Background
Alzheimer’s Disease (AD) plasma biomarkers have been proposed for amyloid positivity identification and for differentiating between diagnoses. Phosphorylated Tau‐217 (pTau‐217) has ...demonstrated good predictive ability for AD vs healthy controls. Neurofilament Light chain (NfL) differentiates between Frontotemporal Dementia (FTD) and other dementia. These factors have not be extensively tested in real‐world cohorts. The aim of this study was to investigate how pTau‐217 and NfL concentrations differ across clinical diagnoses in an unselected, real‐world memory clinic cohort.
Method
We included 418 consecutive patients from the Amsterdam Dementia Cohort. Patients were split among 12 diagnoses, including SCD, Mild Cognitive Impairment (MCI), probable AD, Dementia with Lewy Bodies (DLB) and FTD (Table 1). pTau‐217 was measured using the novel AlzPath assay, while NfL was measured using the Quanterix Simoa assay. were used to classify patients as high or low for pTau‐217 and NfL levels. The pTau‐217 cutoff (0.58 pg/mL) was the Youden index cutoff derived from the present data, based on amyloid‐positive AD vs amyloid‐negative SCD diagnosis (n = 57), using amyloid status derived from cerebrospinal fluid or Amyloid positron emission tomography for classification. (18.2 pg/mL) was chosen based on the sample’s median age (64 years) and taking the value associated with the 90th percentile of normal NfL levels (NfL interface for physicians (shinyapps.io)).
Result
pTau‐217 levels were highest in patients with AD and Primary Progressive Aphasia (PPA), and lowest in those with Vascular Dementia (VaD) and other neurological diagnosis (Figure 1). NfL levels were highest in patients with VaD and FTD, and lowest in SCD and psychiatric diagnoses. The cutoffs highlighted similar trends, with higher proportions patients with elevated pTau‐217 levels observed in possible and probable AD, MCI, and DLB. Higher proportions of patients with high NfL levels were observed in FTD, PPA, VaD, and possible AD (Figure 2).
Conclusion
pTau‐217 concentrations vary as expected across the different diagnoses, with highest concentrations in AD pathology diagnostic groups. The elevated levels observed in DLB and PPA could be due to underlying AD co‐pathology. Following previous results, NfL concentrations were highest in FTD and lowest in psychiatry and SCD.
Background
Phosphorylated (P‐)tau, amyloid‐beta (Abeta)1‐42/1‐40, glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are the current key Alzheimer’s disease (AD) blood‐based ...biomarkers. Interpreting results of the four biomarkers simultaneously in a clinical context is challenging. A decision algorithm could aid in the interpretation, tailored to clinically relevant questions: 1) identify positive amyloid status among preclinical and prodromal AD stages, 2) discriminate AD‐dementia from frontotemporal dementia (FTD), 3) discriminate AD‐dementia from dementia with Lewy bodies (DLB). We aimed to develop such an interpretation tool.
Method
We included 1199 participants from the Amsterdam Dementia Cohort (table 1) with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD‐dementia, FTD (mixed pathologies) or DLB. Plasma P‐tau181, Abeta1‐42/1‐40, GFAP and NfL were measured with Simoa. NfL levels were adjusted for age (method: https://doi.org/10.1002/acn3.51676). We used LASSO regression with bootstrap (1000 iterations) to identify which plasma markers robustly contribute to the prediction of the outcomes of our clinically relevant questions. When a marker was selected in >95% of the iterations in at least one of the clinical scenarios, we qualified it as a contributing marker. Subsequently, we constructed UpSet plots applying Youden’s cutoffs as interpretation tool for the plasma results.
Result
P‐tau181, GFAP and NfL were selected as contributing biomarkers. Abeta1‐42/1‐40 was not selected. The panel of P‐tau181, GFAP and NfL had an AUC = 83% (95%CI: 76‐90%) to identify amyloid positivity in SCD+MCI, AUC = 87% (95%CI: 79‐94%) to differentiate AD‐dementia from FTD, and AUC = 73% (95%CI: 62‐84%) to differentiate AD‐dementia from DLB. The UpSet plots show the simultaneous interpretation of P‐tau181, GFAP and NfL results for each clinically relevant question (figure 1): e.g., when all three biomarkers are abnormal in participants with SCD+MCI, there is 83% agreement with an abnormal PET or CSF amyloid status, and when all three plasma markers are normal, there is 88% agreement with a normal amyloid status.
Conclusion
The combination of P‐tau181, GFAP and NfL in plasma could support decision making in different clinical contexts. UpSet plots enable easy interpretation of a combination of the markers, and could serve as a tool to support both detection and differential diagnosis of Alzheimer’s disease.
To examine neurobiological changes underlying obsessive–compulsive symptoms (OCS) we examined intrapair differences in behavior and fMRI brain activation in monozygotic twins discordant for OCS, ...using a Tower of London planning paradigm. Despite only mild evidence for impairment at the behavioral level, twins with OCS showed significantly decreased brain activation during planning in dorsolateral prefrontal cortex, thalamus pulvinar, and inferior parietal cortex. These findings are consistent with the hypothesis of disturbed cortico-striato-thalamo-cortical (CSTC) circuitry underlying OCS. In contrast to previous studies in patients with obsessive–compulsive disorder (OCD) we did not find robust evidence for reduced responsiveness in striatal brain regions. Together, these findings suggest that neurobiological mechanisms underlying OCS of environmental origin partly overlap with neurobiological changes in patients with OCD, where the disorder is likely caused by a combination of genetic and environmental influences. A difference between genetical and environmental etiologies may relate to the amount of reduced striatal responsiveness.
Background
Individuals with mild cognitive impairment (MCI) and abnormal amyloid are at increased risk to develop dementia and are considered to have prodromal Alzheimer’s disease (AD). Still, the ...precise pathophysiological processes that lead to dementia remain unclear. We studied in prodromal AD whether alterations can be detected in cerebrospinal fluid (CSF) proteomics that are related to progression to dementia.
Method
We selected from the Amsterdam Dementia Cohort 44 individuals with prodromal AD (67±7 years old, 22(44%) female), who had CSF proteomic data measured with Olink multiplex panels. Of 1010 proteins available, 501 (49%) were detected in at least 10 individuals per group and considered for further analyses. To aid interpretation, protein concentrations were Z transformed according to a normal control group (from the EMIF preclinAD study: 56 individuals with normal cognition and normal CSF amyloid and tau (68±6 years old, 28(50%) female) measured within the same experiment. Within prodromal AD, associations of protein levels with progression to dementia were tested with Cox proportional Hazard models, adjusting for p‐tau levels, age and sex. ClueGO was used for biological pathway enrichment analyses.
Result
Fourteen (33%) individuals with prodromal AD developed dementia over 2.6±1.4 years. In total 49 of the 501 proteins were associated with progression to dementia: for 90% of proteins a standard deviation lower concentration was associated with a 2 to 9‐fold increased risk to develop dementia (Figure 1a). Figure 1b shows a progression curve for individuals labelled according to tertiles of a protein summary score combining these proteins, with individuals having low concentrations showing an 4‐fold increased risk to progress to dementia compared to individuals with high concentrations (p<.01). Proteins associated with progression showed enrichment for several biological pathways that clustered together into 6 groups and were associated with regulation of MAPK cascade, angiogenesis, leukocyte activation in immune response, extracellular matrix organisation and regulation of neuronal death (Figure 1c; all pfdr <.05).
Conclusion
Neurodevelopmental pathways, angiogenesis and the leukocyte activation in immune response are involved in early AD pathophysiology and related to subsequent progression to dementia. Furthermore, CSF proteomics may have potential as a stratification tool to select fast decliners within prodromal AD.
Abstract
Background
Individuals with mild cognitive impairment (MCI) and abnormal amyloid are at increased risk to develop dementia and are considered to have prodromal Alzheimer’s disease (AD). ...Still, the precise pathophysiological processes that lead to dementia remain unclear. We studied in prodromal AD whether alterations can be detected in cerebrospinal fluid (CSF) proteomics that are related to progression to dementia.
Method
We selected from the Amsterdam Dementia Cohort 44 individuals with prodromal AD (67±7 years old, 22(44%) female), who had CSF proteomic data measured with Olink multiplex panels. Of 1010 proteins available, 501 (49%) were detected in at least 10 individuals per group and considered for further analyses. To aid interpretation, protein concentrations were Z transformed according to a normal control group (from the EMIF preclinAD study: 56 individuals with normal cognition and normal CSF amyloid and tau (68±6 years old, 28(50%) female) measured within the same experiment. Within prodromal AD, associations of protein levels with progression to dementia were tested with Cox proportional Hazard models, adjusting for p‐tau levels, age and sex. ClueGO was used for biological pathway enrichment analyses.
Result
Fourteen (33%) individuals with prodromal AD developed dementia over 2.6±1.4 years. In total 49 of the 501 proteins were associated with progression to dementia: for 90% of proteins a standard deviation lower concentration was associated with a 2 to 9‐fold increased risk to develop dementia (Figure 1a). Figure 1b shows a progression curve for individuals labelled according to tertiles of a protein summary score combining these proteins, with individuals having low concentrations showing an 4‐fold increased risk to progress to dementia compared to individuals with high concentrations (p<.01). Proteins associated with progression showed enrichment for several biological pathways that clustered together into 6 groups and were associated with regulation of MAPK cascade, angiogenesis, leukocyte activation in immune response, extracellular matrix organisation and regulation of neuronal death (Figure 1c; all pfdr <.05).
Conclusion
Neurodevelopmental pathways, angiogenesis and the leukocyte activation in immune response are involved in early AD pathophysiology and related to subsequent progression to dementia. Furthermore, CSF proteomics may have potential as a stratification tool to select fast decliners within prodromal AD.
Background
Age related hearing loss has been associated with increased prevalence and incidence of dementia. Underlying mechanisms that connect hearing loss with dementia remain largely unclear.
...Methods
We studied the association of hearing loss and other risk markers for dementia in two cohorts with normal cognition and different age: 65 participants from the EMIF‐AD 90+ study (mean age 92.7 years, 56.9% female) and 60 participants from the EMIF‐AD PreclinAD study (mean age 74.4, 43.3% female). Individuals were selected when they had hearing function (‘digits‐in‐noise test’) and neuropsychological testing available. Amyloid binding potential (BPND) was derived from dynamic PET scans. We used linear regression analysis and generalized estimating equations to test the association of hearing loss and BPND. We used linear mixed models to test the association of hearing function and cognition over time. In the oldest‐to‐old individuals, magnetic resonance imaging was available at the time of hearing function testing, and we performed mediation analyses to study whether cognitive decline is mediated through regional brain regions. All models included age, sex, and amyloid status as covariates, and longitudinal analyses were corrected for education years.
Results
Oldest‐to‐old individuals showed worse hearing functioning than the younger cohort (p< .001). In oldest‐to‐old hearing loss was not associated with BPND (p = .70), whereas younger individuals showed an association of hearing loss with higher BPND (p = .003, figure 1). Oldest‐to‐old individuals showed associations of worse hearing with a steeper decline in memory (β ± SE = ‐0.018 ± 0.007), global cognition (β ± SE = ‐0.017 ± 0.007) and language (β ± SE = ‐0.014 ± 0.007), while in the younger cohort worse hearing was associated with steeper decline in language only (β ± SE = ‐0.086 ± 0.02, figure 2). Mediation analyses demonstrated that the hippocampus and nucleus accumbens fully mediate the effects of hearing loss on memory and global cognition in the older individuals (figure 3‐4).
Conclusions
Hearing loss was associated with amyloid burden in younger individuals only, and with cognitive decline in both age groups. These results suggest that mechanisms linking hearing loss with risk for dementia depends on age.
Background
The earliest cognitive changes in Alzheimer’s disease (AD), even before amyloid‐beta (Aβ) is abnormal, remain largely unclear. We recently observed in a cohort of cognitively normal older ...monozygotic twins that 15% of twin‐pairs were discordant for Aβ status (Fig. 1). In this cohort, we investigated early cognitive changes by comparing cognitive decline over 4 years among twin‐pairs discordant for Aβ status (one twin normal Aβ and co‐twin abnormal Aβ), twin‐pairs with both normal Aβ (concordant Aβ‐), and twin‐pairs with both abnormal Aβ (concordant Aβ+). We expected the rate of cognitive decline to depend on baseline Aβ status with the least decline in concordant Aβ‐ twins and increasing decline from discordant Aβ‐, discordant Aβ+ to concordant Aβ+ twins.
Method
From the EMIF‐AD PreclinAD study we selected monozygotic twins with normal cognition at baseline who had a 18Fflutemetamol PET scan and at least one cognitive follow‐up available (n=188; 90 twin‐pairs) (Table 1). We defined Aβ group status using visual read of dynamic 18Fflutemetamol PET images. We tested whether twin Aβ concordance status at baseline was associated with cognitive performance at baseline and over 4 years time with two repeated measures in memory, attention, executive function (EF) and language domains using linear mixed models adjusted for age, sex, education and genetic relatedness.
Result
At baseline concordant Aβ+ twins showed impaired performance in all domains (Fig. 2). Discordant Aβ+ and concordant Aβ+ twins showed lower memory scores compared to concordant Aβ‐ twins (discordant Aβ+, p=0.02; concordant Aβ+, p=0.04). Over time, we found that for concordant Aβ‐ twins memory improved over time (p=0.002), discordant Aβ‐ twins did not change over time (p=0.15), while discordant Aβ+ and concordant Aβ+ twins declined on memory (concordant Aβ+, p=0.03; discordant Aβ+, p=0.07). No significant changes over time were observed in the other domains.
Conclusion
Our findings provide further support that the earliest cognitive changes in AD are found in the memory domain and that subtle memory changes may already by present before amyloid pathology can be detected on a PET scan.
Recently, the US Food and Drug Administration approved the tau-binding radiotracer
Fflortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired ...patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables.
We included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen κ. To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE).
We included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent (κ = 0.95, CI 0.91-0.99). None of the amyloid-negative CU participants (0/92 0%) and 1 amyloid-negative participant with DLB (1/12 8.3%) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 25.0%), 85 with AD (85/97 87.6%), and 3 with DLB (3/7 42.9%) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (β = -0.52, CI -0.74 to -0.30,
< 0.001) and participants with AD (β = -0.30, CI -0.58 to -0.02,
= 0.04).
The excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population.
This study provides Class II evidence that
Fflortaucipir visual read accurately distinguishes patients with low tau-tracer binding from those with high tau-tracer binding and is associated with amyloid positivity and cognitive decline.
While language is expressed in multiple modalities, including sign, writing, or whistles, speech is arguably the most common. The human vocal tract is capable of producing the bewildering diversity ...of the 7000 or so currently spoken languages, but relatively little is known about its genetic bases, especially in what concerns normal variation. Here, we capitalize on five cohorts totaling 632 Dutch twins with structural magnetic resonance imaging (MRI) data. Two raters placed clearly defined (semi)landmarks on each MRI scan, from which we derived 146 measures capturing the dimensions and shape of various vocal tract structures, but also aspects of the head and face. We used Genetic Covariance Structure Modeling to estimate the additive genetic, common environmental or non-additive genetic, and unique environmental components, while controlling for various confounds and for any systematic differences between the two raters. We found high heritability,
h
2
, for aspects of the skull and face, the mandible, the anteroposterior (horizontal) dimension of the vocal tract, and the position of the hyoid bone. These findings extend the existing literature, and open new perspectives for understanding the complex interplay between genetics, environment, and culture that shape our vocal tracts, and which may help explain cross-linguistic differences in phonetics and phonology.
Background
Different tau‐PET patterns have been observed in Alzheimer’s disease (AD) which may be associated with demographic factors, copathology and resilience. We and others previously found that ...not all Aβ‐positive AD patients are tau‐PET positive. It is currently not known whether tau pathology develops in these groups over time. Therefore, we aimed to examine longitudinal tau binding in tau‐PET negative individuals with symptomatic AD.
Method
We included 97 Aβ‐positive participants with clinical diagnosis of mild cognitive impairment or dementia due to AD (MCI/AD) of which 12 (13%) were tau‐PET negative. To compare, we included 131 tau‐PET negative cognitively unimpaired individuals (CU) of which 93 (71%) were Aβ‐negative and 38 (29%) Aβ‐positive. Tau‐status was defined by 18Fflortaucipir PET consensus visual read of two nuclear physicians according to US Food and Drug Administration‐approved guidelines. 18Fflortaucipir SUVr at baseline (N = 225) and after ±2 years (N = 81) was quantified in an early tau region reflecting Braak I (entorhinal cortex), the medial temporal lobe (MTL), and a combined visual read region of interest (ROI) (parietal, occipital, and posterior lateral temporal lobe). We used age‐and sex‐adjusted linear mixed models to compare tau accumulation.
Result
Demographics are shown in table 1. Compared to MCI/AD A+T+, MCI/AD A+T‐ were older (p<0.001) and more often male (p = 0.015). MCI/AD A+T‐ did not differ from CU A‐T‐ in baseline tau‐PET SUVr, but had a slightly lower SUVr in Braak I compared to CU A+T‐ (p = 0.040) (figure 1). After ±2 years, all MCI/AD A+T‐ participants who underwent follow up remained visual read tau negative. However, MCI/AD A+T‐ showed a steeper increase in Braak I and MTL tau‐PET SUVr compared to CU A‐T‐ (figure 2A,B) and in Braak I compared to CU A+T‐ (β = 0.31, p = 0.036). Interestingly, MCI/AD A+T‐ showed a significantly steeper tau‐PET SUVr increase compared to MCI/AD A+T+ in Braak I (β = 0.29, p = 0.029) (figure 2A).
Conclusion
Although visual read tau‐PET status remains stable over time, our results indicate that tau‐negative MCI/AD patients do accumulate tau over time, most pronounced in early tau regions. This highlights the relevance of quantifying tau regionally over time in tau‐PET negative individuals with clinical AD diagnosis.
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![Performance of a [ 18 F]Flo...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1526-632X_0028-3878/small "Performance of a [ 18 F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia With Lewy Bodies")
