Increased levels of the bullous pemphigoid BP180 autoantibody are associated with more severe dementia in Alzheimer's disease

Abstract Bullous pemphigoid (BP) is a subepidermal blistering skin disease, which has shown a strong association with neurological diseases in epidemiological studies. The BP autoantigens BP180 and BP230 are expressed in the cutaneous basement membrane and the central nervous system. Using BP180 and BP230 ELISA assays and immunoblotting against BP180, we analyzed the IgG reactivity in the sera of 115 patients with Alzheimer’s disease (AD) and 40 neurologically healthy controls. BP180 autoantibodies were found in 18% of patients with AD, whereas only 3% of controls had positive results (P = 0.019). BP230 values were higher and more often elevated in patients with AD than controls, but not significantly. None of the positive AD sera that recognized the full-length human BP180 in immunoblotting reacted with the cutaneous basement membrane in indirect immunofluorescence analysis. Moreover, a retrospective evaluation of the hospital records of the patients with AD revealed neither BP diagnosis nor BP-like symptoms. Interestingly, increased BP180-NC16A autoantibody values correlated with cognitive decline measured by mini-mental state examination scores, but not with the concentration of AD biomarkers in cerebrospinal fluid. Our findings further the understanding of the role of BP180 as a shared autoantigen in neurodermatological interactions and the association between BP and neurodegenerative diseases

Use of gliptins reduces levels of SDF-1/CXCL12 in bullous pemphigoid and type 2 diabetes, but does not increase autoantibodies against BP180 in diabetic patients

Abstract The use of dipeptidyl peptidase 4 (DPP4) inhibitors, (also known as gliptins), is associated with an increased risk of bullous pemphigoid (BP), an autoimmune blistering skin disease. To explore the mechanism behind gliptin-associated BP we investigated circulating autoantibodies against the major BP autoantigen BP180 in serum samples from patients with type 2 diabetes (T2D) with preceding gliptin medication (n = 136) or without (n = 136). Sitagliptin was the most frequently prescribed gliptin (125/136 patients). Using an ELISA assay, we showed that IgG autoantibodies against the immunodominant NC16A domain of BP180 were found in 5.9% of gliptin treated and in 6.6% of non-gliptin treated T2D patients. We found that 28% of gliptin treated patients had IgG autoantibodies recognizing the native full-length BP180 in ELISA, but among non-gliptin treated the seropositivity was even higher, at 32%. Further ELISA analysis of additional serum samples (n = 57) found no major changes in the seropositivity against BP180 during a follow-up period of about nine years. In immunoblotting, full-length BP180 was recognized by 71% of gliptin treated and 89% of non-gliptin treated T2D patients, but only by 46% of the age-and sex-matched controls. The chemokine stromal derived factor-1(SDF-1/CXCL12) is one of the major substrates of DPP4. Immunostainings showed that the expression of SDF-1 was markedly increased in the skin of BP patients, but not affected by prior gliptin treatment. We found that the use of gliptins decreased the serum level of SDF-1α in both BP and T2D patients. Our results indicate that the autoantibodies against the linear full-length BP180 are common in patients with T2D, but seropositivity is unaffected by the use of sitagliptin

Low prevalence of cancer in patients with frontotemporal lobar degeneration

Abstract Several studies have reported reduced risk of cancer in patients with Alzheimer’s disease (AD) or Parkinson’s disease. The relationship between cancer and frontotemporal lobar degeneration (FTLD) has not been previously reported. Here, our aim was to evaluate the occurrence of cancer in Finnish FTLD patients with a high proportion of C9ORF72 repeat expansion carriers in comparison to age- and sex-matched group of AD patients and control subjects classified as not cognitively impaired (NCI). The prevalence of cancer was 9.7% in FTLD, 18.7% in AD, and 17.4% in NCI (FTLD versus AD p = 0.012, FTLD versus NCI p = 0.029) groups. No differences were observed between C9ORF72 repeat expansion carriers and non-carriers inside the FTLD group. To our knowledge, this is the first study showing significantly lower prevalence of cancer in FTLD patients compared to patients with AD or NCI subjects. Our data suggest an inverse association between neurodegeneration and cancer and that FTLD-specific mechanisms may underlie the especially strong inverse association observed in this study

BP180 autoantibodies target different epitopes in multiple sclerosis or Alzheimer’s disease than in bullous pemphigoid

Abstract Neurologic patients have an increased risk for bullous pemphigoid (BP), in which autoantibodies target BP180, a cutaneous basement membrane protein also expressed in the brain. Here we show that 53.6% of sera from patients with multiple sclerosis (MS) (n = 56) had IgG reactivity against full-length BP180 in immunoblotting, while in BP180 non-collagenous 16A ELISA (n = 143), only 7.7% of MS samples studied were positive. Epitope mapping with 13 fusion proteins covering the entire BP180 polypeptide revealed that in MS and Alzheimer’s disease (AD) patients, IgG autoantibodies target regions located in the intracellular and mid-extracellular parts of BP180, but not the well-known BP epitopes located in the non-collagenous 16A domain and the distal part of extracellular domain. In indirect immunofluorescence analysis, 8.1% of MS sera recognized the cutaneous basement membrane and in full-length BP180 ELISA analysis, 7.5% MS and AD sera were positive, indicating that these autoantibodies rarely recognize BP180 in its native conformation. Thus, in MS and AD patients, BP180 autoantibodies have a different epitope profile than in patients with BP, and seldom bind to native BP180. This explains the inability of these autoantibodies to cause skin symptoms. Our results suggest that the autoantibodies against BP180 alone are not sufficient to induce BP in MS and AD patients

CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics

Abstract Objective: To examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer’s disease-related amyloid β (Aβ) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders. Methods: The study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson’s disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer’s disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ species (Aβ38, Aβ40 and Aβ42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1). Results: Patients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aβ40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aβ40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers. Conclusions: The combination of the CSF biomarkers T-tau, Aβ40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH

Peripheral inflammatory markers and clinical correlations in patients with frontotemporal lobar degeneration with and without the C9orf72 repeat expansion

Abstract In this study, our aim was to evaluate potential peripheral inflammatory changes in frontotemporal lobar degeneration (FTLD) patients carrying or not the C9orf72 repeat expansion. To this end, levels of several inflammatory markers (MCP-1, RANTES, IL-10, IL-17A, IL-12p, IFN-γ, IL-1β, IL-8, and hs-CRP) and blood cells counts in plasma and/or serum of FTLD patients (N = 98) with or without the C9orf72 repeat expansion were analyzed. In addition, we evaluated whether the analyzed peripheral inflammatory markers correlated with disease progression or distinct clinical phenotypes under the heterogenous FTLD spectrum. Elevated levels of pro-inflammatory RANTES or MCP-1 and decreased levels of anti-inflammatory IL-10 were found to associate with Parkinsonism and a more rapid disease progression, indicated by longitudinal measurements of either MMSE or ADCS-ADL decline. These findings were observed in the total cohort in general, whereas the C9orf72 repeat expansion carriers showed only slight differences in IL-10 and hemoglobin levels compared to non-carriers. Furthermore, these C9orf72 repeat expansion-associated differences were observed mostly in male subjects. The females in general showed elevated levels of several pro-inflammatory markers compared to males regardless of the C9orf72 genotype. Our study suggests that pro-inflammatory changes observed in the early symptomatic phase of FTLD are associated with distinct clinical profiles and a more rapid disease progression, and that the C9orf72 repeat expansion and gender may also affect the inflammatory profile in FTLD

Serum neurofilament light chain in FTLD:association with C9orf72, clinical phenotype, and prognosis

Abstract Objective: The aim of the present study was to compare the levels of serum neurofilament light chain (sNfL) in frontotemporal lobar degeneration (FTLD) patients of different clinical subtypes (bvFTD, PPA, and FTLD‐MND) and with or without the C9orf72 repeat expansion, and to correlate sNfL levels to disease progression, assessed by the brain atrophy rate and survival time. Methods: The sNfL levels were determined from 78 FTLD patients (C9orf72 repeat expansion carriers [n = 26] and non‐carriers [n = 52]) with Single Molecule Array (SIMOA). The progression of brain atrophy was evaluated using repeated T1‐weighted MRI scans and the survival time from medical records. Results: In the total FTLD cohort, sNfL levels were significantly higher in C9orf72 repeat expansion carriers compared to non‐carriers. Considering clinical phenotypes, sNfL levels were higher in the C9orf72 repeat expansion carriers than in the non‐carriers in bvFTD and PPA groups. Furthermore, sNfL levels were the highest in the FTLD‐MND group (median 105 pg/mL) and the lowest in the bvFTD group (median 27 pg/mL). Higher sNfL levels significantly correlated with frontal cortical atrophy rate and subcortical grey matter atrophy rate. The higher sNfL levels also associated with shorter survival time. Interpretation: Our results indicate that the C9orf72 repeat expansion carriers show elevated sNFL levels compared to non‐carriers and that the levels differ among different clinical phenotypes of FTLD. Higher sNfL levels correlated with a shorter survival time and cortical and subcortical atrophy rates. Thus, sNfL could prove as a potential prognostic biomarker in FTLD

Cerebrospinal fluid and MRI biomarkers in neurodegenerative diseases:a retrospective memory clinic-based study

Abstract Background: Cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers of neurodegenerative diseases are relatively sensitive and specific in highly curated research cohorts, but proper validation for clinical use is mostly missing. Objective: We studied these biomarkers in a novel memory clinic cohort with a variety of different neurodegenerative diseases. Methods: This study consisted of 191 patients with subjective or objective cognitive impairment who underwent neurological, CSF biomarker (Aβ42, p-tau, and tau) and T1-weighted MRI examinations at Kuopio University Hospital. We assessed CSF and imaging biomarkers, including structural MRI focused on volumetric and cortical thickness analyses, across groups stratified based on different clinical diagnoses, including Alzheimer’s disease (AD), frontotemporal dementia, dementia with Lewy bodies, Parkinson’s disease, vascular dementia, and mild cognitive impairment (MCI), and subjects with no evidence of neurodegenerative disease underlying the cognitive symptoms. Imaging biomarkers were also studied by profiling subjects according to the novel amyloid, tau, and, neurodegeneration (AT(N)) classification. Results: Numerous imaging variables differed by clinical diagnosis, including hippocampal, amygdalar and inferior lateral ventricular volumes and entorhinal, lingual, inferior parietal and isthmus cingulate cortical thicknesses, at a false discovery rate (FDR)-corrected threshold for significance (analysis of covariance; p < 0.005). In volumetric comparisons by AT(N) profile, hippocampal volume significantly differed (p < 0.001) between patients with normal AD biomarkers and patients with amyloid pathology. Conclusion: Our analysis suggests that CSF and MRI biomarkers function well also in clinical practice across multiple clinical diagnostic groups in addition to AD, MCI, and cognitively normal groups

Cerebrospinal fluid biomarkers that reflect clinical symptoms in idiopathic normal pressure hydrocephalus patients

Abstract Background: The relationship between cerebrospinal fluid (CSF) biomarkers and the clinical features of idiopathic normal pressure hydrocephalus (iNPH) has been inconclusive. We aimed to evaluate CSF biomarkers reflecting Alzheimer’s disease (AD)-related amyloid β (Aβ) aggregation, tau pathology, neuroinflammation and axonal degeneration in relation to the clinical features of pre- and post-shunt surgery in iNPH patients. Methods: Mini Mental State Examination (MMSE) scores and gait velocity were evaluated pre- and postoperatively in cohorts of 65 Finnish (FIN) and 82 Swedish (SWE) iNPH patients. Lumbar CSF samples were obtained prior to shunt surgery and analysed for soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ); amyloid-β isoforms of 42, 40 and 38 (Aβ42, Aβ40, Aβ38); total tau (T-tau); phosphorylated tau (P-tau181); neurofilament light (NfL) and monocyte chemoattractant protein 1 (MCP1). Results: Preoperative patient characteristics showed no significant differences between patients in the FIN and SWE cohorts. Patients in both cohorts had significantly improved gait velocity after shunt surgery (p < 0.0001). Low CSF T-tau and absence of apolipoprotein E ε4 predicted over 20% gait improvement postoperatively (p = 0.043 and p = 0.008). Preoperative CSF T-tau, P-tau181 and NfL correlated negatively with MMSE scores both pre- (p < 0.01) and post-surgery (p < 0.01). Furthermore, T-tau, NfL and Aβ₄₂ correlated with MMSE outcomes (p < 0.05). Low preoperative CSF P-tau181 (p = 0.001) and T-tau with NfL (p < 0.001 and p = 0.049) best predicted pre- and postoperative MMSE scores greater than or equal to 26. Conclusions: CSF biomarkers of neurodegeneration appeared to correlate with pre- and postoperative cognition, providing a window into neuropathological processes. In addition, preoperative CSF neurodegeneration biomarkers may have potential in the prediction of gait and cognitive outcomes after shunt surgery

Alterations in mitochondria-endoplasmic reticulum connectivity in human brain biopsies from idiopathic normal pressure hydrocephalus patients

Abstract Idiopathic normal pressure hydrocephalus (iNPH) is a neuropathology with unknown cause characterised by gait impairment, cognitive decline and ventriculomegaly. These patients often present comorbidity with Alzheimer’s disease (AD), including AD pathological hallmarks such as amyloid plaques mainly consisting of amyloid β-peptide and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Even though some of the molecular mechanisms behind AD are well described, little is known about iNPH. Several studies have reported that mitochondria-endoplasmic reticulum contact sites (MERCS) regulate amyloid β-peptide metabolism and conversely that amyloid β-peptide can influence the number of MERCS. MERCS have also been shown to be dysregulated in several neurological pathologies including AD. In this study we have used transmission electron microscopy and show, for the first time, several mitochondria contact sites including MERCS in human brain biopsies. These unique human brain samples were obtained during neurosurgery from 14 patients that suffer from iNPH. Three of these 14 patients presented comorbidities with other dementias: one patient with AD, one with AD and vascular dementia and one patient with Lewy body dementia. Furthermore, we report that the numbers of MERCS are increased in biopsies obtained from patients diagnosed with dementia. Moreover, the presence of both amyloid plaques and neurofibrillary tangles correlates with decreased contact length between endoplasmic reticulum and mitochondria, while amyloid plaques alone do not seem to affect endoplasmic reticulum-mitochondria apposition. Interestingly, we report a significant positive correlation between the number of MERCS and ventricular cerebrospinal fluid amyloid β-peptide levels, as well as with increasing age of iNPH patients