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the clinical assessment of cognitive impairment. Introduction of
the novel imaging techniques, MRI and PET and CSF biomarker
have enriched the visualisation of neuropathological features in
living individuals who have a higher risk to develop dementia.
Moreover, identification of the cognitive impaired but not demented
patients has ultimately led to identify early Alzheimer patients
to be included in the trials. In parallel with improvement of
the clinical assessment, genetic research has shed more light in
understanding not only the classical mutations but rather diverse
genetic polymorphisms and gene-gene interactions. Ultimately,
the novel experimental disease-modifying-drugs and therapeutic
substances have shown a promising effect to ameliorate the
accumulation of amyloid protein in the brain. This symposium
will stress the latest “breaking the ice” developments in clinical
and experimental dementia research.
CSF biomarkers for Alzheimer’s disease
–
update on established
biomarkers and new developments
(Kaj Blennow, MD, PhD,
Professor, Clinical Neurochemistry Laboratory, Dept. of Neuro-
science and Physiology, Gothenburg University, M¨olndal Campus,
M¨olndal, Sweden): Research advances in Alzheimer’s disease
(AD) molecular pathogenesis have given several drug candidates
targeting
b
-amyloid (A
b
) and recently also tau pathology that are
tested in clinical trials. However, the list of anti-A
b
trials failing
to show clinical benefits indicate that trials need enrol patients
before neurodegeneration is too advanced, to give drug candidates
a chance to show clinical efficacy, and to enrich for patients that
do have AD pathology. To manage this, biomarkers will have a
critical role.
The CSF biomarkers total tau (T-tau), phospho-tau (P-tau) and A
b
(A
b
42 or A
b
42/40 ratio) have consistently been found to have high
diagnostic accuracy to identify AD already in the early (prodromal)
disease stage. Given that CSF A
b
42 show identical diagnostic
performance for AD as amyloid PET at only a fraction of the cost,
it is likely that CSF biomarkers will be important tools for AD
diagnostics.
However, standardization is needed since current ELISA methods
have high between-lab and between-batch variability. The IFCC-
WG for CSF proteins aims to develop a Certified Reference
Material (CRM) for distribution to assay vendors and laboratories to
harmonize assay readouts. A mass spectrometry-based Reference
Measurement Procedure (RMP) has been developed for A
b
42.
Biotech companies are developing high-quality fully automated
assays with minimal analytical variability. Taken together, these
efforts will allow uniform cut-off levels and enable the large-scale
introduction of CSF biomarkers in diagnostic routine.
New developments include assays to monitor soluble A
b
oligomers
and synaptic dysfunction. Recent studies show a marked increase
in CSF levels of both the presynaptic protein SNAP-25 and the
dendritic protein neurogranin in AD dementia and prodromal AD,
with higher neurogranin levels predicting a more rapid cognitive
decline and with progression to AD dementia. This type of synaptic
biomarkers may be valuable to select early AD cases for inclusion
in trials, and to monitor drug effects on synaptic function and
integrity.
Dementia genetics
–
current status and future potential
(Ole
A. Andreassen MD PhD, Professor, NORMENT KG Jebsen Centre,
University of Oslo, Oslo University Hospital, Oslo, Norway): The
heritability of late onset Alzheimer’s disease (AD) is fairly high, but
most of the genetic risk is unknown. ApoE was for a long time the
only identified risk gene, but recent technological developments
have revolutionized this type of research. Now it is possible to
genome-wide association studies (GWAS) of hundred thousand
participants, and the largest study to date identified 19 single
nucleotide polymorphisms (SNPs) tagging risk loci.
Epidemiological findings suggest a relationship between (AD), and
other neuropsychiatric disorders, as well as inflammation and
dyslipidemia. However, the nature of these relationships is not well
understood. We investigated whether these phenotypic associations
arise from a shared genetic basis (‘pleiotropy’). We investigate
overlap in (SNPs) associated with clinically diagnosed AD and
Parkinson’s disease (PD) and between AD and C-reactive protein
(CRP), triglycerides (TG), high (HDL) and low-density lipoprotein
(LDL) levels.
We demonstrate polygenic overlap between AD, inflammation, and
plasma lipids and identify three novel genome-wide significant
variants conferring increased risk of Alzheimer’s disease. Our
findings identify the tau-associated MAPT locus as a site of genetic
overlap between AD and PD, and support the hypothesis that
inflammatory mechanisms and dyslipidaemia influence Alzheimer’s
pathogenesis.
Studies of rare gene variants have recently revealed gene variants
with protective properties (in APP) which may lead to development
of new drug targets. We also recently found risk variants in TREM2
and ABCA7, which suggest an involvement in immune mechanisms
and membrane transport in AD pathology.
The recent findings in the molecular genetics mechanisms
of dementia have provided new knowledge about disease
pathogenesis, as well as new opportunities for development of
new treatment regimens.
The role of imaging in dementia: Methods for research and
clinical practice
(Lars-Olof Wahlund, Professor, Section for Clinical
Geriatrics, NVS department, Karolinska Institutet, Stockholm,
Sweden;
lars-olof.wahlund@ki.se): Neuroimaging has become
increasingly important in the clinical assessment of dementia as
well as in clinical research. Today we use imaging biomarkers for
several of dementia disorders. With MRI and CT the structural
changes in dementia can be assess with high precision. The specific
changes seen in for instance Alzheimer’s disease are easily detected
early in the disease process using MRI or CT. This knowledge has
been implemented in the new suggested criteria for Alzheimer’s
diseases publish by Dubois et al some years ago. Last years it
has become possible to study the key pathological processes in the
brain of Alzheimer’s disease by assessing amyloid in the brain using
PET technique. This fact and the fact that glucose metabolism can
be studied in several dementia disorders has made it possible to
use these techniques for biomarkers in disease modifying clinical
trials. The talk will include a review of the most modern methods
used in dementia workup as well as in dementia research for
both diagnostic purposes and as biomarker for effect evaluation in
clinical trials on disease modifying drugs.
Novel and experimental therapeutics in Alzheimer’s Disease
(Nenad Bogdanovic MD, PhD, Professor, Geriatric Department,
Memory Clinic, Oslo University Hospital, UiO, Oslo, Norway):
Alzheimer’s disease (AD) is presently incurable and treatable only
in terms of modest delay of symptomatic progression. The unmet
need for more effective pharmacological intervention is becoming
mandatory as the patient population increases. Only symptomatic
drug therapies have been approved for treating AD; cholinesterase
inhibitors (ChEIs), and memantine, an NMDA receptor agonist, or
donepezil, a ChEI. The lack of novel treatment options beyond
ChEIs and memantine is due to insufficiently understanding of
Alzheimer’s disease pathophysiology.
Last 20 years, the Amyloid Cascade Hypothesis (John Hardy 1992)
is providing the neurobiological rationale in the development
of the new drugs against AD, suggesting that decreasing beta-
amyloid protein load in patients could have an ameliorating effect.
Unfortunately failure of several amyloid clearance therapies within
the last 3–4 years has dramatically broadened the landscape of
pathways that are under investigation. Moreover, it has been shown
that making a diagnose of AD based on the presence of the beta-
amyloid in the brain is not an easy task without employment of
biomarkers and the failure of some very promising compounds