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Authors: Wennström, Malin | Londos, Elisabet | Minthon, Lennart | Nielsen, Henrietta M

Article Type: Research Article

Abstract: Neurodegenerative dementia, most frequently represented by Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n = 26), DLB (n = 18), and non-demented controls (n = 24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in …orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-Tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation. Show more

Keywords: Alpha-synuclein, Alzheimer's disease, biomarker, dementia with Lewy bodies, orexin

DOI: 10.3233/JAD-2012-111655

Citation: Journal of Alzheimer's Disease, vol. 29, no. 1, pp. 125-132, 2012

Authors: Nielsen, Henrietta M. | Hall, Sara | Surova, Yulia | Nägga, Katarina | Nilsson, Christer | Londos, Elisabet | Minthon, Lennart | Hansson, Oskar | Wennström, Malin

Article Type: Research Article

Abstract: The proteoglycan NG2 plays a major role in proliferation, migration, and differentiation of pericytes and NG2 cells in the brain. We have previously reported decreased soluble NG2 (sNG2) levels in cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) and a relationship between sNG2 and AD biomarkers in these patients. To further investigate whether alterations in sNG2 is specific to AD pathology, we measured levels of sNG2 in CSF from a patient cohort consisting of non-demented controls (n = 51), patients with Parkinson's disease (PD) (n = 61), and patients with dementia with Lewy bodies (DLB) (n = 37), two …synucleinopathies whereof the latter disorder frequently coincides with amyloid-β pathology similar to AD. We found decreased sNG2 concentrations in DLB patients, but not in PD patients, compared to controls. Levels of sNG2 in controls and PD patients correlated to T-tau, P-tau, α-synuclein, and neurosin. Only one correlation, between sNG2 and neurosin, was found in DLB patients. Analysis of a second cohort consisting of controls (n = 23) and DLB patients (n = 31) showed that the result was reproducible, as lower levels of sNG2 again were found in DLB patients compared to controls. We conclude that lower levels of sNG2 levels indicate a DLB-related impact on NG2 expressing cells foremost associated with neuropathology linked to accumulation of amyloid-β and not α-synuclein. Show more

Keywords: α-synuclein, Alzheimer's disease markers, amyloid-β, biomarker, cerebrospinal fluid, dementia with Lewy bodies, NG2, neurosin, Parkinson's disease, synucleinopathies

DOI: 10.3233/JAD-132246

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 343-350, 2014

Authors: Edlund, Anna K. | Chen, Kewei | Lee, Wendy | Protas, Hillary | Su, Yi | Reiman, Eric | Caselli, Richard | Nielsen, Henrietta M.

Article Type: Research Article

Abstract: Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain. Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose (CMRgl), gray matter volume, …and neuropsychological test scores. Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI. Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores. Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD. Show more

Keywords: APOE, apolipoprotein E, cerebral glucose metabolism, glucose, insulin

DOI: 10.3233/JAD-210065

Citation: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 339-354, 2021

Authors: Patra, Kalicharan | Giannisis, Andreas | Edlund, Anna K. | Sando, Sigrid Botne | Lauridsen, Camilla | Berge, Guro | Grøntvedt, Gøril Rolfseng | Bråthen, Geir | White, Linda R. | Nielsen, Henrietta M.

Article Type: Research Article

Abstract: The APOE ɛ 4 gene variant is the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE ɛ 3 conventionally is considered as ‘risk neutral’ although APOE ɛ 3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with either a homozygous …APOE ɛ 3 (n  = 31 control subjects, and n  = 14 MCI versus n  = 5 AD patients) or APOE ɛ 4 genotype (n  = 1 control subject, n  = 21 MCI and n  = 7 AD patients). Total plasma apoE levels were lower in APOE ɛ 4-carriers and overall correlated significantly to CSF Aβ42 , p(Thr181)-tau and t-tau levels. Apolipoprotein E dimers were only observed in the APOE ɛ 3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but were unrelated to plasma homocysteine levels. Importantly, the APOE ɛ 3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8±9.6% versus 26.7±6.3%, p  = 0.025) paralleled by an increase in apoE monomers (67.8±18.3% versus 48.5±11.2%, p  = 0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOE ɛ 3 subjects. Show more

Keywords: Alzheimer’s disease, apolipoprotein A-II, apolipoprotein E, biomarkers, dementia, dimers

DOI: 10.3233/JAD-190175

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1217-1231, 2019