Different Inflammatory Signatures in Alzheimer's Disease and Frontotemporal Dementia Cerebrospinal Fluid.

BACKGROUND: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. OBJECTIVE: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. METHODS: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing. RESULTS: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14-1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20-1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10-1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05). CONCLUSION: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders.

Increased Number of Plasma B Cells Producing Autoantibodies Against Aß42 Protofibrils in Alzheimer's Disease.

The Alzheimer's disease (AD)-related peptide amyloid-ß (Aß) has a propensity to aggregate into various assemblies including toxic soluble Aß protofibrils. Several studies have reported the existence of anti-Aß antibodies in humans. However, it is still debated whether levels of anti-Aß antibodies are altered in AD patients compared to healthy individuals. Formation of immune complexes with plasma Aß makes it difficult to reliably measure the concentration of circulating anti-Aß antibodies with certain immunoassays, potentially leading to an underestimation. Here we have investigated anti-Aß antibody production on a cellular level by measuring the amount of anti-Aß antibody producing cells instead of the plasma level of anti-Aß antibodies. To our knowledge, this is the first time the anti-Aß antibody response in plasma has been compared in AD patients and age-matched healthy individuals using the enzyme-linked immunospot (ELISpot) technique. Both AD patients and healthy individuals had low levels of B cells producing antibodies binding Aß40 monomers, whereas the number of cells producing antibodies toward Aß42 protofibrils was higher overall and significantly higher in AD compared to healthy controls. This study shows, by an alternative and reliable method, that there is a specific immune response to the toxic Aß protofibrils, which is significantly increased in AD patients.

Frontotemporal dementia-amyotrophic lateral sclerosis complex is simulated by neurodegeneration with brain iron accumulation.

We describe a case of late onset neurodegeneration with brain iron accumulation (NBIA) presenting as frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS). A male patient presented at age 66 with change of personality: disinhibition, emotional blunting, and socially inappropriate behavior, coupled with dysarthria, dystonia, and corticospinal tract involvement. Magnetic resonance imaging showed general cortical atrophy, iron deposits in the globus pallidus, and the "eye of the tiger" sign. Neuropsychologic performance was globally reduced, especially executive functions. Fluorodeoxyglucose positron emission tomography showed hypometabolism predominantly in frontal and temporal areas. Repeated neurophysiologic examinations showed signs of chronic denervation. The patient was diagnosed with NBIA but fulfilled consensus criteria for FTD and had a clinical picture of ALS, without neurophysiologic confirmation. Our finding introduces NBIA as a possible cause of FTD and as a differential diagnosis of the FTD-ALS complex.

Oligomerization partially explains the lowering of Abeta42 in Alzheimer's disease cerebrospinal fluid.

BACKGROUND/OBJECTIVE: The lowering of natively analyzed Abeta42 in cerebrospinal fluid (CSF) is used as a diagnostic tool in Alzheimer's disease (AD). The presence of Abeta oligomers can interfere with such analyses causing underestimation of Abeta levels due to epitope masking. The aim was to investigate if the lowering of CSF Abeta42 seen in AD is caused by oligomerization. METHODS: Abeta42 was analyzed under both denaturing and non-denaturing conditions. An Abeta42 oligomer ratio was calculated from these quantifications. The presence of oligomers leads to Abeta42 epitope masking during non-denaturing assays, resulting in a higher ratio. RESULTS: The Abeta42 oligomer ratio was used for the assessment of oligomerized Abeta in human CSF, after being evaluated in transgenic mouse brain homogenates. AD and mild cognitive impairment (MCI) samples displayed the expected decrease in natively measured Abeta42 compared to healthy controls and frontotemporal dementia, but not when analyzing under denaturing conditions. Accordingly, AD and MCI CSF had a higher Abeta42 oligomer ratio in CSF. CONCLUSION: Combining denaturing and non-denaturing quantifications of Abeta42 into an oligomer ratio enables the assessment of Abeta oligomers in biological samples. The increased Abeta42 oligomer ratio for AD and MCI indicates the presence of oligomers in CSF and that the lowering of natively measured Abeta42 is caused by oligomerization.

Association study of cholesterol-related genes in Alzheimer's disease.

Alzheimer's disease (AD) is a genetically complex disorder, and several genes related to cholesterol metabolism have been reported to contribute to AD risk. To identify further AD susceptibility genes, we have screened genes that map to chromosomal regions with high logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European screening sample of 115 sporadic AD patients and 191 healthy control subjects, we analyzed single nucleotide polymorphisms in 28 cholesterol-related genes for association with AD. The genes HMGCS2, FDPS, RAFTLIN, ACAD8, NPC2, and ABCG1 were associated with AD at a significance level of P < or = 0.05 in this sample. Replication trials in five independent European samples detected associations of variants within HMGCS2, FDPS, NPC2, or ABCG1 with AD in some samples (P = 0.05 to P = 0.005). We did not identify a marker that was significantly associated with AD in the pooled sample (n = 2864). Stratification of this sample revealed an APOE-dependent association of HMGCS2 with AD (P = 0.004). We conclude that genetic variants investigated in this study may be associated with a moderate modification of the risk for AD in some samples.