Tau accumulation starts during the preclinical phase of Alzheimer's disease and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated ...with tau accumulation and spread. Studying genetically identical twin-pairs may give insight into genetic and environmental contributions to tau pathology, as similarities in identical twin-pairs largely result from genetic factors, while differences in identical twin-pairs can largely be attributed to non-shared, environmental factors. This study aimed to examine similarities and dissimilarities in a cohort of genetically identical older twin-pairs in 1) tau load and 2) spatial distribution of tau, measured with 18Fflortaucipir PET. We selected 78 genetically identical twins (39 pairs; average age 73 ± 6), enriched for amyloid-β pathology and APOE ε4 carriership, who underwent dynamic 18Fflortaucipir PET. We extracted binding potentials (BPND) in entorhinal, temporal, widespread neocortical and global regions, and examined within-pair similarities in BPND using age and sex corrected intra-class correlations. Furthermore, we tested whether twin-pairs showed a more similar spatial 18Fflortaucipir distribution compared to non-twin pairs, and whether the participant's co-twin could be identified solely based on the spatial 18Fflortaucipir distribution. Last, we explored whether environmental (e.g. physical activity, obesity) factors could explain observed differences in twins of a pair in 18Fflortaucipir BPND. On visual inspection, Alzheimer's disease-like 18Fflortaucipir PET patterns were observed, and although we mainly identified similarities in twin-pairs, some pairs showed strong dissimilarities. 18Fflortaucipir BPND was correlated in twins in the entorhinal (r = 0.40; p = 0.01), neocortical (r = 0.59; p < 0.01) and global (r = 0.56; p < 0.01) regions, but not in the temporal region (r = 0.20; p = 0.10). The 18Fflortaucipir distribution pattern was significantly more similar between twins of the same pair (mean r = 0.27; SD = 0.09) than between non-twin pairings of participants (mean r = 0.01; SD = 0.10) (p < 0.01), also after correcting for proxies of off-target binding. Based on the spatial 18Fflortaucipir distribution, we could identify with an accuracy of 86% which twins belonged to the same pair. Finally, within-pair differences in 18Fflortaucipir BPND were associated with within-pair differences in depressive symptoms (0.37<β<0.56), physical activity (-0.41<β<-0.42) and social activity (-0.32<β<-0.36) (all p < 0.05). Overall, identical twin-pairs were comparable in tau load and spatial distribution, highlighting the important role of genetic factors in the accumulation and spreading of tau pathology. Considering also the presence of dissimilarities in tau pathology in identical twin-pairs, our results additionally support a role for (potentially modifiable) environmental factors in the onset of Alzheimer's disease pathological processes, which may be of interest for future prevention strategies.
Semiquantitative PET measures such as SUV ratio (SUVr) have several advantages over quantitative measures, such as practical applicability and relative computational simplicity. However, SUVr may ...potentially be affected by changes in blood flow, whereas quantitative measures such as nondisplaceable binding potential (BP
) are not. For
F-flortaucipir PET, the sensitivity of SUVr for changes in blood flow is currently unknown. Therefore, we compared semiquantitative (SUVr) and quantitative (BP
) parameters of longitudinal
F-flortaucipir PET scans and assessed their vulnerability to changes in blood flow.
Subjects with subjective cognitive decline (
= 38) and Alzheimer disease patients (
= 24) underwent baseline and 2-y follow-up dynamic
F-flortaucipir PET scans. BP
and relative tracer delivery were estimated using receptor parametric mapping, and SUVr at 80-100 min was calculated. Regional SUVrs were compared with corresponding distribution volume ratio (BP
+ 1) using paired
tests. Additionally, simulations were performed to model effects of larger flow changes in different binding categories.
Results in subjective cognitive decline and Alzheimer disease showed only minor differences between SUVr and BP
changes over time. Relative tracer delivery changes were small in all groups. Simulations illustrated a variable bias for SUVr depending on the amount of binding.
SUVr provided an accurate estimate of changes in specific binding for
F-flortaucipir over a 2-y follow-up during which changes in flow were small. Notwithstanding, simulations showed that large(r) flow changes may affect
F-flortaucipir SUVr. Given that it is currently unknown to what order of magnitude pharmacotherapeutic interventions may induce changes in cerebral blood flow, caution may be warranted when changes in flow are potentially large(r), as in clinical trials.
Semiquantitative PET measures such as SUV ratio (SUVr) have several advantages over quantitative measures, such as practical applicability and relative computational simplicity. However, SUVr may ...potentially be affected by changes in blood flow, whereas quantitative measures such as nondisplaceable binding potential (BPND) are not. For 18F-flortaucipir PET, the sensitivity of SUVr for changes in blood flow is currently unknown. Therefore, we compared semiquantitative (SUVr) and quantitative (BPND) parameters of longitudinal 18F-flortaucipir PET scans and assessed their vulnerability to changes in blood flow. Methods: Subjects with subjective cognitive decline (n = 38) and Alzheimer disease patients (n = 24) underwent baseline and 2-y follow-up dynamic 18F-flortaucipir PET scans. BPND and relative tracer delivery were estimated using receptor parametric mapping, and SUVr at 80–100 min was calculated. Regional SUVrs were compared with corresponding distribution volume ratio (BPND + 1) using paired t tests. Additionally, simulations were performed to model effects of larger flow changes in different binding categories. Results: Results in subjective cognitive decline and Alzheimer disease showed only minor differences between SUVr and BPND changes over time. Relative tracer delivery changes were small in all groups. Simulations illustrated a variable bias for SUVr depending on the amount of binding. Conclusion: SUVr provided an accurate estimate of changes in specific binding for 18F-flortaucipir over a 2-y follow-up during which changes in flow were small. Notwithstanding, simulations showed that large(r) flow changes may affect 18F-flortaucipir SUVr. Given that it is currently unknown to what order of magnitude pharmacotherapeutic interventions may induce changes in cerebral blood flow, caution may be warranted when changes in flow are potentially large(r), as in clinical trials.
Background
The 2017 Alzheimer’s disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity ...(Phases 1–2), clinical validity (Phases 3–4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research.
Methods
We critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer’s Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers.
Results
The 2020 update applies to all AD diagnostic biomarkers. In Phases 2–3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures.
Discussion
This revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
To assess the
Fflortaucipir binding distribution across
mutations in presymptomatic and symptomatic carriers.
We compared regional
Fflortaucipir binding potential (BP
) derived from a 130-minute ...dynamic
Fflortaucipir PET scan in 9 (pre)symptomatic
mutation carriers (4 with P301L 1 symptomatic, 2 with R406W 1 symptomatic, 1 presymptomatic L315R, 1 presymptomatic S320F, and 1 symptomatic G272V carrier) with 30 cognitively normal controls and 52 patients with Alzheimer disease.
FFlortaucipir BP
images showed overall highest binding in the symptomatic carriers. This was most pronounced in the symptomatic R406W carrier in whom tau binding exceeded the normal control range in the anterior cingulate cortex, insula, amygdala, temporal, parietal, and frontal lobe. Elevated medial temporal lobe BP
was observed in a presymptomatic R406W carrier. The single symptomatic carrier and 1 of the 3 presymptomatic P301L carriers showed elevated
Fflortaucipir BP
in the insula, parietal, and frontal lobe compared to controls. The symptomatic G272V carrier exhibited a widespread elevated cortical BP
, with at neuropathologic examination a combination of 3R pathology and encephalitis. The L315R presymptomatic mutation carrier showed higher frontal BP
compared to controls. The BP
values of the S320F presymptomatic mutation carrier fell within the range of controls.
Presymptomatic
mutation carriers already showed subtle elevated tau binding, whereas symptomatic
mutation carriers showed a more marked increase in
Fflortaucipir BP
. Tau deposition was most pronounced in R406W
(pre)symptomatic mutation carriers, which is associated with both 3R and 4R tau accumulation. Thus,
Fflortaucipir may serve as an early biomarker for
mutation carriers in mutations that cause 3R/4R tauopathies.
Purpose
In vivo Alzheimer’s disease (AD) biomarkers for tau pathology are cerebrospinal fluid (CSF) phosphorylated tau (p-tau) and
18
Fflortaucipir positron emission tomography (PET). Our aim was to ...assess associations between CSF p-tau with
18
Fflortaucipir PET and the associations of both tau biomarkers with cognition and atrophy.
Methods
We included 78 amyloid positive cognitively impaired patients (clinical diagnoses mild cognitive impairment (MCI,
n
= 8) and AD dementia (
n
= 45) and 25 cognitively normal subjects with subjective cognitive decline (SCD) (40% amyloid-positive)). Dynamic 130 min
18
Fflortaucipir PET scans were acquired to generate binding potential (BP
ND
) images using receptor parametric mapping and standardized uptake values ratios of 80–100 min (SUVr
80-100min
) post injection. We obtained regional BP
ND
and SUVr from entorhinal, limbic, and neocortical regions-of-interest (ROIs), closely aligning to the neuropathological tau staging schemes. Cognition was assessed using MMSE and composite scores of four cognitive domains, and atrophy was measured using gray matter volume covering the major brain lobes. First, we used linear regressions to investigate associations between CSF p-tau (independent variable) and tau PET (dependent variable). Second, we used linear regressions to investigate associations between CSF p-tau, tau PET (separate independent variables, model 1), and cognition (dependent variable). We then assessed the independent effects of CSF p-tau and tau PET on cognition by simultaneously adding the other tau biomarker as a predictor (model 2). Finally, we performed the same procedure for model 1 and 2, but replaced cognition with atrophy. Models were adjusted for age, sex, time lag between assessments, education (cognition only), and total intracranial volume (atrophy only).
Results
Higher
18
Fflortaucipir BP
ND
was associated with higher CSF p-tau (range of standardized betas (sβ) across ROIs, 0.43–0.46; all
p
< 0.01).
18
Fflortaucipir BP
ND
was more strongly associated with cognition and atrophy than CSF p-tau. When
18
Fflortaucipir BP
ND
and CSF p-tau were entered simultaneously,
18
Fflortaucipir BP
ND
(range sβ = − 0.20 to – 0.57, all
p
< 0.05) was strongly associated with multiple cognitive domains and atrophy regions. SUVr showed comparable results to BP
ND
.
Conclusion
Regional
18
Fflortaucipir BP
ND
correlated stronger with cognition and neurodegeneration than CSF p-tau, suggesting that tau PET more accurately reflects disease severity in AD.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Screening for Fabry disease in patients with small fiber neuropathy has been suggested, especially since Fabry disease is potentially treatable. However, the diagnostic yield of testing for Fabry ...disease in isolated small fiber neuropathy patients has never been systematically investigated. Our aim is to determine the presence of Fabry disease in patients with small fiber neuropathy.
Patients referred to our institute, who met the criteria for isolated small fiber neuropathy were tested for Fabry disease by measurement of alpha-Galactosidase A activity in blood, lysosomal globotriaosylsphingosine in urine and analysis on possible GLA gene mutations.
725 patients diagnosed with small fiber neuropathy were screened for Fabry disease. No skin abnormalities were seen except for redness of the hands or feet in 30.9% of the patients. Alfa-Galactosidase A activity was tested in all 725 patients and showed diminished activity in eight patients. Lysosomal globotriaosylsphingosine was examined in 509 patients and was normal in all tested individuals. Screening of GLA for mutations was performed for 440 patients, including those with diminished α-Galactosidase A activity. Thirteen patients showed a GLA gene variant. One likely pathogenic variant was found in a female patient. The diagnosis Fabry disease could not be confirmed over time in this patient. Eventually none of the patients were diagnosed with Fabry disease.
In patients with isolated small fiber neuropathy, and no other signs compatible with Fabry disease, the diagnostic yield of testing for Fabry disease is extremely low. Testing for Fabry disease should be considered only in cases with additional characteristics, such as childhood onset, cardiovascular disease, renal failure, or typical skin lesions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of this study was to investigate the test–retest (TRT) repeatability of various parametric quantification methods for 18FFlortaucipir positron emission tomography (PET). We included eight ...subjects with dementia or mild cognitive impairment due to Alzheimer’s disease and six cognitively normal subjects. All underwent two 130-min dynamic 18FFlortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40–60, 80–100 and 110–130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest–test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68–2.15) to 6.84% (2.99–11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78–3.58) vs. SUVr80–100: 3.05% (1.28–5.52), p < 0.001. Furthermore, for SUVr80–100 and SUVr110–130, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Purpose
We aimed to investigate associations between tau pathology and relative cerebral blood flow (rCBF), and their relationship with cognition in Alzheimer’s disease (AD), by using a single ...dynamic
18
Fflortaucipir positron emission tomography (PET) scan.
Methods
Seventy-one subjects with AD (66 ± 8 years, mini-mental state examination (MMSE) 23 ± 4) underwent a dynamic 130-min
18
Fflortaucipir PET scan. Cognitive assessment consisted of composite scores of four cognitive domains. For tau pathology and rCBF, receptor parametric mapping (cerebellar gray matter reference region) was used to create uncorrected and partial volume-corrected parametric images of non-displaceable binding potential (BP
ND
) and
R
1
, respectively. (Voxel-wise) linear regressions were used to investigate associations between BP
ND
and/or
R
1
and cognition
.
Results
Higher
18
Fflortaucipir BP
ND
was associated with lower
R
1
in the lateral temporal, parietal and occipital regions. Higher medial temporal BP
ND
was associated with worse memory, and higher lateral temporal BP
ND
with worse executive functioning and language. Higher parietal BP
ND
was associated with worse executive functioning, language and attention, and higher occipital BP
ND
with lower cognitive scores across all domains. Higher frontal BP
ND
was associated with worse executive function and attention. For
18
Fflortaucipir
R
1
, lower values in the lateral temporal and parietal ROIs were associated with worse executive functioning, language and attention, and lower occipital
R
1
with lower language and attention scores. When
18
Fflortaucipir BP
ND
and
R
1
were modelled simultaneously, associations between lower
R
1
in the lateral temporal ROI and worse attention remained, as well as for lower parietal
R
1
and worse executive functioning and attention.
Conclusion
Tau pathology was associated with locally reduced rCBF. Tau pathology and low rCBF were both independently associated with worse cognitive performance. For tau pathology, these associations spanned widespread neocortex, while for rCBF, independent associations were restricted to lateral temporal and parietal regions and the executive functioning and attention domains. These findings indicate that each biomarker may independently contribute to cognitive impairment in AD.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Both plasma tau phosphorylated at threonine-181 (pTau181) and tau PET show potential for detecting Alzheimer's disease (AD) pathology and predicting clinical progression. In this study, we performed ...a head-to-head comparison between plasma pTau181 and tau PET along the AD continuum.
We included participants from the Amsterdam Dementia Cohort who underwent
F-flortaucipir (tau) PET and had a plasma sample biobanked within 12 mo from tau PET. Fifty subjective cognitive decline (SCD) participants (31 Aβ-negative and 19 Aβ-positive) and 60 Aβ-positive participants with mild cognitive impairment (MCI) or dementia due to AD were included. A subset had 2-y longitudinal plasma pTau181 and tau PET available (
= 40). Longitudinal neuropsychological test data covering 3.2 ± 2.7 y from both before and after tau PET were available. Plasma pTau181 and tau PET were compared in their accuracies in discriminating between cognitive stage (MCI/AD vs. SCD) and preclinical Aβ status (SCD Aβ-positive vs. SCD Aβ-negative), their associations with cross-sectional and longitudinal neuropsychological test performance, and their longitudinal changes over time.
When discriminating between preclinical Aβ status, the area under the curve (AUC) for plasma pTau181 (0.83) and tau PET (entorhinal, 0.87; temporal, 0.85; neocortical, 0.67) were equally high (all DeLong
> 0.05), but tau PET outperformed plasma pTau181 in discriminating MCI/AD from SCD (AUC for plasma pTau181: 0.74; AUCs for tau PET: entorhinal, 0.89; temporal, 0.92; neocortical, 0.89) (all
< 0.01). Overall, tau PET showed stronger associations with cognitive decline and was associated with a wider variety of cognitive tests than plasma pTau181 (plasma pTau181, -0.02 > β < -0.12; tau PET, -0.01 > β < -0.22). Both plasma pTau181 and tau PET increased more steeply over time in MCI/AD than in SCD (
< 0.05), but only tau PET annual changes were associated with cognitive decline.
Our results suggest that plasma pTau181 and tau PET perform equally well in identifying Aβ pathology but that tau PET better monitors disease stage and clinical progression.
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