The concept of the right temporal variant of frontotemporal dementia (rtvFTD) is still equivocal. The syndrome accompanying predominant right anterior temporal atrophy has previously been described ...as memory loss, prosopagnosia, getting lost and behavioural changes. Accurate detection is challenging, as the clinical syndrome might be confused with either behavioural variant FTD (bvFTD) or Alzheimer's disease. Furthermore, based on neuroimaging features, the syndrome has been considered a right-sided variant of semantic variant primary progressive aphasia (svPPA). Therefore, we aimed to demarcate the clinical and neuropsychological characteristics of rtvFTD versus svPPA, bvFTD and Alzheimer's disease. Moreover, we aimed to compare its neuroimaging profile against svPPA, which is associated with predominant left anterior temporal atrophy. Of 619 subjects with a clinical diagnosis of frontotemporal dementia or primary progressive aphasia, we included 70 subjects with a negative amyloid status in whom predominant right temporal lobar atrophy was identified based on blinded visual assessment of their initial brain MRI scans. Clinical symptoms were assessed retrospectively and compared with age- and sex-matched patients with svPPA (n = 70), bvFTD (n = 70) and Alzheimer's disease (n = 70). Prosopagnosia, episodic memory impairment and behavioural changes such as disinhibition, apathy, compulsiveness and loss of empathy were the most common initial symptoms, whereas during the disease course, patients developed language problems such as word-finding difficulties and anomia. Distinctive symptoms of rtvFTD compared to the other groups included depression, somatic complaints, and motor/mental slowness. Aside from right temporal atrophy, the imaging pattern showed volume loss of the right ventral frontal area and the left temporal lobe, which represented a close mirror image of svPPA. Atrophy of the bilateral temporal poles and the fusiform gyrus were associated with prosopagnosia in rtvFTD. Our results highlight that rtvFTD has a unique clinical presentation. Since current diagnostic criteria do not cover specific symptoms of the rtvFTD, we propose a diagnostic tree to be used to define diagnostic criteria and call for an international validation.
Several promising plasma biomarkers for Alzheimer's disease have been recently developed, but their neuropathological correlates have not yet been fully determined. To investigate and compare ...independent associations between multiple plasma biomarkers (p‐tau181, p‐tau217, p‐tau231, Aβ42/40, GFAP, and NfL) and neuropathologic measures of amyloid and tau, we included 105 participants from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with antemortem plasma samples and a postmortem neuropathological exam, 48 of whom had longitudinal p‐tau217 and p‐tau181. When simultaneously including plaque and tangle loads, the Aβ42/40 ratio and p‐tau231 were only associated with plaques (ρAβ42/4095%CI = −0.53−0.65, −0.35, ρp‐tau23195%CI = 0.280.10, 0.43), GFAP was only associated with tangles (ρGFAP95%CI = 0.390.17, 0.57), and p‐tau217 and p‐tau181 were associated with both plaques (ρp‐tau21795%CI = 0.400.21, 0.56, ρp‐tau18195%CI = 0.360.15, 0.50) and tangles (ρp‐tau21795%CI = 0.520.34, 0.66; ρp‐tau18195%CI = 0.360.17, 0.52). A model combining p‐tau217 and the Aβ42/40 ratio showed the highest accuracy for predicting the presence of Alzheimer's disease neuropathological change (ADNC, AUC95%CI = 0.890.82, 0.96) and plaque load (R2 = 0.55), while p‐tau217 alone was optimal for predicting tangle load (R2 = 0.45). Our results suggest that high‐performing assays of plasma p‐tau217 and Aβ42/40 might be an optimal combination to assess Alzheimer's‐related pathology in vivo.
Synopsis
This study conducted a head‐to‐head comparison between multiple plasma biomarkers and neuropathological measures of amyloid plaques and neurofibrillary tangles.
Plasma p‐tau217 and p‐tau181 are independently associated with both amyloid plaques and tau neurofibrillary tangles, the main pathological hallmarks of Alzheimer's disease.
Plasma p‐tau217 may be a better Alzheimer's biomarker than p‐tau181 as it shows stronger associations with Alzheimer's pathology and is more sensitive to early pathological changes.
Plasma p‐tau217 longitudinal changes may help in predicting the presence of Alzheimer's pathology.
Plasma Aβ42/40 and plasma p‐tau231 are specifically associated with amyloid pathology, whereas plasma glial fibrillary acidic protein (GFAP) is specifically associated with tau pathology.
Plasma neurofilament light (NfL) is increased in participants with cerebral white matter rarefaction even after accounting for the presence of Alzheimer's disease pathology.
This study conducted a head‐to‐head comparison between multiple plasma biomarkers and neuropathological measures of amyloid plaques and neurofibrillary tangles.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Purpose
To examine associations between the
APOE-ε2
and
APOE-ε4
alleles and core Alzheimer’s disease (AD) pathological hallmarks as measured by amyloid-β (Aβ) and tau PET in older individuals without ...dementia.
Methods
We analyzed data from 462 ADNI participants without dementia who underwent Aβ (
18
Fflorbetapir or
18
Fflorbetaben) and tau (
18
Fflortaucipir) PET, structural MRI, and cognitive testing. Employing
APOE-ε3
homozygotes as the reference group, associations between
APOE-ε2
and
APOE-ε4
carriership with global Aβ PET and regional tau PET measures (entorhinal cortex (ERC), inferior temporal cortex, and Braak-V/VI neocortical composite regions) were investigated using linear regression models. In a subset of 156 participants, we also investigated associations between
APOE
genotype and regional tau accumulation over time using linear mixed models. Finally, we assessed whether Aβ mediated the cross-sectional and longitudinal associations between
APOE
genotype and tau.
Results
Compared to
APOE-ε3
homozygotes,
APOE-ε2
carriers had lower global Aβ burden (β
std
95% confidence interval (CI): − 0.31 − 0.45, − 0.16,
p
= 0.034) but did not differ on regional tau burden or tau accumulation over time
. APOE-ε4
participants showed higher Aβ (β
std
95%CI: 0.64 0.42, 0.82,
p
< 0.001) and tau burden (β
std
range: 0.27-0.51, all
p
< 0.006). In mediation analyses,
APOE-ε4
only retained an Aβ-independent effect on tau in the ERC.
APOE-ε4
showed a trend towards increased tau accumulation over time in Braak-V/VI compared to
APOE-ε3
homozygotes (β
std
95%CI: 0.10 − 0.02, 0.18,
p
= 0.11), and this association was fully mediated by baseline Aβ.
Conclusion
Our data suggest that the established protective effect of the
APOE-ε2
allele against developing clinical AD is primarily linked to resistance against Aβ deposition rather than tau pathology.
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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
Abstract
Alterations in cognitive performance have been noted in nondemented subjects with elevated accumulation of amyloid-β (Aβ) fibrils. However, it is not yet understood whether brain function is ...already influenced by Aβ deposition during the very earliest stages of the disease. We therefore investigated associations between 18FFlutemetamol PET, resting-state functional connectivity, gray and white matter structure and cognitive performance in 133 cognitively normal elderly that exhibited normal global Aβ PET levels. 18FFlutemetamol uptake in regions known to accumulate Aβ fibrils early in preclinical AD (i.e., mainly certain parts of the default-mode network) was positively associated with dynamic but not static functional connectivity (r = 0.77). Dynamic functional connectivity was further related to better cognitive performance (r = 0.21–0.72). No significant associations were found for Aβ uptake with gray matter volume or white matter diffusivity. The findings demonstrate that the earliest accumulation of Aβ fibrils is associated with increased functional connectivity, which occurs before any structural alterations. The enhanced functional connectivity may reflect a compensatory mechanism to maintain high cognitive performance in the presence of increasing amyloid accumulation during the earliest phases of AD.
Abstract
Background
Blood-based biomarkers for Alzheimer’s disease (AD) might facilitate identification of participants for clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD ...diagnostics. We examined the potential of plasma markers Abeta
(1-42/1-40)
, glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) to identify cerebral amyloidosis and/or disease severity.
Methods
We included individuals with a positive (
n
= 176: 63 ± 7 years, 87 (49%) females) or negative (
n
= 76: 61 ± 9 years, 27 (36%) females) amyloid PET status, with syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET−), mild cognitive impairment (26 PET+, 24 PET−), or AD-dementia (132 PET+). Plasma Abeta
(1-42/1-40)
, GFAP, and NfL were measured by Simoa. We applied two-way ANOVA adjusted for age and sex to investigate the associations of the plasma markers with amyloid PET status and syndrome diagnosis; logistic regression analysis with Wald’s backward selection to identify an optimal panel that identifies amyloid PET positivity; age, sex, and education-adjusted linear regression analysis to investigate associations between the plasma markers and neuropsychological test performance; and Spearman’s correlation analysis to investigate associations between the plasma markers and medial temporal lobe atrophy (MTA).
Results
Abeta
(1-42/1-40)
and GFAP independently associated with amyloid PET status (
p
= 0.009 and
p
< 0.001 respectively), and GFAP and NfL independently associated with syndrome diagnosis (
p
= 0.001 and
p
= 0.048 respectively). The optimal panel identifying a positive amyloid status included Abeta
(1-42/1-40)
and GFAP, alongside age and APOE (AUC = 88% (95% CI 83–93%), 82% sensitivity, 86% specificity), while excluding NfL and sex. GFAP and NfL robustly associated with cognitive performance on global cognition and all major cognitive domains (GFAP: range standardized β (sβ) = − 0.40 to − 0.26; NfL: range sβ = − 0.35 to − 0.18; all:
p
< 0.002), whereas Abeta
(1-42/1-40)
associated with global cognition, memory, attention, and executive functioning (range sβ = 0.22 – 0.11; all:
p
< 0.05) but not language. GFAP and NfL showed moderate positive correlations with MTA (both: Spearman’s rho> 0.33,
p
< 0.001). Abeta
(1-42/1-40)
showed a moderate negative correlation with MTA (Spearman’s rho = − 0.24,
p
= 0.001).
Discussion and conclusions
Combination of plasma Abeta
(1-42/1-40)
and GFAP provides a valuable tool for the identification of amyloid PET status. Furthermore, plasma GFAP and NfL associate with various disease severity measures suggesting potential for disease monitoring.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
PET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)‐related demographic, cognitive, genetic and neuroimaging markers. We examined 771 ...participants with normal cognition, mild cognitive impairment or dementia from BioFINDER‐2 (n = 400) and ADNI (n = 371). All had tau‐PET (18FRO948 in BioFINDER‐2, 18Fflortaucipir in ADNI) and CSF p‐tau181 biomarkers available. Plasma p‐tau181 and plasma/CSF p‐tau217 were available in BioFINDER‐2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66 and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p‐tau181 and p‐tau217 levels were independently of tau PET associated with higher age, and APOEɛ4‐carriership and Aβ‐positivity, while increased tau‐PET signal in the temporal cortex was associated with worse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p‐tau181 and p‐tau217 levels being more tightly linked with early markers of AD (especially Aβ‐pathology), while tau‐PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression.
SYNOPSIS
Tau pathology in Alzheimer's disease (AD) can be measured using neuroimaging (PET) and biofluid (CSF and plasma) markers. This study explores whether the tau biomarkers are comparable to each other or carry unique information about AD‐related demographic, cognitive, genetic and neuroimaging markers.
Concordance ranged between 66 and 86% for biofluid‐ versus PET‐based tau biomarkers.
CSF and plasma p‐tau181 and p‐tau217 levels were independently associated with aging, APOE ɛ4, and Aβ positivity.
Increased tau PET signal was more strongly associated with worse cognitive performance and reduced cortical thickness.
The majority of results were consistent between the discovery and the replication cohort.
Results support the hypothesis that the three tau biomarkers provide partially independent information.
Tau pathology in Alzheimer's disease (AD) can be measured using neuroimaging (PET) and biofluid (CSF and plasma) markers. This study explores whether the tau biomarkers are comparable to each other or carry unique information about AD‐related demographic, cognitive, genetic and neuroimaging markers.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To characterize the course of Alzheimer's disease (AD) over a longer time interval, we aimed to construct a disease course model for the entire span of the disease using two separate cohorts ranging ...from preclinical AD to AD dementia. We modelled the progression course of 436 patients with AD continuum and investigated the effects of apolipoprotein E ε4 (APOE ε4) and sex on disease progression. To develop a model of progression from preclinical AD to AD dementia, we estimated Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-cog 13) scores. When calculated as the median of ADAS-cog 13 scores for each cohort, the estimated time from preclinical AD to MCI due to AD was 7.8 years and preclinical AD to AD dementia was 15.2 years. ADAS-cog 13 scores deteriorated most rapidly in women APOE ε4 carriers and most slowly in men APOE ε4 non-carriers (p < 0.001). Our results suggest that disease progression modelling from preclinical AD to AD dementia may help clinicians to estimate where patients are in the disease course and provide information on variation in the disease course by sex and APOE ε4 status.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
In Alzheimer’s disease (AD), younger symptom onset is associated with accelerated disease progression and tau spreading, yet the mechanisms underlying faster disease manifestation are ...unknown. To address this, we combined resting-state fMRI and longitudinal tau-PET in two independent samples of controls and biomarker-confirmed AD patients (ADNI/BioFINDER,
n
= 240/57). Consistent across both samples, we found that younger symptomatic AD patients showed stronger tau-PET in globally connected fronto-parietal hubs, i.e., regions that are critical for maintaining cognition in AD. Stronger tau-PET in hubs predicted faster subsequent tau accumulation, suggesting that tau in globally connected regions facilitates connectivity-mediated tau spreading. Further, stronger tau-PET in hubs mediated the association between younger age and faster tau accumulation in symptomatic AD patients, which predicted faster cognitive decline. These independently validated findings suggest that younger AD symptom onset is associated with stronger tau pathology in brain hubs, and accelerated tau spreading throughout connected brain regions and cognitive decline.
Neuropsychiatric symptoms (NPS) are common in individuals with Alzheimer's disease (AD) dementia, but substantial heterogeneity exists in the manifestation of NPS. Sex differences may explain this ...clinical variability. We aimed to investigate the sex differences in the prevalence and severity of NPS in AD dementia.
Literature searches were conducted in Embase, MEDLINE/PubMed, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, PsycINFO, and Google Scholar from inception to February 2021. Study selection, data extraction, and quality assessment were conducted in duplicate. Effect sizes were calculated as odds ratios (OR) for NPS prevalence and Hedges' g for NPS severity. Data were pooled using random-effects models. Sources of heterogeneity were examined using meta-regression analyses.
Sixty-two studies were eligible representing 21,554 patients (61.2% females). The majority of the included studies had an overall rating of fair quality (71.0%), with ten studies of good quality (16.1%) and eight studies of poor quality (12.9%). There was no sex difference in the presence of any NPS (k = 4, OR = 1.35 95% confidence interval 0.78, 2.35) and overall NPS severity (k = 13, g = 0.04 - 0.04, 0.12). Regarding specific symptoms, female sex was associated with more prevalent depressive symptoms (k = 20, OR = 1.60 1.28, 1.98), psychotic symptoms (general psychosis k = 4, OR = 1.62 1.12, 2.33; delusions k = 12, OR = 1.56 1.28, 1.89), and aberrant motor behavior (k = 6, OR = 1.47 1.09, 1.98). In addition, female sex was related to more severe depressive symptoms (k = 16, g = 0.24 0.14, 0.34), delusions (k = 10, g = 0.19 0.04, 0.34), and aberrant motor behavior (k = 9, g = 0.17 0.08, 0.26), while apathy was more severe among males compared to females (k = 11, g = - 0.10 - 0.18, - 0.01). There was no association between sex and the prevalence and severity of agitation, anxiety, disinhibition, eating behavior, euphoria, hallucinations, irritability, and sleep disturbances. Meta-regression analyses revealed no consistent association between the effect sizes across studies and method of NPS assessment and demographic and clinical characteristics.
Female sex was associated with a higher prevalence and greater severity of several specific NPS, while male sex was associated with more severe apathy. While more research is needed into factors underlying these sex differences, our findings may guide tailored treatment approaches of NPS in AD dementia.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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