Outcomes of Patients With Mild Cognitive Impairment With Lewy Bodies or Alzheimer Disease at 3 and 5 Years After Diagnosis.

BACKGROUND AND OBJECTIVES: Retrospective studies indicate that dementia with Lewy bodies (DLB) may be preceded by a mild cognitive impairment (MCI) prodrome. Research criteria for the prospective identification of MCI with Lewy bodies (MCI-LB) have been developed. We aimed to assess the prognosis of a prospectively identified MCI-LB cohort at 2 key milestones, 3- and 5 years after diagnosis, to examine classification stability over time and rates of adverse outcomes (dementia or death). METHODS: This was a retrospective examination of data from 2 longitudinal observational cohort studies where participants with MCI were prospectively recruited from North East England and differentially classified as MCI due to Alzheimer disease (MCI-AD), possible MCI-LB, or probable MCI-LB. Adverse outcomes (DLB/other dementia or death) and stability of disease-specific classifications were examined in each group. RESULTS: Of 152 participants with baseline MCI (54 MCI-AD, 29 possible MCI-LB, and 69 probable MCI-LB), 126 were followed for up to 3 years (mean age 75.3 years; 40% female). We found that prospective probable MCI-LB classifications were both sensitive (91%) and specific (94%) to classifications either remaining as probable MCI-LB or progressing to DLB (in some cases autopsy confirmed) for 3 or more years after. Classifications were at least as stable as those in MCI-AD. In this cohort with disease-specific MCI classifications, rates of progression to dementia were high: 55% of MCI-LB had developed DLB within 3 years. Dementia occurred in 47% of MCI-AD over the same duration (odds ratio 1.68, 95% CI 0.66-4.26, p = 0.278). Premature death was a common competing risk, occurring in 9% of MCI-AD and 11% of MCI-LB within 3 years. DISCUSSION: These findings support that prospectively identified probable MCI-LB is a prodromal presentation of DLB and that disease-specific classifications of MCI may reliably identify different prodromal dementias.

Ligand Profiling as a Diagnostic Tool to Differentiate Patient-Derived α-Synuclein Polymorphs.

Amyloid fibrils are characteristic of many neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. While different diseases may have fibrils formed of the same protein, the supramolecular morphology of these fibrils is disease-specific. Here, a method is reported to distinguish eight morphologically distinct amyloid fibrils based on differences in ligand binding properties. Eight fibrillar polymorphs of α-synuclein (αSyn) were investigated: five generated de novo using recombinant αSyn and three generated using protein misfolding cyclic amplification (PMCA) of recombinant αSyn seeded with brain homogenates from deceased patients diagnosed with Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Fluorescence binding assays were carried out for each fibril using a toolkit of six different ligands. The fibril samples were separated into five categories based on a binary classification of whether they bound specific ligands or not. Quantitative binding measurements then allowed every fibrillar polymorph to be uniquely identified, and the PMCA fibrils derived from PD, MSA, and DLB patients could be unambiguously distinguished. This approach constitutes a novel and operationally simple method to differentiate amyloid fibril morphologies and to identify disease states using PMCA fibrils obtained by seeding with patient samples.

Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review.

Background: Psychosis, characterized by delusions and/or hallucinations, is frequently observed during the progression of Alzheimer's disease (AD) and other neurodegenerative dementias (ND) (i.e., dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD)) and cause diagnostic and management difficulties. Objective: This review aims at presenting a concise and up-to-date overview of psychotic symptoms that occur in patients with ND with a comparative approach. Methods: A systematic review was conducted following the PRISMA guidelines. 98 original studies investigating psychosis phenotypes in neurodegenerative dementias were identified (40 cohort studies, 57 case reports). Results: Psychosis is a frequently observed phenomenon during the course of ND, with reported prevalence ranging from 22.5% to 54.1% in AD, 55.9% to 73.9% in DLB, and 18% to 42% in FTD. Throughout all stages of these diseases, noticeable patterns emerge depending on their underlying causes. Misidentification delusions (16.6-78.3%) and visual hallucinations (50-69.6%) are frequently observed in DLB, while paranoid ideas and somatic preoccupations seem to be particularly common in AD and FTD, (respectively 9.1-60.3% and 3.10-41.5%). Limited data were found regarding psychosis in the early stages of these disorders. Conclusions: Literature data suggest that different ND are associated with noticeable variations in psychotic phenotypes, reflecting disease-specific tendencies. Further studies focusing on the early stages of these disorders are necessary to enhance our understanding of early psychotic manifestations associated with ND and help in differential diagnosis issues.

Differences in the treatment needs of patients with dementia with Lewy bodies and their caregivers and differences in their physicians' awareness of those treatment needs according to the clinical department visited by the patients: a subanalysis of an observational survey study.

BACKGROUND: We investigated whether the treatment needs of patients with dementia with Lewy bodies (DLB) and their caregivers, along with their attending physicians' perception of those treatment needs, differ according to the clinical department visited by the patients. METHODS: This was a subanalysis of a multicenter, cross-sectional, observational survey study. Data from the main study were classified according to the clinical department visited by the patient: psychiatric group (P-group), geriatric internal medicine group (G-group), and neurology group (N-group). The treatment needs of patients and caregivers were defined as "the symptom that causes them the most distress", and the frequency of each answer was tabulated. RESULTS: This subanalysis included 134, 65, and 49 patient-caregiver pairs in the P-, G-, and N-groups, respectively. Statistically significant differences in patient background characteristics such as patient age; initial symptom domains; use of cholinesterase inhibitors, levodopa, antipsychotics, and Yokukansan; and total scores of the Mini-Mental State Examination, Neuropsychiatric Inventory-12, and Movement Disorder Society-Unified Parkinson's Disease Rating Scale Parts II and III were shown among the three subgroups. While there were no differences in patients' treatment needs among the subgroups, residual analysis showed that in the N-group, parkinsonism was more of a problem than other symptom domains (p = 0.001). There were significant differences in caregivers' treatment needs among the three subgroups (p < 0.001). The patient-physician concordance rates for the symptom domains that caused patients the most distress were: P-group, 42.9% (kappa coefficient [κ] = 0.264); G-group, 33.3% (κ = 0.135), and N-group, 67.6% (κ = 0.484). The caregiver-physician concordance rates for the symptom domains that caused the caregivers the most distress were: P-group, 54.8% (κ = 0.351), G-group, 50.0% (κ = 0.244), and N-group, 47.4% (κ = 0.170). CONCLUSION: This subanalysis revealed differences in the treatment needs of patients with DLB and their caregivers according to the clinical department they attended. There might be a lack of awareness of those treatment needs by the attending physicians, regardless of their specialty. TRIAL REGISTRATION: UMIN Clinical Trials Registry UMIN000041844.

The cingulate island sign in a mixed memory clinical cohort: Prevalence and diagnostic accuracy.

INTRODUCTION: Visual rating of the cingulate island sign (CIS) on [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) has a high specificity for dementia with Lewy bodies (DLB) in selected cohorts such as DLB versus Alzheimer's disease (AD). In a mixed memory clinical population this study aimed to uncover the prevalence of CIS, the diagnostic accuracy for DLB, and the relationship between CIS and disease severity. METHODS: CIS on [18F]FDG-PET was retrospectively assessed with the visual CIS rating scale (CISRs) in 1000 patients with a syndrome diagnosis of mild cognitive impairment (MCI) or dementia with no restrictions in etiological diagnosis. RESULTS: In this cohort 24.3 % had a CISRs score ≥1 and 3.5 % had a CISRs score = 4. The prevalence of a CISRs score ≥1 was highest in DLB (74.0 %, n = 57). A CISRs score ≥1 was present in at least 9 % in other diagnostic groups. The prevalence of CIS across disease severities showed no statistically significant difference (p = 0.23). To differentiate DLB from non-DLB the optimal cut-off was a CISRs score ≥1 (balanced accuracy = 77.1 %) in MCI/mild dementia and a CISRs score ≥2 (balanced accuracy = 80.6 %) in moderate/severe dementia. The positive predictive value of a CISRs score = 4 for DLB was 57.7 % in MCI/mild dementia and 33.3 % in moderate/severe dementia. CONCLUSION: The CISRs is useful in differentiating DLB from other etiologies in a mixed memory clinical population. Balanced accuracy and positive predictive value may vary across disease severities in the population studied.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Markers for the detection of Lewy body disease versus Alzheimer's disease in mild cognitive impairment: a systematic review and meta-analysis.

BACKGROUND: Mild cognitive impairment (MCI) may evolve into dementia. Early recognition of possible evolution to Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB) is of importance, but actual diagnostic criteria have some limitations. In this systematic review and meta-analysis, we aimed to find the most accurate markers that can discriminate patients with DLB versus AD, in MCI stage. METHODS: We searched several databases up to 17 August 2023 including studies comparing markers that may distinguish DLB-MCI from AD-MCI. We reported data regarding sensitivity, specificity, and the area under the curves (AUCs) with their 95% confidence intervals (CIs). RESULTS: Among 2219 articles initially screened, eight case-control studies and one cohort study were included for a total of 832 outpatients with MCI. The accuracy of cerebrospinal fluid (CSF) markers was the highest among the markers considered (AUC > 0.90 for the CSF markers), with the AUC of CSF Aß42/Aß40 of 0.94. The accuracy for clinical symptom scales was very good (AUC = 0.93), as evaluated in three studies. Although limited to one study, the accuracy of FDG-PET (cingulate island sign ratio) was very good (AUC = 0.95) in discriminating DLB from AD in MCI, while the accuracy of SPECT markers and EEG frequencies was variable. CONCLUSIONS: Few studies have assessed the accuracy of biomarkers and clinical tools to distinguish DLB from AD at the MCI stage. While results are promising for CSF markers, FDG-PET and clinical symptoms scales, more studies, particularly with a prospective design, are needed to evaluate their accuracy and clinical usefulness. CLINICAL TRIAL REGISTRATION: Prospero (CRD42023422600).

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

OBJECTIVE: More 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. METHODS: Using 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. RESULTS: Following 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). INTERPRETATION: Our 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.

Identifying parkinsonism in mild cognitive impairment.

INTRODUCTION: Clinical parkinsonism is a core diagnostic feature for mild cognitive impairment with Lewy bodies (MCI-LB) but can be challenging to identify. A five-item scale derived from the Unified Parkinson's Disease Rating Scale (UPDRS) has been recommended for the assessment of parkinsonism in dementia. This study aimed to determine whether the five-item scale is effective to identify parkinsonism in MCI. METHODS: Participants with MCI from two cohorts (n = 146) had a physical examination including the UPDRS and [123I]-FP-CIT SPECT striatal dopaminergic imaging. Participants were classified as having clinical parkinsonism (P+) or no parkinsonism (P-), and with abnormal striatal dopaminergic imaging (D+) or normal imaging (D-). The five-item scale was the sum of UPDRS tremor at rest, bradykinesia, action tremor, facial expression, and rigidity scores. The ability of the scale to differentiate P+D+ and P-D- participants was examined. RESULTS: The five-item scale had an AUROC of 0.92 in Cohort 1, but the 7/8 cut-off defined for dementia had low sensitivity to identify P+D+ participants (sensitivity 25%, specificity 100%). Optimal sensitivity and specificity was obtained at a 3/4 cut-off (sensitivity 83%, specificity 88%). In Cohort 2, the five-item scale had an AUROC of 0.97, and the 3/4 cut-off derived from Cohort 1 showed sensitivity of 100% and a specificity of 82% to differentiate P+D+ from P-D- participants. The five-item scale was not effective in differentiating D+ from D- participants. CONCLUSIONS: The five-item scale is effective to identify parkinsonism in MCI, but a lower threshold must be used in MCI compared with dementia.

Diagnostic value of CSF chromogranin A to discriminate between Alzheimer's disease and dementia with Lewy bodies.

BACKGROUND: Chromogranin A (CgA) seems to be involved in the pathophysiology of different neurodegenerative pathologies such as Alzheimer's disease (AD) and dementia with Lewy Bodies (DLB). CgA is present in the aggregates of amyloid plaques and in Lewy bodies but CgA also has a function in neuroinflammatory processes via microglia. Our objective was to determine if there is a difference in the CgA concentration in the cerebrospinal fluid (CSF) of AD and DLB patients and whether the CgA concentration can discriminate between the two diseases. METHODS: Using the previously described AlphaLewyMA cohort, we included 117 patients with a CSF CgA assay: 15 control subjects (CS group), 64 DLB patients, 17 AD patients and 21 patients with both AD and probable DLB criteria (AD/DLB group). CgA concentration was assessed using the MSD platform. RESULTS: CSF CgA was increased in the AD and AD/DLB groups compared with the DLB group (p = 0.0006 between AD and DLB, p = 0.0013 between AD/DLB and DLB). No significant difference in CgA concentration was found between DLB and CS. ROC curve analysis showed an area under the curve of 0.791 between AD and DLB. CgA concentrations were correlated with t-Tau and P-Tau regardless of the pathology (for Tau: p = 0.022 for AD; p < 0.0001 for DLB; p = 0.004 for AD/DLB; for P-Tau: p = 0.032 for AD; p < 0.0001 for DLB; p = 0.0009 for AD/DLB). Aß42 was positively correlated with CgA in the DLB group but not in the AD and AD/DLB groups (for DLB: p < 0.0001; for AD: p = 0.57; for AD/DLB: p = 0.58). CONCLUSIONS: CSF CgA concentrations are increased in AD but not in DLB and correlate with P-Tau and Tau whatever the disease. These results suggest a link between tauopathy/neurodegeneration and CgA.

Plasma biomarkers of Alzheimer's disease in the continuum of dementia with Lewy bodies.

INTRODUCTION: Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease. METHODS: The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans. RESULTS: Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB. DISCUSSION: The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP.

Patient- and proxy-reported quality of life in advanced dementia with Lewy bodies.

INTRODUCTION: Little is known regarding quality of life (QoL) in dementia with Lewy bodies (DLB), particularly in advanced stages. METHODS: Dyads of individuals with moderate-advanced DLB and their primary caregivers were recruited from specialty clinics, advocacy organizations, and research registries. The study collected demographics, disease-related measures, and measures of patient/caregiver experiences. RESULTS: The Quality of Life in Alzheimer's Disease (QoL-AD) was completed by the person with DLB and the caregiver (proxy) in 61 dyads; 85 dyads had only a proxy-completed QoL-AD. Patient- and proxy-reported scores were moderately correlated (r = 0.57, P < 0.0001). Worse patient-reported QoL correlated with daytime sleepiness, autonomic symptom burden, and behavioral symptoms. Proxy ratings correlated with dementia severity, daytime sleepiness, behavioral symptoms, dependence in activities of daily living, and caregiver experience measures. DISCUSSION: Patient- and proxy-reported quality of life (QoL) should be assessed separately in advanced DLB. Some symptoms associated with QoL have available therapeutic options. Research is needed regarding strategies to optimally improve QoL in DLB. HIGHLIGHTS: Patient and proxy quality of life (QoL) ratings had moderate correlation in advanced dementia with Lewy bodies. Daytime sleepiness affected patient- and proxy-reported QoL. Behavioral symptoms affected patient- and proxy-reported QoL. Autonomic symptom burden affected patient-reported QoL. Dementia severity, dependence, and caregiver experiences affected proxy ratings.

Postural Control Characteristics in Alzheimer's Disease, Dementia With Lewy Bodies, and Vascular Dementia.

BACKGROUND: Dementia often results in postural control impairment, which could signify central nervous system dysfunction. However, no studies have compared postural control characteristics among various types of dementia. This study aimed to compare static postural control in patients with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular dementia (VaD). METHODS: Cross-sectional relationship between the clinical diagnoses (AD, DLB, VaD, or normal cognition [NC]) of outpatients at a memory clinic and their upright postural control characteristics were examined. In the postural control test, participants were instructed to maintain a static upright standing on a stabilometer for 60 seconds under the eyes-open and eyes-closed conditions. Forty postural control parameters, including distance, position, and velocity in the anterior-posterior and medio-lateral directions, derived from the trajectory of the center of mass sway, were calculated. The characteristics of each type of dementia were compared to those of NC, and the differences among the 3 types of dementia were evaluated using linear regression models. RESULTS: The study included 1 789 participants (1 206 with AD, 111 with DLB, 49 with VaD, and 423 with NC). Patients with AD exhibited distinct postural control characteristics, particularly in some distance and velocity parameters, only in the eyes-closed condition. Those with DLB exhibited features in the mean position in the anterior-posterior direction. In patients with VaD, significant differences were observed in most parameters, except the power spectrum. CONCLUSIONS: Patients with AD, DLB, and VaD display disease-specific postural control characteristics when compared to cognitively normal individuals.

The Relationship Between First Presenting Neuropsychiatric Symptoms in Older Adults and Autopsy-Confirmed Memory Disorders.

OBJECTIVES: Although dementia is typically considered a disease of cognitive decline, almost all patients present with neuropsychiatric symptoms (NPS) at some stage of their disease. Few studies have assessed the timing of NPS onset in relation to pathological diagnoses of neurodegenerative diseases. We sought to examine the association between the first presenting clinically significant NPS in aging individuals and neuropathological diagnoses of memory disorders. DESIGN: This retrospective longitudinal cohort study utilized the National Alzheimer's Coordinating Center (NACC) dataset, which includes participant data from 37 Alzheimer's Disease Research Centers collected between 2005 and 2022. PARTICIPANTS: Participants (N = 5,416) aged 45 years or older with Clinical Dementia Rating-Global ratings of less than or equal to 1 were included in this analysis. A total of 4,033 (74.5%) participants presented with at least one NPS at any NACC visit. MEASUREMENTS: To measure first NPS, the NACCBEHF variable was used, a clinician-rated variable defined as "the predominant symptom that was first recognized as a decline in the subject's behavior." Neuropathologic variables included assessments of Alzheimer's Disease, Frontotemporal Dementia, Lewy Body Dementia, Cerebral Amyloid Angiopathy, Hippocampal Sclerosis, and Cerebrovascular Disease. RESULTS: Presentation with any clinically significant first NPS was associated with several neuropathological diagnoses including Alzheimer's Disease, Frontotemporal Lobar Dementia with TDP-43 pathology, and Lewy Body Dementia. While specific first NPS were associated with Frontotemporal Dementia neuropathology (personality change and disinhibition) and Lewy Body Dementia neuropathology (psychosis and REM behavior disturbance), Alzheimer's Disease neuropathology was associated with the majority of NPS. CONCLUSIONS: Since neuropsychiatric symptoms are frequently the first presenting symptom of dementia, their associations with well-defined neuropathological diagnoses may help clinicians predict the subtype of future dementias.

A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research.

Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life. Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome. On the basis of this definition, we propose that individuals with pathological n-αsyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal α-synuclein disease integrated staging system (NSD-ISS), rooted in the biological anchors (S and D) and the degree of functional impairment caused by clinical signs or symptoms. Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. A biological definition of neuronal α-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.