Using CSF biomarkers to understand mechanisms of behavioral changes and effects of drug treatment in dementia

Dementia is affecting millions of people around the world, and the global prevalence will continuously rise. Neuropsychiatric symptoms (NPS) in dementia are frequent and constitute a key driving force in the disease burden for both patients, families, caregivers and society. The clinical presentation includes symptoms such as agitation, depression, anxiety, apathy and irritability, which are highly frequent in patients with dementia. NPS have a significant negative impact on a patient’s ability to perform activities of daily living and also contribute largely to the disease-associated health care costs. Current knowledge of the pathophysiological mechanisms causing NPS is lacking, and improved understanding of these processes is of great importance in order to improve treatment of NPS.

The main purpose of this thesis was to examine the pathophysiological mechanisms underlying NPS by investigating their associations to cerebrospinal fluid (CSF) biomarkers reflecting core Alzheimer’s dementia (AD) pathology (phosphorylatedtau [P-tau], total-Tau [T-tau], β-amyloid 1-42 [Aβ-1-42]), synaptic degeneration (neurogranin [Ng], growth-associated protein 43 [GAP-43]) and axonal degeneration (neurofilament light protein [NFL]) in patients with dementia. Secondary aims included investigation of how treatment with an acetylcholinesterase inhibitor (AChEI) (Galantamine) or antipsychotic (Risperidone) impacts both the clinical symptoms and CSF biomarker patterns. In the first study, we showed that agitation correlated with increased levels of P-tau and T-tau in CSF, but not with Aβ-1-42. Thus, suggesting an association between agitation and tau-mediated pathology. The second study was an open randomized clinical trial comparing the efficacy of Galantamine and Risperidone for the treatment of agitation in patients with dementia. Both drugs were effective in reducing levels of agitation. However, Risperidone was more efficient at decreasing NPS, although at the cost of lower tolerability and increased rate of adverse events. In the third study, we showed that treatment with Risperidone, but not Galantamine, was associated with a decrease of CSF Aβ-1-42. Indicating a potential association between Risperidone and progression of amyloid pathology. In the fourth study, we investigated the association between NPS and biomarkers for synaptic degeneration (Ng, GAP-43) and axonal degeneration (NFL). Levels of Ng, GAP-43 and NFL did not differ between AD patients with high vs low levels of NPS. We also found associations between CSF markers for synaptic (Ng, GAP-43) and axonal degeneration (NFL) with NPS, especially of the psychotic spectrum, in patients with vascular dementia (VaD).

In conclusion, our results implicate tau-mediated pathology and synaptic dysfunction as contributing components to the presence of NPS in AD and VaD. In contrast, no clear evidence supporting the role of amyloid pathology in NPS was observed. Interestingly, treatment with Risperidone affected CSF Aβ-1-42 levels, providing a possible pathway for the previously observed association between use of antipsychotics and accelerated rate of cognitively decline seen in patients with dementia.

List of scientific papers

I. Bloniecki V, Aarsland D, Cummings J, Blennow K, Freund-Levi Y. Agitation in dementia: relation to core cerebrospinal fluid biomarker levels. Dement Geriatr Cogn Dis Extra. 2014;4(2):335–43.
https://doi.org/10.1159/000363500

II. Freund-Levi Y, Bloniecki V, Auestad B, Tysen Bäckström AC, Lärksäter M, Aarsland D. Galantamine versus Risperidone for Agitation in People with Dementia: A Randomized, Twelve-Week, Single-Center Study. Dement Geriatr Cogn Disord. 2014;38(3–4):234–44.
https://doi.org/10.1159/000362204

III. Bloniecki V, Aarsland D, Blennow K, Cummings J, Falahati F, Winblad B, Freund-Levi Y. Effects of Risperidone and Galantamine Treatment on Alzheimer’s Disease Biomarker Levels in Cerebrospinal Fluid. J Alzheimer’s Dis. 2017;57(2):387–93.
https://doi.org/10.3233/JAD-160758

IV. Bloniecki V, Zetterberg H, Aarsland D, Vannini P, Kvartsberg H, Winblad B, Blennow K, Freund-Levi Y. Are neuropsychiatric symptoms in dementia linked to CSF biomarkers of synaptic and axonal degeneration? [Manuscript]