CSF alpha‐synuclein aggregates by seed amplification and clinical presentation of AD

Pilotto, Andrea; Bongianni, Matilde; Tirloni, Clara; Galli, Alice; Padovani, Alessandro; Zanusso, Gianluigi

doi:10.1002/alz.13109

Cited by 20 publications

(7 citation statements)

References 24 publications

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“…We speculate these two individuals were indeed true‐positives. Additionally, in our cohort, 14–16% of AD patients showed αSyn‐SAA positivity, a frequency consistent with previous studies 21,52 . However, our AD group, with a mean age just below 65 years, is relatively young compared to another study 12 reporting a mean age of 74 for their AD group positive for LB pathology.…”

Section: Discussionsupporting

confidence: 90%

“…Additionally, in our cohort, 14–16% of AD patients showed αSyn‐SAA positivity, a frequency consistent with previous studies. 21 , 52 However, our AD group, with a mean age just below 65 years, is relatively young compared to another study 12 reporting a mean age of 74 for their AD group positive for LB pathology. Indeed, younger individuals are less likely to have multiple pathologies, and our younger cohort may not fully reflect the multiple pathologies likely to develop over the next decade of life.…”

Section: Discussionmentioning

confidence: 56%

“…In neurologically normal individuals, aSyn-SAA detection might indicate pathological a-synuclein deposition before symptom onset, 22 whereas in people with AD, a-synuclein deposition can influence clinical presentation and disease progression. 12,52 We found two cognitively normal participants with aSyn-SAA detected at LP who later developed at least one core clinical feature, supporting the shift toward using synuclein biomarkers, like aSyn-SAA, in research cohorts to identify neurologically normal people likely to develop symptoms of LB diseases. We speculate these two individuals were indeed true-positives.…”

Section: Discussionmentioning

confidence: 60%

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Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra

Plastini,

Abdelnour,

Young

et al. 2024

Ann Clin Transl Neurol

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ObjectiveMore than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α‐synuclein seed amplification assay (αSyn‐SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co‐pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD.MethodsUsing receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn‐SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra.ResultsFollowing a decade‐long follow‐up, the clinically or autopsy‐defined diagnosis changed for nine participants. αSyn‐SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non‐LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co‐pathology, amyloidosis was present in 18%, 48%, and 71% (χ2(2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2(2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co‐occurring biomarkers for αSyn‐SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2(3) = 13.87, p = 0.003).InterpretationOur study shows that using a combination of αSyn‐SAA and AD biomarkers can identify people with αSyn, ADNC, and co‐pathology better and earlier than traditional clinical diagnostic criteria alone.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 60%

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Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra

Plastini,

Abdelnour,

Young

et al. 2024

Ann Clin Transl Neurol

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“…This prevalence is remarkably similar to the 33% of AD subjects with concomitant LBD reported by a large neuropathological analysis carried out in 1153 AD cases 3 . These results, in addition to recently published data on a smaller AD cohort, 38 demonstrate that a significant proportion of AD subjects have underlying αSyn pathology and this condition can be identified by αS‐SAA. Identification of αSyn pathology in vivo might help with better patient stratification and enrollment for clinical trials, as well as evaluating if αSyn pathology may influence the clinical response/outcome.…”

Section: Discussionsupporting

confidence: 87%

Investigating alpha‐synuclein co‐pathology in Alzheimer's disease by means of cerebrospinal fluid alpha‐synuclein seed amplification assay

Bellomo,

Toja,

Paolini Paoletti

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONLewy body disease, a frequently observed co‐pathology in Alzheimer's disease (AD), can be identified antemortem in cerebrospinal fluid (CSF) by α‐synuclein seed amplification assay (αS‐SAA). The prevalence and clinical impact of CSF αS‐SAA positivity in AD are still unknown.METHODSαS‐SAA was performed on CSF samples from 240 AD patients (preclinical, prodromal, and dementia stages), 85 controls, 84 patients with Parkinson's disease (PD), and 21 patients with PD with dementia or dementia with Lewy bodies. In AD patients, associations between αS‐SAA positivity and cognitive changes were also evaluated.RESULTSIn agreement with available neuropathological studies, αS‐SAA positivity was observed in 30% of AD patients (vs 9% in controls), and was associated with cognitive decline, visuospatial impairment, and behavioral disturbances.DISCUSSIONαS‐SAA positivity in AD patients reflects the prevalence observed in neuropathological series and is associated with a worse clinical outcome. These data confirm the validity of CSF αS‐SAA positivity as biomarker of synucleinopathy.

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“…Consistently, the 30-40% of AD patients, mostly in later disease stages, also present with extrapyramidal signs like bradykinesia, tremor, and gait disturbances [5]. This may also suggest a possible overlap with alphasynuclein pathology which has been recently described in AD patients [27] and de nitively need to be veri ed in on-going studies. As for the extra-striatal dopaminergic targets, we found signi cant alterations in regions belonging to the mesolimbic pathway, namely the anterior and middle cingulate cortex, the amygdala, the hippocampus, and the ventral frontal cortex in AD-DEM stage.…”

Section: Discussionmentioning

confidence: 55%

Dopaminergic deficits along the spectrum of Alzheimer’s Disease

Pilotto,

Galli,

Sala

et al. 2024

Preprint

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Both post-mortem and in vivo data argue for dopamine dysfunction in patients with Alzheimer’s Disease (AD). However, the timing and regional progression of dopaminergic systems alterations in AD are still debated. Aim of the study was to investigate in vivo the pattern of dopaminergic changes and connectivity using DAT-SPECT imaging in patients across the AD spectrum. Fifty-nine A + T + N + AD patients (n = 21 MCI-AD; n = 38 AD-DEM) and n = 45 age and sex-matched controls (CG) entered the study and underwent 123I-FP-CIT dopaminergic imaging. The occipital binding was used as reference region to obtain single-subject binding in different brain regions. Between-groups differences in 123I-FP-CIT binding in both mesolimbic and nigrostriatal dopaminergic pathways were assessed using an ANCOVA test-adjusting for the effect of center of imaging acquisition, age, and sex. Regions resulting from the voxel-wise direct comparison between MCI-AD and AD-DEM were considered as a seed of interest for a voxel-wise interregional correlation analysis. Both MCI-AD and AD-DEM patients showed dopaminergic depletion within the basal ganglia, whereas cortico-limbic regions (namely hippocampus, amygdala, anterior and middle cingulate, frontal cortex and thalamus) resulted impaired only in the dementia phase. The brain voxel-wise interregional correlation analysis showed a progressive pattern of disruption of caudate/thalamus dopaminergic connectivity to hippocampus and amygdala from MCI-AD to AD-DEM stages. This study indicates basal ganglia dopaminergic alterations and connectivity disruption in the nigrostriatal and mesolimbic systems already in early stage AD, extending to several cortico-limbic regions in dementia phases.

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CSF alpha‐synuclein aggregates by seed amplification and clinical presentation of AD

Cited by 20 publications

References 24 publications

Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra

Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra

Investigating alpha‐synuclein co‐pathology in Alzheimer's disease by means of cerebrospinal fluid alpha‐synuclein seed amplification assay

Dopaminergic deficits along the spectrum of Alzheimer’s Disease

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