alpha-synuclein and Frontotemporal-Dementia

Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer's disease (AD), Parkinson's disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. This widely accepted perspective arose from the prion hypothesis, which resulted from investigations on scrapie, a common transmissible disease of sheep and goats. The prion hypothesis argued that the causative infectious agent of scrapie was a novel proteinaceous pathogen devoid of functional nucleic acids and distinct from viruses, viroids, and bacteria. At the time, it seemed impossible that an infectious agent like the one causing scrapie could replicate and exist as diverse microbiological strains without nucleic acids. However, aggregates of a misfolded host-encoded protein, designated the prion protein (PrP), were shown to be the cause of scrapie as well as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS), which are similar NDs in humans. This review discusses historical research on diseases caused by PrP misfolding, emphasizing principles of pathogenesis that were later found to be core features of other NDs. For example, the discovery that familial prion diseases can be caused by mutations in PrP was important for understanding prion replication and disease susceptibility not only for rare PrP diseases but also for far more common NDs involving other proteins. We compare diseases caused by misfolding and aggregation of APP-derived Aβ peptides, tau, and α-synuclein with PrP prion disorders and argue for the classification of NDs caused by misfolding of these proteins as prion diseases. Deciphering the molecular pathogenesis of NDs as prion-mediated has provided new approaches for finding therapies for these intractable, invariably fatal disorders and has revolutionized the field.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Animals; Creutzfeldt-Jakob Syndrome; Frontotemporal Dementia; Gene Expression; Gerstmann-Straussler-Scheinker Disease; Humans; Mice; Mutation; Parkinson Disease; Prion Proteins; Prions; Protein Folding; Scrapie; Sheep; tau Proteins

Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Besides the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study was to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from The Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-β, and α-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local false discovery rate threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-β (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-β burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of α-synuclein co-pathology in the substantia nigra correlated with disinhibition (R = 0.24), tau pathology in the substantia nigra correlated with depression (R = 0.25) and in the locus coeruleus with both depression and perseverative/compulsive behaviour (R = 0.26 and R = 0.32). The quantitative assessment of TDP-43 in the granular layer validated the higher burden of TDP-43 pathology in brain donors with hallucinations compared to those without hallucinations (P = 0.007). Our results show that psychiatric symptoms of FTLD are linked to subcort

Topics: alpha-Synuclein; Amyloid beta-Peptides; Brain; DNA-Binding Proteins; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Hallucinations; Humans; Pick Disease of the Brain; tau Proteins

Increasing evidence supports the use of plasma biomarkers of neurodegeneration and neuroinflammation to screen and diagnose patients with dementia. However, confirmatory studies are required to demonstrate their usefulness in the clinical setting.. We evaluated plasma and cerebrospinal fluid (CSF) samples from consecutive patients with frontotemporal dementia (FTD) (n = 59), progressive supranuclear palsy (PSP) (n = 31), corticobasal syndrome (CBS) (n = 29), dementia with Lewy bodies (DLB) (n = 49), Alzheimer disease (AD) (n = 97), and suspected non-AD physiopathology (n = 51), as well as plasma samples from 60 healthy controls (HC). We measured neurofilament light chain (NfL), phospho-tau181 (p-tau181), and glial fibrillary acid protein (GFAP) using Simoa (all plasma biomarkers and CSF GFAP), CLEIA (CSF p-tau181), and ELISA (CSF NfL) assays. Additionally, we stratified patients according to the A/T/N classification scheme and the CSF α-synuclein real-time quaking-induced conversion assay (RT-QuIC) results.. We found good correlations between CSF and plasma biomarkers for NfL (rho = 0.668, p < 0.001) and p-tau181 (rho = 0.619, p < 0.001). Plasma NfL was significantly higher in disease groups than in HC and showed a greater increase in FTD than in AD [44.9 (28.1-68.6) vs. 21.9 (17.0-27.9) pg/ml, p < 0.001]. Conversely, plasma p-tau181 and GFAP levels were significantly higher in AD than in FTD [3.2 (2.4-4.3) vs. 1.1 (0.7-1.6) pg/ml, p < 0.001; 404.7 (279.7-503.0) vs. 198.2 (143.9-316.8) pg/ml, p < 0.001]. GFAP also allowed discriminating disease groups from HC. In the distinction between FTD and AD, plasma p-tau181 showed better accuracy (AUC 0.964) than NfL (AUC 0.791) and GFAP (AUC 0.818). In DLB and CBS, CSF amyloid positive (A+) subjects had higher plasma p-tau181 and GFAP levels than A- individuals. CSF RT-QuIC showed positive α-synuclein seeding activity in 96% DLB and 15% AD patients with no differences in plasma biomarker levels in those stratified by RT-QuIC result.. In a single-center clinical cohort, we confirm the high diagnostic value of plasma p-tau181 for distinguishing FTD from AD and plasma NfL for discriminating degenerative dementias from HC. Plasma GFAP alone differentiates AD from FTD and neurodegenerative dementias from HC but with lower accuracy than p-tau181 and NfL. In CBS and DLB, plasma p-tau181 and GFAP levels are significantly influenced by beta-amyloid pathology.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; Frontotemporal Dementia; Glial Fibrillary Acidic Protein; Humans; tau Proteins

Amyloid plaques and tau tangles are pathological hallmarks of Alzheimer's disease (AD). Parkinson's disease (PD) results from the accumulation of α-synuclein. TAR DNA-binding protein (TDP-43) and total tau protein (T-Tau) play roles in FTD pathology. All of the pathological evidence was found in the biopsy. However, it is impossible to perform stein examinations in clinical practice. Assays of biomarkers in plasma would be convenient. It would be better to investigate the combinations of various biomarkers in AD, PD and FTD. Ninety-one subjects without neurodegenerative diseases, 76 patients with amnesic mild cognitive impairment (aMCI) or AD dementia, combined as AD family, were enrolled. One hundred and nine PD patients with normal cognition (PD-NC) or dementia (PDD), combined as PD family, were enrolled. Twenty-five FTD patients were enrolled for assays of plasma amyloid β 1-40 (Aβ

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; DNA-Binding Proteins; Frontotemporal Dementia; Humans; Parkinson Disease; Peptide Fragments; tau Proteins

Objective diagnostic biomarkers are needed to support a clinical diagnosis.. To analyze markers in various neurodegenerative disorders to identify diagnostic biomarker candidates for mainly α-synuclein (aSyn)-related disorders (ASRD) in serum and/or cerebrospinal fluid (CSF).. Upon initial testing of commercially available kits or published protocols for the quantification of the candidate markers, assays for the following were selected: total and phosphorylated aSyn (pS129aSyn), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), tau protein (tau), ubiquitin C-terminal hydrolase L1 (UCHL-1), glial fibrillary acidic protein (GFAP), calcium-binding protein B (S100B), soluble triggering receptor expressed on myeloid cells 2 (sTREM-2), and chitinase-3-like protein 1 (YKL-40). The cohort comprised participants with Parkinson's disease (PD, n = 151), multiple system atrophy (MSA, n = 17), dementia with Lewy bodies (DLB, n = 45), tau protein-related neurodegenerative disorders (n = 80, comprising patients with progressive supranuclear palsy (PSP, n = 38), corticobasal syndrome (CBS, n = 16), Alzheimer's disease (AD, n = 11), and frontotemporal degeneration/amyotrophic lateral sclerosis (FTD/ALS, n = 15), as well as healthy controls (HC, n = 20). Receiver operating curves (ROC) with area under the curves (AUC) are given for each marker.. CSF total aSyn was decreased. NfL, pNfH, UCHL-1, GFAP, S100B, and sTREM-2 were increased in patients with neurodegenerative disease versus HC (P < 0.05). As expected, some of the markers were highest in AD (i.e., UCHL-1, GFAP, S100B, sTREM-2, YKL-40). Within ASRD, CSF NfL levels were higher in MSA than PD and DLB (P < 0.05). Comparing PD to HC, interesting serum markers were S100B (AUC: 0.86), sTREM2 (AUC: 0.87), and NfL (AUC: 0.78). CSF S100B and serum GFAP were highest in DLB.. Levels of most marker candidates tested in serum and CSF significantly differed between disease groups and HC. In the stratification of PD versus other tau- or aSyn-related conditions, CSF NfL levels best discriminated PD and MSA. CSF S100B and serum GFAP best discriminated PD and DLB. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Topics: alpha-Synuclein; Amyotrophic Lateral Sclerosis; Biomarkers; Frontotemporal Dementia; Humans; Multiple System Atrophy; tau Proteins

In Alzheimer's disease (AD), tau, a microtubule-associated protein (MAP), becomes hyperphosphorylated, aggregates, and accumulates in the somato-dendritic compartment of neurons. In parallel to its intracellular accumulation in AD, tau is also released in the extracellular space, as revealed by its increased presence in cerebrospinal fluid (CSF). Consistent with this, recent studies, including ours, have reported that neurons secrete tau, and several therapeutic strategies aim to prevent the intracellular tau accumulation. Previously, we reported that late endosomes were implicated in tau secretion. Here, we explore the possibility of preventing intracellular tau accumulation by increasing tau secretion. Using neuronal models, we investigated whether overexpression of the vesicle-associated membrane protein 8 (VAMP8), an R-SNARE found on late endosomes, could increase tau secretion. The overexpression of VAMP8 significantly increased tau secretion, decreasing its intracellular levels in the neuroblastoma (N2a) cell line. Increased tau secretion by VAMP8 was also observed in murine hippocampal slices. The intracellular reduction of tau by VAMP8 overexpression correlated to a decrease of acetylated tubulin induced by tau overexpression in N2a cells. VAMP8 staining was preferentially found on late endosomes in N2a cells. Using total internal reflection fluorescence (TIRF) microscopy, the fusion of VAMP8-positive vesicles with the plasma membrane was correlated to the depletion of tau in the cytoplasm. Finally, overexpression of VAMP8 reduced the intracellular accumulation of tau mutants linked to frontotemporal dementia with parkinsonism and α-synuclein by increasing their secretion. Collectively, the present data indicate that VAMP8 could be used to increase tau and α-synuclein clearance to prevent their intracellular accumulation.

Topics: Acetylation; alpha-Synuclein; Animals; Cell Line, Tumor; Cell Membrane; Down-Regulation; Endosomes; Frontotemporal Dementia; Hippocampus; Mice; Microscopy, Fluorescence; Mutagenesis; Neurons; Phosphorylation; R-SNARE Proteins; rab5 GTP-Binding Proteins; Secretory Vesicles; tau Proteins; Tubulin

To investigate whether (1) phosphorylated α-synuclein (p-syn) deposits in skin nerves could be useful in differentiating dementia with Lewy bodies (DLB) from different forms of dementia and (2) small fiber neuropathy (SFN) is associated with DLB.. We studied 18 well-characterized patients with DLB (11 with autonomic dysfunction), 23 patients with nonsynucleinopathy dementia (NSD; 13 with young-onset Alzheimer disease dementia, 6 frontotemporal dementia, and 4 vascular dementia), and 25 healthy controls. All participants underwent skin biopsies from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of p-syn, considered the pathologic form of α-synuclein.. No p-syn was detected in any skin sample in patients with NSD and controls but was found in all patients with DLB. SFN was found in patients with DLB and the autonomic denervation of skin was more severe in patients with autonomic dysfunctions.. (1) In autonomic skin nerves, p-syn is a sensitive biomarker for DLB diagnosis, helping to differentiate DLB from other forms of dementia, although this needs to be confirmed in a larger, more representative sample; and (2) skin autonomic neuropathy is part of the DLB pathology and may contribute to autonomic symptoms.. This study provides Class III evidence that p-syn in skin nerve fibers on skin biopsy accurately distinguishes DLB from other forms of dementia.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Autonomic Pathways; Biomarkers; Dementia, Vascular; Diagnosis, Differential; Female; Frontotemporal Dementia; Humans; Leg; Lewy Body Disease; Male; Microscopy, Confocal; Middle Aged; Phosphorylation; Skin

The p.A53T point mutation in SNCA, the alpha-synuclein gene, has been linked to a rare dominant form of Parkinson's disease (PD).. Here, we describe two apparently unrelated cases of p.A53T (G209A) SNCA mutation carriers with an atypical initial manifestation and disease course. Moreover, cerebrospinal fluid (CSF) levels of tau, p-tau and amyloid Aβ42 were measured in these patients and in an additional cohort of 5 symptomatic and 2 asymptomatic p.A53T carriers without an initial manifestation of dementia.. Both patients exhibited an early onset frontal-dysexecutive dysfunction with apathy and emotional blunting resembling frontotemporal dementia (FTD). Motor symptoms typical of Parkinson's disease appeared only later in the disease course and were less prominent than cognitive ones, which included language impairment. Autonomic dysfunction and myoclonus also emerged in a more advanced disease stage. In both patients, Brain Magnetic Resonance Imaging showed fronto-temporo-parietal atrophy, and CSF analysis showed elevated tau protein levels. In contrast, tau protein levels were normal in a cohort of 7 other p.A53T mutation carriers (5 symptomatic/2 asymptomatic). A screen of Greek patients presenting with frontotemporal dementia failed to identify any additional subjects with the p.A53T SNCA mutation.. Although cognitive decline has been recognized as a feature of the full-blown clinical picture of p.A53T related parkinsonism, a predominant frontotemporal dementia-like phenotype at presentation has not been previously described. This may represent a subtype of this disorder, with distinctive clinical, imaging and CSF biochemical characteristics, in which additional genetic or epigenetic factors may play a role.

Topics: Adult; alpha-Synuclein; Frontotemporal Dementia; Heterozygote; Humans; Male; Middle Aged; Mutation, Missense; Pedigree; Phenotype

Several clinical studies point to a high prevalence of psychotic symptoms in frontotemporal dementia associated with C9ORF72 mutations, but clinicopathological studies addressing the association between C9ORF72 mutations and delusions are lacking.. Seventeen patients with pathologically proven frontotemporal lobar degeneration (FTLD) associated with C9ORF72 mutations were identified from Neurodegenerative Disease Brain Bank. Of the 17 cases with C9ORF72 mutation, 4 exhibited well-defined delusions. The clinical history, neurological examination, neuropsychological testing, neuroimaging analysis, and postmortem assessment of the patients with delusions were evaluated and compared with the other cases.. The content of the delusions was mixed including persecution, infidelity, and grandiosity. All cases showed parkinsonism; voxel-based morphometry analysis showed greater precuneus atrophy in patients with delusions than those without delusions. All 4 had unclassifiable FTLD with TAR DNA-binding protein inclusions, with characteristics of both type A and type B. Three cases had additional τ pathology and another had α-synuclein pathology.. C9ORF72 carriers with well-defined delusions likely associated with additional pathologies and parietal atrophy in neuroimaging. Patients presenting with middle-aged onset of delusions should be screened for C9ORF72 mutations, especially if family history and parkinsonism are present.

Topics: Adult; Aged; alpha-Synuclein; Atrophy; Autopsy; Delusions; DNA-Binding Proteins; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Heterozygote; Humans; Male; Middle Aged; Mutation; Neuroimaging; Neurologic Examination; Neuropsychological Tests; Open Reading Frames; Parietal Lobe; Parkinsonian Disorders; tau Proteins

α-Synuclein (SNCA) locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown.. To report a novel family carrying a heterozygous 6.4 Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia and late-onset pallidopyramidal syndromes and study phenotype-genotype correlations in SNCA locus duplications.. We report the clinical and neuropathologic features of a family carrying a 6.4 Mb duplication of the SNCA locus. To identify candidate disease modifiers, we completed a genetic analysis of the family and conducted statistical analysis on previously published cases carrying SNCA locus duplications using regression modeling with robust standard errors to account for clustering at the family level.. We assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role.. We identified a large 6.4 Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive α-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of Parkinson disease-related risk factors and the disease-predisposing H1/H1 microtubule-associated protein tau haplotype. Statistical analysis of previously published cases suggested there is a trend toward increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios from the univariable analyses were 1.17 (95% CI, 0.81-1.68) and 1.34 (95% CI, 0.78-2.31), respectively. Sex was significantly associated with both disease risk and severity; men compared with women had increased disease risk and severity and the corresponding odds ratios from the univariable analyses were 8.36 (95% CI, 1.97-35.42) and 5.55 (95% CI, 1.39-22.22), respectively.. These findings further expand the phenotypic spectrum of SNCA locus duplications. Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors. Identification of disease modifiers accounting for the substantial phenotypic heterogeneity of patients with SNCA locus duplications could provide insight into molecular events involved in α-synuclein aggregation.

Topics: Age of Onset; alpha-Synuclein; Brain; Female; Frontotemporal Dementia; Gene Dosage; Gene Duplication; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Humans; Microsatellite Repeats; Middle Aged; Odds Ratio; Parkinsonian Disorders; Pedigree; Penetrance; Risk Factors; Severity of Illness Index; Sex Factors

To determine the histopathologic bases for the observed incidence of parkinsonism in families with C9ORF72 expansions, which typically cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia.. DNA was extracted from 377 brains with the histopathologic diagnosis of idiopathic Parkinson disease or related disorders and analyzed for C9ORF72 expansions. α-Synuclein and p62 immunohistochemistry of the substantia nigra (SN) was undertaken in brains of 17 ALS cases with (C9ORF72+) and 51 without (C9ORF72-) the C9ORF72 expansion.. Only 1 of 338 cases with pathologically confirmed idiopathic Parkinson disease had a C9ORF72 expansion. Similarly, only 1 of 17 C9ORF72+ brains displayed features suggestive of α-synucleinopathy. In contrast, p62-positive, TDP-43-negative neuronal cytoplasmic inclusions within the SN were considerably more frequent in C9ORF72+ brain tissue than in the C9ORF72- brains (p = 0.005). Furthermore, there was a more marked loss of dopaminergic neurons in the SN of C9ORF72+ ALS brains than C9ORF72- ALS brains (p = 0.029).. SN involvement is common in C9ORF72+ ALS but can be clearly distinguished from Parkinson disease-related mechanisms by the presence of p62-positive inclusions and the absence of α-synuclein-positive Lewy bodies or Lewy neurites.

Topics: alpha-Synuclein; Amyotrophic Lateral Sclerosis; C9orf72 Protein; DNA Repeat Expansion; DNA-Binding Proteins; Female; Frontotemporal Dementia; Humans; Inclusion Bodies; Male; Middle Aged; Neurons; Parkinson Disease; Proteins

Patients exhibiting the classic manifestations of parkinsonism - tremors, rigidity, postural instability, slowed movements and, sometimes, sleep disturbances and depression - may also display severe cognitive disturbances. All of these particular motoric and behavioral symptoms may arise from Parkinson's disease [PD] per se, but they can also characterize Lewy Body dementia [LBD] or concurrent Parkinson's and Alzheimer's diseases [PD & AD]. Abnormalities of both movement and cognition are also observed in numerous other neurologic diseases, for example Huntington's Disease and the frontotemporal dementia. Distinguishing among these diseases in an individual patient is important in "personalizing" his or her mode of treatment, since an agent that is often highly effective in one of the diagnoses (e.g., L-dopa or muscarinic antagonists in PD) might be ineffective or even damaging in one of the others. That such personalization, based on genetic, biochemical, and imaging-based biomarkers, is feasible is suggested by the numerous genetic abnormalities already discovered in patients with parkinsonism, Alzheimer's disease and Huntington's disease (HD) and by the variety of regional and temporal patterns that these diseases can produce, as shown using imaging techniques.

Topics: alpha-Synuclein; Alzheimer Disease; Antiparkinson Agents; Biomarkers; Cognition; Cognition Disorders; Diagnosis, Differential; Diagnostic Imaging; Frontotemporal Dementia; Genetic Markers; Genetic Testing; Glucosylceramidase; Humans; Huntington Disease; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Levodopa; Lewy Body Disease; Mutation; Parkinson Disease; Precision Medicine; Protein Serine-Threonine Kinases

The neuropeptide oxytocin, produced in the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus, is now understood to function as a neurotransmitter critical for various aspects of social cognition and pro-social behaviour. While patients with Frontotemporal dementia (FTD) display prominent and progressive deficits in such social behaviours, the integrity of these nuclei in FTD is not known.. We conducted a quantitative neuropathologic examination of the SON and PVN from patients with FTLD with TDP-43 proteinopathy, Alzheimer's disease, Lewy body disease and controls to determine whether significant pathologic changes or neuronal loss may contribute to the striking behavioural symptoms of FTD.. Contrary to predictions, we found both nuclei to be free of significant pathologic change (TDP-43) in FTLD. In contrast, tau related pathology was found in the PVN in Alzheimer's disease, and alpha-synuclein pathology in the SON in patients with Lewy body dementia.. These results indicate that the SON and PVN are resistant to FTLD TDP-43 pathology. They also support prior suggestions that the SON is resistant to Alzheimer's disease (AD) related pathology, and extend this to demonstrate SON susceptibility to alpha-synuclein pathology in patients with Lewy body dementia.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; DNA-Binding Proteins; Female; Frontotemporal Dementia; Humans; Lewy Body Disease; Male; Middle Aged; Neurons; Paraventricular Hypothalamic Nucleus; Supraoptic Nucleus; tau Proteins

Olfactory dysfunction is a frequent and early feature of patients with neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) and is very uncommon in patients with frontotemporal dementia (FTD). Mechanisms underlying this clinical manifestation are poorly understood but the premature deposition of protein aggregates in the olfactory bulb (OB) of these patients might impair its synaptic organization, thus accounting for the smell deficits. Tau, β-amyloid and alpha-synuclein deposits were studied in 41 human OBs with histological diagnosis of AD (n = 24), PD (n = 6), FTD (n = 11) and compared with the OB of 15 control subjects. Tau pathology was present in the OB of all patients, irrespective of the histological diagnosis, while β-amyloid and alpha-synuclein protein deposit were frequently observed in AD and PD, respectively. Using stereological techniques we found an increased number of dopaminergic periglomerular neurons in the OB of AD, PD and FTD patients when compared with age-matched controls. Moreover, volumetric measurements of OBs showed a significant decrease only in AD patients, while the OB volume was similar to control in PD or FTD cases. The increased dopaminergic tone created in the OBs of these patients could reflect a compensatory mechanism created by the early degeneration of other neurotransmitter systems and might contribute to the olfactory dysfunction exhibited by patients with neurodegenerative disorders.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autopsy; Case-Control Studies; Dopamine; Female; Frontotemporal Dementia; Humans; Male; Olfactory Bulb; Parkinson Disease; tau Proteins

There is increasing evidence that in Lewy body-associated dementias (encompassing Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB)), the adaptive immune system is altered and the degenerative process includes glial cells in addition to neuronal structures. We therefore aimed to determine levels of autoantibodies against amyloid and glial-derived structures in these dementia types. Using a newly developed Enzyme-linked immunosorbent assay (ELISA), we measured levels of IgG autoantibodies against neuronal and glial structures in serum and cerebrospinal fluid of a total of 91 subjects (13 PDD, 14 DLB, 11 Alzheimer's disease (AD), 11 frontotemporal dementia (FTD), 11 vascular dementia patients (VaD), and 31 healthy controls). Autoantibody levels against α-synuclein, amyloid-β₄₂ (Aβ₄₂), myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), and S100B were determined. In all groups, autoantibody levels were about three magnitudes higher in serum than in CSF. Serum autoantibody levels against α-synuclein, Aβ₄₂, MOG, MBP, and S100B were higher in PDD/DLB compared to tau-associated dementias (AD, FTD), VaD, and controls, respectively, with most of them reaching highly significant p-values. In cerebrospinal fluid (CSF), levels of antibodies against oligodendrocyte-derived antigens (MOG, MBP) were significantly increased in PDD/DLB. Increased levels of autoantibodies against both neuronal- and glial-derived antigens in serum and CSF of Lewy body-associated dementias indicate an altered activity of the adaptive immune system in these dementia types. The potential of neural-derived IgG autoantibodies as part of a biomarker panel for the diagnosis of Lewy body-associated dementias should be further evaluated.

Topics: Aged; alpha-Synuclein; Alzheimer Disease; Amyloid beta-Peptides; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Female; Frontotemporal Dementia; Humans; Lewy Body Disease; Male; Myelin Basic Protein; Myelin Proteins; Myelin-Oligodendrocyte Glycoprotein; Nerve Growth Factors; Peptide Fragments; S100 Calcium Binding Protein beta Subunit; S100 Proteins