Maternal immune activation (MIA) during pregnancy has been linked to an increased risk of developing psychiatric pathologies in later life. This link may be bridged by a defective microglial phenotype in the offspring induced by MIA, as microglia have key roles in the development and maintenance of neuronal signaling in the central nervous system. The beneficial effects of the immunomodulatory treatment with minocycline on schizophrenic patients are consistent with this hypothesis. Using the MIA mouse model, we found an altered microglial transcriptome and phagocytic function in the adult offspring accompanied by behavioral abnormalities. The changes in microglial phagocytosis on a functional and transcriptional level were similar to those observed in a mouse model of Alzheimer’s disease hinting to a related microglial phenotype in neurodegenerative and psychiatric disorders. Minocycline treatment of adult MIA offspring reverted completely the transcriptional, functional and behavioral deficits, highlighting the potential benefits of therapeutic targeting of microglia in psychiatric disorders.

In early Alzheimer’s dementia, there is a need for PET biomarkers of disease progression with close associations to cognitive dysfunction that may aid to predict further cognitive decline and neurodegeneration. Amyloid biomarkers are not suitable for that purpose. The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) are widely abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as attention, learning and memory. Post-mortem studies reported lower expression of α4β2-nAChRs in more advanced Alzheimer’s dementia. However, there is ongoing controversy whether α4β2-nAChRs are reduced in early Alzheimer’s dementia. Therefore, using the recently developed α4β2-nAChR-specific radioligand (−)-¹⁸F-flubatine and PET, we aimed to quantify the α4β2-nAChR availability and its relationship to specific cognitive dysfunction in mild Alzheimer’s dementia. Fourteen non-smoking patients with mild Alzheimer’s dementia, drug-naïve for cholinesterase therapy, were compared with 15 non-smoking healthy controls matched for age, sex and education by applying (−)-¹⁸F-flubatine PET together with a neuropsychological test battery. The one-tissue compartment model and Logan plot method with arterial input function were used for kinetic analysis to obtain the total distribution volume (V_T) as the primary, and the specific binding part of the distribution volume (V_S) as the secondary quantitative outcome measure of α4β2-nAChR availability. V_S was determined by using a pseudo-reference region. Correlations between V_T within relevant brain regions and Z-scores of five cognitive functions (episodic memory, executive function/working memory, attention, language, visuospatial function) were calculated. V_T (and V_S) were applied for between-group comparisons. Volume of interest and statistical parametric mapping analyses were carried out. Analyses revealed that in patients with mild Alzheimer’s dementia compared to healthy controls, there was significantly lower V_T, especially within the hippocampus, fronto-temporal cortices, and basal forebrain, which was similar to comparisons of V_S. V_T decline in Alzheimer’s dementia was associated with distinct domains of impaired cognitive functioning, especially episodic memory and executive function/working memory. Using (−)-¹⁸F-flubatine PET in patients with mild Alzheimer’s dementia, we show for the first time a cholinergic α4β2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4β2-nAChR availability and impairment of distinct cognitive domains, notably episodic memory and executive function/working memory. This shows the potential of (−)-¹⁸F-flubatine as PET biomarker of cholinergic α4β2-nAChR dysfunction and specific cognitive decline. Thus, if validated by longitudinal PET studies, (−)-¹⁸F-flubatine might become a PET biomarker of progression of neurodegeneration in Alzheimer’s dementia.