Citations

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer's disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.

Abstract Background Immunohistochemically detected phosphorylated α‐synuclein (p‐α‐syn) in cutaneous nerves has been found in >95% of patients meeting consensus criteria for dementia with Lewy bodies (DLB); however, its performance in prodromal stages (mild cognitive impairment‐Lewy body [MCI‐LB]) and clinical practice is unknown. Objective We evaluated skin biopsy for p‐α‐syn in a convenience cohort of patients with suspected MCI‐LB or DLB in a tertiary care setting. Methods 53 patients underwent commercially available skin biopsy for skin nerve p‐α‐syn as part of a clinical evaluation for suspected MCI‐LB/DLB. Consensus MCI‐LB/DLB criteria blinded to skin biopsy result were applied through retrospective chart review; those not definitively meeting criteria were considered questionable synucleinopathy (QS). Results Median age at skin biopsy was 70 years (range, 43–87 years) with 81% men. 36 patients (68%) had positive skin biopsies. 32/43 (74%) patients meeting clinical consensus criteria for DLB/MCI‐LB had a positive skin biopsy, with higher frequency in MCI‐LB (87%) compared with DLB (60%). 4/10 (40%) QS had positive biopsies. One patient with a positive skin biopsy had no evidence of central nervous system (CNS) α‐syn on autopsy. Conclusions Positive skin biopsy for p‐α‐syn occurs across the spectrum of cognitive presentations of Lewy body disease including prodromal DLB, albeit at a lower frequency in this retrospective review of atypical cases compared with typical clinical presentations. A positive skin biopsy may not reflect CNS synucleinopathy as the etiology for a patient's symptoms in some cases. Longitudinal studies of skin biopsies for p‐α‐syn in suspected MCI‐LB/DLB with autopsy confirmation are needed. © 2025 International Parkinson and Movement Disorder Society.

Abstract Background Clinically available plasma p ‐tau217 assays may be utilized in the determination of eligibility for amyloid‐lowering therapies. Our institution recently introduced a plasma p ‐tau217 assay in clinical practice using a two‐cutpoint approach that optimizes the accuracy while minimizing false positive risk and categorizing ≤20% of results as intermediate. In this study, we prospectively evaluate the performance of a plasma p ‐tau217 assay for detection of amyloid pathology using these predefined cutpoints. Method Patients recruited were being considered for lecanemab therapy at a tertiary care subspecialty clinic. Plasma p ‐tau217 was measured using the clinically available Fujirebio Lumipulse p ‐tau217 assay at Mayo Clinic, and results (pg/mL) were classified as either negative (≤0.185), intermediate (0.186–0.324) or positive (≥0.325). Amyloid pathology was determined by amyloid‐PET and/or CSF p ‐tau181/Aβ42. Result Ninety‐three patients were recruited between November 2023 and December 2024. Of these, 49 underwent amyloid‐PET, 4 had CSF p ‐tau181/Aβ42 measurements, and 40 had both PET and CSF results (with 3/40 discordant cases), for use in the assessment of amyloid pathology. The three discordant cases were considered amyloid positive for purposes of plasma p ‐tau217 comparison. Overall amyloid positivity was 90%. Plasma p ‐tau217 results were positive in 83% (77/93), negative in 6% (6/93), and intermediate in 11% (10/93) of patients. An elevated p ‐tau217 predicted the presence of amyloid positivity with a diagnostic accuracy of 96% (95% CI 90% − 99%). In the intermediate range, 80% of patients were positive for amyloid pathology. In patients with a definitive p ‐tau217 result (positive or negative), the positive and negative predictive values were 97% and 83%. There were three patients with discordant results: one PET+/p‐tau217‐, one PET‐/p‐tau217+, and one CSF‐/p‐tau217+. Clinical presentation of these discordant cases was examined, and relevant findings will be discussed. Conclusion The Lumipulse plasma p ‐tau217 assay exhibited acceptable diagnostic accuracy for the determination of amyloid pathology when compared to either amyloid‐PET or CSF p ‐tau181/Aβ42. This prospective study confirms the utility a two‐cutpoint approach for interpreting plasma p ‐tau217 for the assessment of amyloid pathology eligibility for amyloid‐lowering therapies in a heterogenous clinical cohort.

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer’s disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.

Objective Colony-stimulating factor-1 receptor (<i>CSF1R</i>)-related disorder (CSF1R-RD) is a rapidly progressive neurodegenerative disease with a median onset of 43 years. More than 200 <i>CSF1R</i> pathogenic variants have been identified. Patients develop rapidly progressive dementia and motor symptoms, with a median disease duration of 6.8 years. The p.R777Q variant causes CSF1R-RD; it is deleterious to protein function. We describe the clinical and pathological features of CSF1R-RD associated with p.R777Q and report a new family carrying this variant. We compare the neuropathological findings of an index patient (with short-duration disease) with those of a patient with long-duration CSF1R-RD.Methods We present clinical and imaging data from a new family with p.R777Q. We also describe the neuropathology of an index patient and contrast these findings with features of a patient with CSF1R-RD with an 11-year disease course caused by the c.2656_2657insC variant.Results We reviewed the literature on 13 individuals from 8 families with the p.R777Q variant from Asia, Europe, and North America. The mean age at onset was 41±14 years, ranging from 22 to 63 years, and the mean survival was 3.3±2.5 years. Neuropathologic studies of our index patient (10-month disease duration) revealed features consistent with CSF1R-RD. Axonal and myelin pathology was severe in the periventricular white matter. Compared with the patient with an 11-year disease duration, the index patient had less severe white matter lesions.Conclusion Compared with CSF1R-RD associated with other variants, the p.R777Q variant has an aggressive course. Compared with the patient with a long disease duration, the index patient had milder neuropathological findings. These differences may be specific to p.R777Q or associated with rapid clinical progression.

Abstract BACKGROUND Understanding long-term sequelae of cancer care is critical. Cognitive impairment is a common and disabling survivorship issue. Because sex influences tumor biology, therapy exposure, and dementia risk, we examined whether cancer care for a prior malignancy alters late-life cognitive outcomes differently in males and females. METHODS We assessed adults ≥50 years, cognitively normal at study entry, from a longitudinal, population-based cohort (Mayo Clinic Study of Aging). Participants were linked to our institutional cancer registry (excluding non-melanoma skin cancers). Mild cognitive impairment (MCI) and dementia were adjudicated by consensus. We fitted multivariable Cox proportional-hazards models to estimate how prevalent cancer diagnosis influenced the risk of developing MCI/dementia. Sex-specific effects were determined by incorporating a cancer×sex interaction term and by generating separate hazard ratios. Analyses were controlled for age, APOE4 status, education, and presence of vascular/metabolic conditions. RESULTS 5793 MCSA participants (female: 49.4%, APOE4 positive: 27.5%) were included in the study, with a mean age of 73 years at study entry. Incident MCI was recorded in 866 participants, and 737 were diagnosed with incident dementia. About 20% (n=1176) of the cohort had a cancer diagnosis, most commonly prostate (n=423) and breast (n=277). There was no independent relationship between history of cancer and risk for MCI or dementia. We found that males with cancer had an increased risk for MCI (HR 1.28, 95% CI 1.04-1.57, p=0.003) and dementia (HR 1.29, 95% CI 1.04-1.6, p=0.053). Conversely, females with cancer had a lower risk for MCI (HR 0.79, 95% CI 0.61-1.01, p=0.063), although this was not statistically significant. CONCLUSIONS Our data suggests male cancer survivors may be more susceptible to cognitive impairment, independent of age, APOE4 status, education, and vascular/metabolic burden. Elucidating the hormonal, treatment-related, and systemic pathways driving this should be a priority for future mechanistic studies.

Abstract INTRODUCTION When cerebrospinal fluid (CSF) and positron emission tomography (PET) measurements for amyloid‐beta‐peptide (Aβ) related pathology are discordant, therapeutic decision‐making becomes uncertain. METHODS Using data from patients with mild cognitive impairment ( n = 541) from the Alzheimer's Disease Neuroimaging Initiative, we examined baseline characteristics and longitudinal clinical outcomes in persons grouped according to normal/abnormal Aβ via concurrent CSF and PET determinations using standard cutpoints. RESULTS Discordant groups for brain Aβ status (CSF+/PET− and CSF−/PET+) each represented about 5% of the mild cognitive impairment (MCI) population. Longitudinally, neither discordant group declined more than the CSF−/PET− group on either a memory measure or the Clinical Dementia Rating Sum of Boxes scores over a median 4 years of observation, while the CSF+/PET+ group exhibited worsening on both measures. DISCUSSION In contrast to the clinical decline observed in the CSF+/PET+ group, persons with MCI and CSF+/PET− or CSF−/PET+ brain amyloid patterns did not exhibit incipient decline. Highlights Discrepant abnormal cerebrospinal fluid (CSF) and positron emission tomography (PET) brain amyloid indicators are uncommon in mild cognitive impairment (MCI). CSF‐PET discrepant persons with MCI tend to have less abnormal values initially. CSF‐PET discrepant persons with MCI have a benign prognosis at 4 years.