, which is considered a sign of processes for neuronal damage. We wanted
to know whether inflammatory markers respond in a similar way," says Dr.

Frederic Brosseron, a scientist at DZNE and one of the first authors
of the current publication in "Neuron." "In fact, we found that most inflammatory markers are elevated, especially when a marker for neuronal
damage is elevated.

This applies even when these individuals do not yet show symptoms of
dementia.

Thus, the inflammatory markers we recorded are particularly useful for
studying neuroinflammation at early stages of disease." Evidence for Neuroprotection Two of these markers in particular -- proteins belonging
to the "TAM receptor family" -- seem to be linked to a damage control
program. In study participants with particularly levels of these high
markers, brain volume was comparatively large and cognitive functions
declined more slowly over time. To verify these findings, Heneka's team evaluated data from a study cohort of ACE Alzheimer Center Barcelona with
more than 700 adults, must of them with mild cognitive impairment. This analysis confirmed the results from the DELCODE study were.

"Inflammatory processes are not bad per se, but rather a normal,
protective reaction of the immune system to threatening stimuli,
especially at the beginning. But they should not last too long, therefore
they need to be regulated," says Heneka. TAM family proteins are known
to influence immune responses and promote disposal of cellular waste,
he explains. "Supporting this protective function would be an interesting approach for pharmaceutical research. This is where I see potential for application of the markers we have identified. For the early detection
of dementia in routine care, measuring these markers is too complex. But
when testing new drugs in clinical trials, there are other technical
options. In trials, indicators are needed to assess whether interventions
are working and whether tested drugs are effective. The TAM markers
could be very useful for this." This research was supported in part by
funding from the international PREADAPT project, which is funded by the
EU Joint Programme -- Neurodegenerative Disease Research (JPND).

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========================================================================== Journal Reference:
1. Frederic Brosseron, Anne Maass, Luca Kleineidam, Kishore Aravind
Ravichandran, Pablo Garci'a Gonza'lez, Ro'isi'n M. McManus,
Christina Ising, Francesco Santarelli, Carl-Christian Kolbe, Lisa
M. Ha"sler, Steffen Wolfsgruber, Marta Marquie', Merce` Boada,
Adelina Orellana, Itziar de Rojas, Sandra Ro"ske, Oliver Peters,
Nicoleta-Carmen Cosma, Arda Cetindag, Xiao Wang, Josef Priller,
Eike J. Spruth, Slawek Altenstein, Anja Schneider, Klaus Fliessbach,
Jens Wiltfang, Bjo"rn H.

Schott, Katharina Bu"rger, Daniel Janowitz, Martin Dichgans, Robert
Perneczky, Boris-Stephan Rauchmann, Stefan Teipel, Ingo Kilimann,
Doreen Goerss, Christoph Laske, Matthias H. Munk, Emrah Du"zel,
Renat Yakupov, Laura Dobisch, Coraline D. Metzger, Wenzel Glanz,
Michael Ewers, Peter Dechent, John Dylan Haynes, Klaus Scheffler,
Nina Roy, Ayda Rostamzadeh, Charlotte E. Teunissen, Natalie
L. Marchant, Annika Spottke, Mathias Jucker, Eicke Latz, Michael
Wagner, David Mengel, Matthis Synofzik, Frank Jessen, Alfredo
Ramirez, Agusti'n Ruiz, Michael T. Heneka. Soluble TAM receptors
sAXL and sTyro3 predict structural and functional protection in
Alzheimer's disease. Neuron, 2022; DOI: 10.1016/j.neuron.2021.12.016 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220112105630.htm
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