Citations

Abstract Introduction The aim of this study was to examine white matter hyperintensities (WMH) and fractional anisotropy (FA) in empirically derived incident mild cognitive impairment (MCI) subtypes. Methods We evaluated 188 participants with incident MCI in the Mayo Clinic Study of Aging (MCSA) identified as having one of four cluster‐derived subtypes: subtle cognitive impairment, amnestic, dysnomic, and dysexecutive. We used linear regression models to evaluate whole brain and regional WMH volumes. We examined fractional anisotropy (FA) on a subset of 63 participants with diffusion tensor imaging. Results Amnestic and dysexecutive subtypes had higher WMH volumes in differing patterns than cognitively unimpaired; the dysexecutive subtype had higher WMH than subtle cognitive impairment. There was widespread WM degeneration in long association and commissural fibers in the amnestic, dysnomic, and dysexecutive subtypes, and corpus callosum FA accounted for significant variability in global cognition. Discussion White matter changes likely contribute to cognitive symptoms in incident MCI.

AbstractBackgroundIsolated REM Sleep Behavior Disorder (iRBD) patients are known to be at high risk for developing an overt synucleinopathy – particularly Dementia with Lewy Bodies (DLB) and Parkinson’s Disease (PD). Reduced nigrostriatal uptake on 123I‐FP‐CIT SPECT reflects dopamine deficiency, which is common in the overt synucleinopathies. We sought to assess how 123I‐FP‐CIT SPECT imaging in iRBD changes longitudinally and whether an abnormal 123I‐FP‐CIT SPECT scan precedes and predicts future transition to an overt synucleinopathy.MethodParticipants with polysomnography‐confirmed iRBD from the Mayo Clinic Alzheimer’s Disease Research Center database +/‐ North American Prodromal Synucleinopathy (NAPS) Consortium who had two or more longitudinal 123I‐FP‐CIT SPECT scans and been followed prospectively for at least 24 months were included in this analysis. Striatonigral dopamine transporter uptake was evaluated semi‐quantitatively with 123I‐FP‐CIT SPECT using DaTQUANT software (GE Healthcare) to calculate z‐scores of putamen uptake.ResultThirty‐five iRBD participants (86% male) were evaluated prospectively (mean 62.5 ± 19.4 months) and underwent two or more 123I‐FP‐CIT SPECT scans at a minimum of 12 months intervals. Thirteen participants (37%) developed an overt synucleinopathy (11 DLB and 2 PD; phenoconverters) and 22 participants (63%) remained as iRBD (stable iRBD). Phenoconverters were older (mean 70.8 ± 7.0 vs 63.4 ± 6.0 years old) and had more negative DaTQUANT putamen z‐scores (mean ‐1.68 ± 1.42 vs ‐0.33 ± 1.52) than stable iRBD participants at baseline. Among phenoconverters, nine participants (69%) had one or more 123I‐FP‐CIT SPECT scans with DaTQUANT putamen z‐score of <‐2.0 prior to phenoconversion, and mean time from initial DaTQUANT putamen z‐score of <‐2.0 to phenoconversion was 36.8 ± 28.7 months. In stable RBD participants, eight participants (36%) showed a decline in DaTQUANT putamen z‐score of >1 between the most recent and the baseline scan, and four participants (18%) presented DaTQUANT putamen z‐score of <‐2.0 at the most recent scan.ConclusionThese findings suggest that a decline in putamen uptake on 123I‐FP‐CIT SPECT in iRBD serves as a predictor and a surrogate biomarker for progression of iRBD to an overt synucleinopathy.

AbstractBackgroundRecent advances in the development of novel Alzheimer’s disease (AD) measures of amyloid, tau, and neurodegeneration in cerebrospinal fluid (CSF) and blood have enabled a better understanding of the links between amyloid‐beta (Aβ), tau species and neurodegeneration in the brain, CSF, and blood. The discoveries of novel tau species in CSF and blood, including specific phospho‐tau (p‐tau) and truncated species containing the microtubule binding region of tau (MTBR‐tau) which aggregates in tau tangles, have greatly expanded our understanding of tau biology and tau target development. The longitudinal Aβ, tau, and neurofilament light chain (NfL) changes previously measured in CSF are now being measured accurately in blood, enabling interpretation and understanding of AD progression in much larger and more robust populations.MethodWe analyzed longitudinal CSF and/or blood plasma mass spectrometry measures of Aβ42/Aβ40, multiple p‐tau species (including p‐tau217, 231, 181, 205, etc.), total tau, MTBR‐tau (e.g., MTBR‐tau243, MTBR‐tau299, and MTBR‐tau354), and NfL in sporadic AD and dominantly inherited AD cohorts. Mass spectrometry results were compared to amyloid and tau aggregation measures by Positron Emission Tomography (PET) scans and clinical and cognitive measures in local and international clinical cohorts including ADNI, AIBL, BioFINDER, Mayo Clinic, the Knight ADRC, and the DIAN.ResultThe longitudinal results indicate that a pathophysiological cascade of events begin with altered CSF and blood plasma Aβ42/Aβ40 ratio, followed by increases in amyloid plaques as measured by amyloid PET, associated with increased phosphorylation of specific CSF tau species (e.g., p‐tau217, p‐tau181, etc.), before increases in p‐tau205, NfL, total tau concentrations, hypometabolism, and atrophy. Finally, some species of MTBR‐tau increase before or with tau aggregation by tau PET and onset of clinical symptoms and correlate with longitudinal tau aggregation and clinical progression.ConclusionThese findings indicate that CSF and blood plasma Aβ, p‐tau, MTBR‐tau and NfL measures are highly precise biomarkers of brain amyloidosis, tauopathy, and neurodegeneration and can accurately identify stages of preclinical and clinical AD.

AbstractBackgroundBlood phosphorylated tau (p‐tau) has proven to be the primary candidate as an accessible and scalable biomarker for Alzheimer’s disease (AD). Both p‐tau181 and p‐tau217 are highly accurate to detect AD within dementia cases. Our recent work in cerebrospinal fluid, however, indicates p‐tau231 to be associated to incipient AD pathology. In light of this, we developed a Single molecule array (Simoa) to detect plasma p‐tau231 and assessed its performance in multiple domains, specifically, its ability to detect preclinical AD.MethodIn all cohorts, plasma p‐tau231 was quantified using an in‐house Simoa method developed at the Clinical Neurochemistry Laboratory, Gothenburg University, Sweden. Data presented in this study are samples acquired from Translational Biomarkers of Aging and Dementia (TRIAD, n=503), King’s College London (n=55), Mayo Clinic Study of Aging (n=145), KARVIAH (n=140), Baltimore Longitudinal Study of Aging (n=430), University College London (n=70), Paris University (n=213), PREVENT‐AD (n=257), University of California (n=309) and ALFA+ (n=385).ResultIn the TRIAD cohort, plasma p‐tau231 demonstrated high accuracy in determining AD from young individuals (AUC=0.95), Aβ‐ elderly (AUC=0.92), Aβ‐ MCI (AUC=0.88) and other neurodegenerative disorders (AUC=0.92). In an autopsy study, plasma p‐tau231 could detect neuropathologically confirmed AD amongst dementia cases (AUC=0.99). In comparing healthy elderly Aβ‐ and Aβ+ individuals, p‐tau231 predicted preclinical Aβ pathology (AUC=0.83). Furthermore, inflection points of the weighted regression curves demonstrate that increases in plasma p‐tau231 occur before plasma p‐tau181 as a function of Aβ deposition load. Plasma p‐tau231 data from additional cohorts will focus on cross‐sectional and longitudinal preclinical datasets. In addition, further data will show the performance of p‐tau231 in symptomatic and presymptomatic PSEN1/APP mutation carriers, memory clinic cohorts, longitudinal neuropathology confirmed and acute neurological injury.ConclusionPlasma p‐tau231 is a new biomarker specific for AD pathology and at higher concentrations relative to p‐tau181 and p‐tau217. Our initial results indicate that plasma p‐tau231 is equivalent to p‐tau181 in diagnostic utility but has greater potential as a biomarker to monitor emerging Aβ pathology. This presentation will give an overview of novel cross‐sectional and longitudinal plasma p‐tau231 data, in more than 3000 individuals, that encompasses the AD continuum, familial AD and other neurological conditions.

AbstractBackgroundBlood‐based biomarkers of amyloid pathology and neurodegeneration are entering clinical use. It is critical to understand what factors affect these plasma marker levels for accurate clinical interpretation. Herein we examined factors associated with plasma Ab42, Ab40, neurofilament light (NfL), total tau (T‐tau), and the ratio of Ab42 to Ab40 (Ab42/40).MethodThe plasma markers were measured for 996 participants (859 cognitively unimpaired [CU], 133 mild cognitive impairment [MCI], 4 dementia) from the Mayo Clinic Study of Aging (MCSA), aged 51 to 95 years. The Quanterix Simoa® HD‐1 analyzer was employed to measure the plasma markers using the Simoa® Neurology 3‐Plex A (N3PA) (T‐tau, Ab42, Ab40) (catalog #101995) and the Simoa® NF‐light (catalog #103180). All other data was collected during in‐person MCSA visits or abstracted from the medical record. Statistical significance was determined using an alpha level of 0.05.ResultAmong CU, all of the plasma markers showed correlation with age. T‐tau (Spearman’s rho = 0.113, p<0.001) showed the weakest correlation and NfL (rho = 0.695, p<0.001) had the strongest. Women had higher levels of T‐tau (Median women: 2.782 vs. 2.390, p<0.001) and lower Ab42/40 (0.033 vs. 0.035, p=0.024) compared to men. In linear regression models predicting z‐scored plasma markers and adjusted for age and sex, several statistically significant predictors were found. For example, higher Charlson comorbidity index and chronic kidney disease were associated with higher levels of all markers; slower gait speed was associated with higher levels for all but Ab42/40 where no relationship was seen. A higher BMI was associated with higher levels of Ab42, Ab40, and T‐tau whereas NfL tended to be lower with increased BMI. Among participants with MCI or dementia, the relationship between gait speed or chronic kidney disease with NfL and T‐tau strengthened considerably.ConclusionMultiple variables affect plasma markers of amyloid pathology and neurodegeneration among CU in the general population. Some relationships differed among MCI and dementia participants. Incorporating this information is critical for accurate interpretation of the marker levels and for the development of reference ranges.

AbstractBackgroundDecreased amyloid β1‐42 (Aβ42) and increased tau (t‐Tau and p‐Tau) concentrations in cerebrospinal fluid (CSF) reflect the pathological changes of Alzheimer’s disease (AD) and aid in the diagnosis of AD dementia. In the United States, the ADmark® assay has been almost exclusively used for the measurement of these biomarkers in clinical practice. Recently, our institution switched from the ADmark® assay to the Roche Elecsys assays. The goal of this study was to determine if differences exist between these methods in classification of patients as having changes indicative of AD pathology.MethodPatients undergoing ADMark® testing (n= 73) were recruited to participate in this IRB‐approved study. Two simultaneous CSF aliquots were obtained. For ADMark®, 2.0mL were collected into a 5mL polypropylene (PP) tube and shipped frozen to Athena Diagnostics per collection instructions for testing (Innotest® immunoassays for Aβ42, t‐Tau, and p‐Tau). For the Roche Elecsys assays (Aβ42, t‐Tau, and p‐Tau), 2.0mL were collected into a 2.5mL low bind PP tube, frozen, and then tested at Mayo Clinic Laboratories. Comparative analysis was performed between the two testing methodologies and to clinical findings.ResultOverall concordance between the ADMark® Aβ42/t‐Tau index (ATI) and Roche p‐Tau/Aβ42 was 89% with 8 (11%) discrepant cases. Four cases were classified as normal by the Roche p‐Tau/Aβ42 but borderline (n=3) or abnormal (n=1) by ADMark® ATI. Four cases were classified as abnormal by the Roche p‐Tau/Aβ42 and borderline by ADMark® ATI. In these cases, the normal Roche p‐Tau/Aβ42 result was most consistent with clinical diagnosis. When compared to clinical diagnosis, cases with clinical suspicion of AD dementia were abnormal in 84% and 92% of cases with the ADMark® ATI and the Roche p‐Tau/Aβ42, respectively. In cases without clinical suspicion of AD dementia, results were abnormal in 19% and 21% of cases with the ADMark® ATI and the Roche p‐Tau/Aβ42, respectively. There were 2 cases with clinical suspicion of AD dementia and 5 cases without suspicion of AD dementia that were classified as borderline by ADMark® ATI.ConclusionRoche p‐Tau/Aβ42 showed comparable performance to ADMark® ATI when correlating results to clinical diagnosis of AD dementia.

AbstractBackgroundThe Neurodegenerative Research Group (NRG) at Mayo clinic has followed patients with degenerative speech and/or language disorders for over a decade. In this presentation I will present data from this cohort to inform a broader discussion about the importance of apraxia of speech (AOS) and its subtypes, heterogeneity within the agrammatic PPA variant, and perils of mixed phenotypes.MethodWe reviewed the NRG database to identify patients who initially presented with isolated (PPAOS), AOS in conjunction with agrammatic aphasia (AOS‐PAA), isolated agrammatic aphasia (PAA), and patients who had PAA or AOS overlapping with another degenerative diagnosis. Data from the following clinical instruments were abstracted: WAB AQ (aphasia severity), UPDRS III (parkinsonism), WAB Praxis (ideomotor apraxia), and the MoCA (cognitive ability). We assessed the effect of baseline diagnosis and AOS subtype on these outcomes over time using Bayesian linear mixed effects models. We qualitatively reviewed longitudinal diagnostic trajectories. Preliminary analyses were done on available autopsy data.ResultPAA was associated with greater aphasia at baseline and more rapid decline; PPAOS was associated with normal language at baseline and slow decline; and PAA‐AOS with intermediate baseline aphasia and decline. However, for those with AOS longitudinal decline differed based on AOS subtype: prosodic PPAOS was associated with the slowest decline and phonetic PAA‐AOS with the fastest. Some patients met criteria for non‐PPA disorders during follow up. However, compared to patients who met criteria for these disorders at enrollment, the speech/language‐first patients remained qualitatively distinct, and neither resembled the cases that were mixed at onset. Preliminary autopsy data suggests that AOS is predictive of tau and that the specific tauopathy may be related to the initial syndrome and AOS subtype.ConclusionThe differences between PAA, PAA‐AOS and PPAOS suggest that these disorders should not be lumped. In fact, the longitudinal trajectories are sufficiently different that doing so would add noise to observational and interventional studies. Instead, more detailed phenotyping, including AOS subtype, can aid prognostication and may improve prediction of the underlying pathology. Finally, caution should be exercised when considering PPAOS and PPA patients for other FTLD diagnostic categories.

AbstractBackgroundAdvancing age is an important risk factor for dementia and cancer. An inverse association between these conditions has been described, yet caution from potential biases/confounders is warranted. Dementia and cancer may represent a spectrum of opposing dysregulated degenerative (apoptosis) and growth (proliferative) pathways respectively (Driver, 2014). Risk or resiliency factors affecting these pathways may influence cognitive outcomes in the oldest‐old. We sought to investigate demographics, clinical characteristics, and the impact of medical comorbidity on possible risk‐resiliency factors for neurodegeneration in nondemented and demented oldest‐old who died and underwent autopsy.MethodMedical records of 161 decedents (female n=134) from the Mayo Clinic 95+ year‐old cohort (age range 95‐106 years‐old) were reviewed. Groups consisting of nondemented (n=72) and demented (n=89) decedents were stratified and compared according to demographics and clinical variables, including history of cancer. Autopsy and neuropathologic evaluation was also conducted.ResultAge at death, sex, race, and education showed no differences between nondemented and demented decedents. History of cancer was higher in nondemented (57%) compared to demented decedents (30%) (p=0.002). APOE ε4 allele presence did not differ amongst groups, while APOE ε2 allele was more common in the nondemented group (p=0.026). History of coronary artery disease was higher in the nondemented (p=0.033). No differences were observed in other vascular risk factors, alcohol use, or depression. Smoking history approached significance and was higher in nondemented compared to demented (p=0.068). MMSE scores were higher in the nondemented group (p<0.001). Neuropathology findings included a lower Braak tangle staging in nondemented (median=III) compared to demented (median=V) groups (p<0.001) and less frequent diffuse plaques observed in the nondemented (67%) compared with those demented (93%) (p<0.001).ConclusionDementia is less frequent among cancer survivors in the 95+ oldest‐old. Disease‐related mechanisms associated with malignancy and surviving it may be protective against neurodegeneration in the oldest old.