Convergence of pathology in dementia with Lewy bodies and Alzheimer’s disease: a role for the novel interaction of alpha-synuclein and presenilin 1 in disease

We studied the diagnostic value of CSF Aβ42/tau versus low Aβ1–42% and high Aβ1–40ox% levels for differential diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), respectively. CSF of 45 patients with AD, 15 with DLB, 21 with Parkinson's disease dementia (PDD), and 40 nondemented disease controls (NDC) was analyzed by Aβ-SDS-PAGE/immunoblot and ELISAs (Aβ42 and tau). Aβ42/tau lacked specificity in discriminating AD from DLB and PDD. Best discriminating biomarkers were Aβ1–42% and Aβ1–40ox% for AD and DLB, respectively. AD and DLB could be differentiated by both Aβ1–42% and Aβ1–40ox% with an accuracy of 80% at minimum. Thus, we consider Aβ1–42% and Aβ1–40ox% to be useful biomarkers for AD and DLB, respectively. We propose further studies on the integration of Aβ1–42% and Aβ1–40ox% into conventional assay formats. Moreover, future studies should investigate the combination of Aβ1–40ox% and CSF alpha-synuclein for the diagnosis of DLB.

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Total alpha-synuclein assay in cerebrospinal fluid is of interest in the differential diagnosis between Alzheimer's disease and dementia with Lewy bodies from the prodromal stage

10.21203/rs.3.rs-18905/v2 ◽

2020 ◽

Author(s):

Olivier BOUSIGES ◽

Nathalie Philippi ◽

Thomas Lavaux ◽

Armand Perret-Liaudet ◽

Ingolf Lachmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Differential Diagnosis ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Enzyme Linked Immunosorbent Assay ◽

Prodromal Stage ◽

Significant Difference

Abstract Background: Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage.Methods: All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace, France, by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD), 32 AD patients at the demented stage (AD-d) and 13 patients with mixed pathology (AD+DLB). CSF levels of total alpha-synuclein were assessed using a commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer’s biomarkers (t-Tau, P-Tau, Aβ42 and Aβ40) were also measured.Results: The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels were significantly higher in AD patients than in DLB patients. Interestingly, the levels appeared to be altered from the prodromal stage in both AD and DLB. Furthermore, alpha-synuclein levels were elevated not only in AD patients with a typical “Alzheimer” profile (i.e. 2 or 3 pathological biomarkers) but also in AD patients with an atypical “Alzheimer” profile (i.e. one or no pathological biomarkers).Conclusions: The modification of total alpha-synuclein levels in the CSF of patients occurs early, from the prodromal stage. Moreover, alpha-synuclein assay appears to be of particular interest in the differential diagnosis of AD in cases where the Alzheimer biomarkers do not have a typical profile of the disease, i.e. when there is only one or no pathological biomarkers.Trial registration: ClinicalTrials.gov, (AlphaLewyMa, Identifier: NCT01876459)

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Alpha-synuclein seeds in olfactory mucosa and cerebrospinal fluid of patients with dementia with Lewy bodies

Brain Communications ◽

10.1093/braincomms/fcab045 ◽

2021 ◽

Vol 3 (2) ◽

Author(s):

Daniela Perra ◽

Matilde Bongianni ◽

Giovanni Novi ◽

Francesco Janes ◽

Valentina Bessi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Real Time ◽

Clinical Diagnosis ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Olfactory Mucosa ◽

Confirmatory Test ◽

Mixed Dementia

Abstract In patients with suspected dementia with Lewy bodies, the detection of the disease-associated α-synuclein in easily accessible tissues amenable to be collected using minimally invasive procedures remains a major diagnostic challenge. This approach has the potential to take advantage of modern molecular assays for the diagnosis of α–synucleinopathy and, in turn, to optimize the recruitment and selection of patients in clinical trials, using drugs directed at counteracting α-synuclein aggregation. In this study, we explored the diagnostic accuracy of α-synuclein real-time quaking-induced conversion assay by testing olfactory mucosa and CSF in patients with a clinical diagnosis of probable (n = 32) or prodromal (n = 5) dementia with Lewy bodies or mixed degenerative dementia (dementia with Lewy bodies/Alzheimer’s disease) (n = 6). Thirty-eight patients with non-α-synuclein-related neurodegenerative and non-neurodegenerative disorders, including Alzheimer’s disease (n = 10), sporadic Creutzfeldt–Jakob disease (n = 10), progressive supranuclear palsy (n = 8), corticobasal syndrome (n = 1), fronto-temporal dementia (n = 3) and other neurological conditions (n = 6) were also included, as controls. All 81 patients underwent olfactory swabbing while CSF was obtained in 48 participants. At the initial blinded screening of olfactory mucosa samples, 38 out of 81 resulted positive while CSF was positive in 19 samples out of 48 analysed. After unblinding of the results, 27 positive olfactory mucosa were assigned to patients with probable dementia with Lewy bodies, five with prodromal dementia with Lewy bodies and three to patients with mixed dementia, as opposed to three out 38 controls. Corresponding results of CSF testing disclosed 10 out 10 positive samples in patients with probable dementia with Lewy bodies and six out of six with mixed dementia, in addition to three out of 32 for controls. The accuracy among results of real-time quaking-induced conversion assays and clinical diagnoses was 86.4% in the case of olfactory mucosa and 93.8% for CSF. For the first time, we showed that α-synuclein real-time quaking-induced conversion assay detects α-synuclein aggregates in olfactory mucosa of patients with dementia with Lewy bodies and with mixed dementia. Additionally, we provided preliminary evidence that the combined testing of olfactory mucosa and CSF raised the concordance with clinical diagnosis potentially to 100%. Our results suggest that nasal swabbing might be considered as a first-line screening procedure in patients with a diagnosis of suspected dementia with Lewy bodies followed by CSF analysis, as a confirmatory test, when the result in the olfactory mucosa is incongruent with the initial clinical diagnosis.

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Differential diagnostic value of total alpha-synuclein assay in the cerebrospinal fluid between Alzheimer's disease and dementia with Lewy bodies from the prodromal stage

10.21203/rs.3.rs-18905/v5 ◽

2020 ◽

Author(s):

Olivier BOUSIGES ◽

Nathalie Philippi ◽

Thomas Lavaux ◽

Armand Perret-Liaudet ◽

Ingolf Lachmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Differential Diagnosis ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Enzyme Linked Immunosorbent Assay ◽

Prodromal Stage ◽

Discriminating Power

Abstract Background: Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage.Methods: All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace, France, by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD), 32 AD patients at the demented stage (AD-d) and 13 patients with mixed pathology (AD+DLB). CSF levels of total alpha-synuclein were assessed using a commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer’s biomarkers (t-Tau, P-Tau, Aβ42 and Aβ40) were also measured.Results: The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels were significantly higher in AD patients than in DLB patients. However, the ROC curves show a moderate discriminating power between AD and DLB (AUC = 0.78) which does not improve the discriminating power of the combination of Alzheimer biomarkers (AUC = 0.95 with or without alpha-synuclein). Interestingly, the levels appeared to be altered from the prodromal stage in both AD and DLB.Conclusions: The modification of total alpha-synuclein levels in the CSF of patients occurs early, from the prodromal stage. The adding of alpha-synuclein total to the combination of Alzheimer’s biomarker does not improve the differential diagnosis between AD and DLB.Trial registration: ClinicalTrials.gov, (AlphaLewyMa, Identifier: NCT01876459)

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Motor Dysfunction Questionnaire and Dopamine Transporter Imaging Composite Scale Improve Differentiating Dementia With Lewy Bodies From Alzheimer's Disease With Motor Dysfunction

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.709215 ◽

2021 ◽

Vol 13 ◽

Author(s):

Pai-Yi Chiu ◽

Cheng-Yu Wei ◽

Guang-Uei Hung ◽

Shey-Lin Wu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dopamine Transporter ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Motor Dysfunction ◽

Dual Model ◽

The Novel ◽

Composite Scale ◽

Cutoff Scores

Objective: Characteristic parkinsonism is the major comorbidity of dementia with Lewy bodies (DLB). We aimed to differentiate DLB from Alzheimer's disease (AD) with motor dysfunction using a composite scale with a characteristic motor dysfunction questionnaire (MDQ) and dopamine transporter (DAT) imaging. It could help detect DLB easily in healthcare settings without movement disorder specialists.Methods: This is a two-phase study. In the design phase, seven questions were selected and composed of a novel MDQ. In the test phase, all participants with DLB, AD, or non-dementia (ND) control completed dementia and parkinsonism survey, the novel designed questionnaire, DAT imaging, and composite scales of MDQ and DAT. The cutoff scores of the MDQ, semiquantitative analysis of the striatal–background ratio (SBR) and visual rating of DAT, and the composite scale of MDQ and DAT for discriminating DLB from AD or ND were derived and compared.Results: A total of 277 participants were included in this study (126 with DLB, 86 with AD, and 65 with ND). Compared with the AD or ND groups, the DLB group showed a significantly higher frequency in all seven items in the MDQ and a significantly lower SBR. For discrimination of DLB from non-DLB with MDQ, SBR, and composite scale, the cutoff scores of 3/2, 1.37/1.38, and 6/5 were suggested for the diagnosis of DLB with the sensitivities/specificities of 0.91/0.72, 0.91/0.80, and 0.87/0.93, respectively. The composite scale significantly improved the accuracy of discrimination compared with either the MDQ or SBR.Conclusion: This study showed that the novel designed simple questionnaire was a practical screening tool and had similar power to DAT scanning to detect DLB. The questionnaire can be applied in clinical practice and population studies for screening DLB. In addition, the composite scale of MDQ and DAT imaging further improved the diagnostic accuracy, indicating the superiority of the dual-model diagnostic tool.

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Differential diagnostic value of total alpha-synuclein assay in the cerebrospinal fluid between Alzheimer's disease and dementia with Lewy bodies from the prodromal stage

10.21203/rs.3.rs-18905/v4 ◽

2020 ◽

Author(s):

Olivier BOUSIGES ◽

Nathalie Philippi ◽

Thomas Lavaux ◽

Armand Perret-Liaudet ◽

Ingolf Lachmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Differential Diagnosis ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Enzyme Linked Immunosorbent Assay ◽

Prodromal Stage ◽

Discriminating Power

Abstract Background: Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage.Methods: All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace, France, by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD), 32 AD patients at the demented stage (AD-d) and 13 patients with mixed pathology (AD+DLB). CSF levels of total alpha-synuclein were assessed using a commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer’s biomarkers (t-Tau, P-Tau, Aβ42 and Aβ40) were also measured.Results: The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels were significantly higher in AD patients than in DLB patients. However, the ROC curves show a moderate discriminating power between AD and DLB (AUC = 0.78) which does not improve the discriminating power of the combination of Alzheimer biomarkers (AUC = 0.95 with or without alpha-synuclein). Interestingly, the levels appeared to be altered from the prodromal stage in both AD and DLB.Conclusions: The modification of total alpha-synuclein levels in the CSF of patients occurs early, from the prodromal stage. The adding of alpha-synuclein total to the combination of Alzheimer’s biomarker does not improve the differential diagnosis between AD and DLB.Trial registration: ClinicalTrials.gov, (AlphaLewyMa, Identifier: NCT01876459)

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Differential diagnostic value of total alpha-synuclein assay in the cerebrospinal fluid between Alzheimer’s disease and dementia with Lewy bodies from the prodromal stage

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00684-5 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Olivier Bousiges ◽

Nathalie Philippi ◽

Thomas Lavaux ◽

Armand Perret-Liaudet ◽

Ingolf Lachmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Differential Diagnosis ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Enzyme Linked Immunosorbent Assay ◽

Prodromal Stage ◽

Discriminating Power

Abstract Background Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage. Methods All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace, France, by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD), 32 AD patients at the demented stage (AD-d), and 13 patients with mixed pathology (AD+DLB). CSF levels of total alpha-synuclein were assessed using a commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer’s biomarkers (t-Tau, P-Tau, Aβ42, and Aβ40) were also measured. Results The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels were significantly higher in AD patients than in DLB patients. However, the ROC curves show a moderate discriminating power between AD and DLB (AUC = 0.78) which does not improve the discriminating power of the combination of Alzheimer biomarkers (AUC = 0.95 with or without alpha-synuclein). Interestingly, the levels appeared to be altered from the prodromal stage in both AD and DLB. Conclusions The modification of total alpha-synuclein levels in the CSF of patients occurs early, from the prodromal stage. The adding of alpha-synuclein total to the combination of Alzheimer’s biomarker does not improve the differential diagnosis between AD and DLB. Trial registration ClinicalTrials.gov, NCT01876459 (AlphaLewyMa)

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Total alpha-synuclein assay in the Cerebro-Spinal-Fluid is of interest in the differential diagnosis between Alzheimer's disease and dementia with Lewy bodies from the prodromal stage

10.21203/rs.3.rs-18905/v1 ◽

2020 ◽

Author(s):

Olivier BOUSIGES ◽

Nathalie Philippi ◽

Thomas Lavaux ◽

Armand Perret-Liaudet ◽

Ingolf Lachmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Differential Diagnosis ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Enzyme Linked Immunosorbent Assay ◽

Prodromal Stage ◽

Significant Difference ◽

T Tau

Abstract Background: Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage. Methods: All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD) and 32 AD patients at the demented stage (AD-d). CSF levels of total alpha-synuclein were assessed using commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer's biomarkers (t-Tau, P-Tau, Aβ42 and Aβ40) were also measured.Results: The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels are significantly higher in AD patients than in DLB patients. Interestingly is that the levels seem to be altered from the prodromal stage in both AD and DLB. Furthermore, by dividing the patients according to the profiles of Alzheimer's biomarkers typically found or not for each of the two pathologies and then classifying the patients according to the level of alpha-synuclein, we find that alpha-synuclein levels are elevated not only for AD patients with typical “Alzheimer” profile (i.e. 2 or 3 pathological biomarkers) but also for AD patients with a non-typical “Alzheimer” profile (i.e. none or one pathological biomarker).Conclusions: The modification of total alpha-synuclein levels in the CSF of patients occurs early from the prodromal stage. Moreover, alpha-synuclein assay appears to be of particular interest in the differential diagnosis of AD in cases where the Alzheimer biomarkers do not have a typical profile of the disease, i.e. when there is only one or no pathological biomarker.Trial registration: ClinicalTrials.gov, (AlphaLewyMa, Identifier: NCT01876459)

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Differential diagnostic value of total alpha-synuclein assay in the cerebrospinal fluid between Alzheimer's disease and dementia with Lewy bodies from the prodromal stage

10.21203/rs.3.rs-18905/v3 ◽

2020 ◽

Author(s):

Olivier BOUSIGES ◽

Nathalie Philippi ◽

Thomas Lavaux ◽

Armand Perret-Liaudet ◽

Ingolf Lachmann ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Differential Diagnosis ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Enzyme Linked Immunosorbent Assay ◽

Prodromal Stage ◽

Discriminating Power

Abstract Background: Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage.Methods: All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace, France, by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD), 32 AD patients at the demented stage (AD-d) and 13 patients with mixed pathology (AD+DLB). CSF levels of total alpha-synuclein were assessed using a commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer’s biomarkers (t-Tau, P-Tau, Aβ42 and Aβ40) were also measured.Results: The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels were significantly higher in AD patients than in DLB patients. However, the ROC curves show a moderate discriminating power between MA and DLB (AUC = 0.78) which does not improve the discriminating power of the combination of Alzheimer biomarkers (AUC = 0.95 with or without alpha-synuclein). Interestingly, the levels appeared to be altered from the prodromal stage in both AD and DLB.Conclusions: The modification of total alpha-synuclein levels in the CSF of patients occurs early, from the prodromal stage. The adding of alpha-synuclein total to the combination of Alzheimer’s biomarker does not improve the differential diagnosis between AD and DLB.Trial registration: ClinicalTrials.gov, (AlphaLewyMa, Identifier: NCT01876459)

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