Although recent clinical trials targeting amyloid in Alzheimers disease (AD) have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with amyloid metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in AD. However, to this date, no studies have assessed whether astrocytosis is independently related to amyloid or tau pathology, respectively, in vivo. To address this question, we determined the levels of the astrocytic marker glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) of 217 amyloid-negative cognitively unimpaired individuals, 71 amyloid-positive cognitively unimpaired individuals, 78 amyloid-positive cognitively impaired individuals, 63 amyloid-negative cognitively impaired individuals and 75 patients with a non-AD neurodegenerative disorder from the Swedish BioFINDER-2 study. Subjects underwent longitudinal amyloid (18F-flutemetamol) and tau (18F-RO948) positron emission tomography (PET) as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all amyloid-positive groups compared with subjects without amyloid pathology (p<0.01). In addition, there were significant associations between plasma GFAP with higher amyloid-PET signal in all amyloid-positive groups, but also in cognitively normal individuals with normal amyloid values (p<0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict amyloid-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, sTREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for amyloid-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-AD patients compared to other groups (p<0.05) and correlated with amyloid-PET only in amyloid-positive cognitively impaired individuals (p=0.005). Finally, plasma GFAP was associated with both longitudinal amyloid-PET and cognitive decline, and mediated the effect of amyloid-PET on tau-PET burden, suggesting that astrocytosis secondary to amyloid aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain amyloid pathology but not tau aggregation, even in cognitively normal individuals with a normal amyloid status. This suggests that plasma GFAP should be incorporated in current hypothetical models of AD pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to amyloid pathology.
Objective: To characterize behavioral and psychological symptoms of dementia (BPSD) in different dementia diagnoses: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), vascular dementia (VaD), frontotemporal dementia (FTD), mixed (Mixed) and unspecified dementia. Design: Registry-based cohort study. Setting and participants: 12,137 individuals with dementia registered in two national quality registries, the Swedish registry for cognitive/dementia disorders (SveDem) and the Swedish BPSD registry, during 2010 - 2016. Methods: BPSD was assessed with the Neuropsychiatric Inventory - Nursing Home Version (NPI-NH). Multivariate logistic regression models were used to evaluate the associations between dementia diagnoses and different BPSDs in reference to a) the AD group and b) each of the other diagnostic groups. All models were adjusted for age, gender, the severity of cognitive impairment at the time of dementia diagnosis, and time between dementia diagnosis and BPSD assessment. Results: In all individuals, the three most common symptoms were aberrant motor behaviour (35,1%), agitation (32,3%), and irritability (28,7%), while euphoria (5,9%) was the least frequent. Compared to AD, we found a lower risk of delusions (in VaD, FTD, unspecified dementia), hallucinations (in VaD and FTD), agitation (in PDD, unspecified dementia), elation/euphoria (in DLB), anxiety (in PDD, unspecified dementia), disinhibition (in PDD); irritability (in DLB, PDD, unspecified dementia), aberrant motor behavior (in Mixed, VaD, unspecified dementia) and sleep and night-time behavior changes (in unspecified dementia). Higher risks of delusions (in DLB), hallucinations (in DLB, PDD), apathy (VaD, FTD), disinhibition (in FTD) and appetite and eating abnormalities (in FTD) were found compared to AD. Conclusions and Implications: In this large contemporary cohort, BPSD was common in all types of dementia, with the most common symptoms being aberrant motor behavior, agitation, and irritability. Additionally, BPSD differed depending on the dementia type.
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