Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring最新文献

Introduction: Blood-based biomarkers seem promising for the diagnosis of Alzheimer's disease (AD).

Methods: We performed a systematic review and meta-analysis on the potential of blood phosphorylated Tau181 (p-tau181) to differentiate amyloid-positive (A+) and amyloid-negative (A-) subjects. Two meta-analyses were conducted, showing the mean p-tau values in blood and cerebrospinal fluid (CSF) in the A+ and A- group, and the second comparing the mean p-tau concentrations in blood and CSF among A+ versus A- participants, by laboratory assessment method.

Results: Eighteen studies (2764 A+ and 5646 A- subjects) were included. The single-group meta-analysis showed mean higher blood p-tau181 values in the A+ than in the A- group. In the head-to-head meta-analysis, blood p-tau reliably differentiated A+ patients from A- participants.

Discussion: Regardless of the laboratory technique, blood p-tau181 reliably differentiates A+ and A- subjects. Therefore, it might have important applications for early diagnosis and inclusion in clinical trials for AD patients.

Highlights: The role of blood-based biomarkers in discriminating AD patients is still uncertain.Blood p-tau181 distinguishes among amyloid-positive and amyloid-negative subjects.Blood p-tau181 might allow early diagnosis and inclusion in clinical trials.

Introduction: Studies have shown that blood biomarkers can differentiate dementia disorders. However, the diagnosis of dementia still relies primarily on cerebrospinal fluid and imaging modalities. The new disease-modifying treatments call for more widely applicable biomarkers.

Methods: Plasma samples (n = 250) from two mixed memory clinic were included. Participants were divided into amyloid beta positives (Aβ+) and Aβ negatives (Aβ-). Plasma phosphorylated tau (p-tau) 181, p-tau231, Aβ1-42 (Aβ42), Aβ40, Aβ42/Aβ40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured by single molecule array.

Results: Significant differences were found among cognitively unimpaired, mild cognitive impairment, Alzheimer's disease (AD), and non-AD, and nearly all of the biomarkers were able to predict amyloid status. When combining p-tau181 and p-tau231 they predicted Aβ positivity with an area under the curve (AUC) of 0.75, and when combining all biomarkers an AUC of 0.86 was found.

Discussion: This study supports previous findings on plasma biomarkers, even when investigated in a typical clinical setting in a consecutive, heterogeneous, mixed memory clinic.

Highlights: This study investigated seven plasma biomarkers in a mixed memory clinic, regardless of amyloid co-pathology or atypical phenotypes.These findings support previous promising results on plasma biomarkers, even when investigated in a heterogeneous population.The combination of phosphorylated tau (p-tau)181 and p-231 performed only slightly worse than a panel of multiple biomarkers, aligning with previous studies.Plasma biomarkers show potential for future applications in primary care, treatment monitoring, and trial selection.

Introduction: This study examined whether sex differences in verbal learning and memory (VLM) are mediated by plasma brain-derived neurotrophic factor (BDNF) expression.

Methods: In a sample of n = 201 participants (63.81 ± 6.04 years, 66.2% female, 65.7% family history of Alzheimer's disease [AD], 38% apolipoprotein E [APOE] ε4+) from the Wisconsin Registry for Alzheimer's Prevention, VLM was measured using trials 3 through 5 and delayed recall from the Rey Auditory Verbal Learning Test. Plasma BDNF was measured using a Human BDNF Quantikine Immunoassay. Mediation analysis used bootstrapping, and stratified mediation models tested the conditional dependence of APOE ε4 carriage.

Results: BDNF partially mediated the sex-VLM relationship (β = -0.07; 95% confidence interval [CI]: -0.18, -0.01). Female APOE ε4 carriers had higher VLM scores (β = -0.53; p = 0.03), while female non-carriers had both higher BDNF levels (β = -0.68; p < 0.01) and VLM scores (β = -1.06; p < 0.01); BDNF was again a significant mediator (β = -0.18; 95% CI: -0.37, -0.05).

Discussion: This study found that circulating BDNF mediates higher verbal memory scores in females-particularly in APOE ε4 non-carriers.

Highlights: Sex differences in verbal learning and memory (VLM) were mediated by plasma brain-derived neurotrophic factor (BDNF) levels.Women exhibited higher VLM scores and plasma BDNF levels compared to men.The protective effect of BDNF in women was attenuated by apolipoprotein E ε4 carriage.Findings suggest sex-specific mechanisms against verbal memory decline in aging.

Background: Late-life depression (LLD) is a heterogenous disorder related to cognitive decline and neurodegenerative processes, raising a need for the development of novel biomarkers. We sought to provide preliminary evidence for acoustic speech signatures sensitive to LLD and their relationship to depressive dimensions.

Methods: Forty patients (24 female, aged 65-82 years) were assessed with the Geriatric Depression Scale (GDS). Vocal features were extracted from speech samples (reading a pre-written text) and tested as classifiers of LLD using random forest and XGBoost models. Post hoc analyses examined the relationship between these acoustic features and specific depressive dimensions.

Results: The classification models demonstrated moderate discriminative ability for LLD with receiver operating characteristic = 0.78 for random forest and 0.84 for XGBoost in an out-of-sample testing set. The top classifying features were most strongly associated with the apathy dimension (R ² = 0.43).

Discussion: Acoustic vocal features that may support the diagnosis of LLD are preferentially associated with apathy.

Highlights: The depressive dimensions in late-life depression (LLD) have different cognitive correlates, with apathy characterized by more pronounced cognitive impairment.Acoustic speech features can predict LLD. Using acoustic features, we were able to train a random forest model to predict LLD in a held-out sample.Acoustic speech features that predict LLD are preferentially associated with apathy. These results indicate a predominance of apathy in the vocal signatures of LLD, and suggest that the clinical heterogeneity of LLD should be considered in development of acoustic markers.

Introduction: We explored associations between measurements of the ocular choroid microvasculature and Alzheimer's disease (AD) risk.

Methods: We measured the choroidal vasculature appearing in optical coherence tomography (OCT) scans of 69 healthy, mid-life individuals in the PREVENT Dementia cohort. The cohort was prospectively split into low-, medium-, and high-risk groups based on the presence of known risk factors (apolipoprotein E [APOE] ε4 genotype and family history of dementia [FH]). We used ordinal logistic regression to test for cross-sectional associations between choroidal measurements and AD risk.

Results: Choroidal vasculature was progressively larger between ordinal risk groups, and significantly associated with risk group prediction. APOE ε4 carriers had thicker choroids and larger vascularity compared to non-carriers. Similar trends were observed for those with a FH.

Discussions: Our results suggest a potential link between the choroidal vasculature and AD risk. However, these exploratory findings should be replicated in a larger sample.

Highlights: Ocular choroidal microvasculature is of interest in relation to neurodegeneration due to its autonomic response to systemic, pathophysiological change.Choroidal changes in the prodromal stage of Alzheimer's disease (AD) are unexplored.The PREVENT Dementia cohort offers a unique, non-invasive study of the microvasculature in mid-life individuals at increased risk for developing AD.Significantly increased ocular choroidal vasculature was associated with increased risk (apolipoprotein E carrier and/or family history of dementia) for AD.These exploratory results suggest a potential association between the ocular choroidal vasculature and AD risk. However, findings should be replicated in a larger sample.

Introduction: Cross-sectional resting-state functional magnetic resonance imaging (rsfMRI) studies have revealed altered complexity with advanced Alzheimer's disease (AD) stages. The current study conducted longitudinal rsfMRI complexity analyses in AD.

Methods: Linear mixed-effects (LME) models were implemented to evaluate altered rates of disease progression in complexity across disease groups.

Results: The LME models revealed complexity of the higher frequency in the CNtoMCI group (those converted from cognitively normal [CN] to mild cognitive impairment [MCI]) decayed faster over time versus CN in the prefrontal and lateral occipital cortex; complexity of the lower frequency decayed faster in AD versus CN in various frontal and temporal regions (p < 0.05 & Benjamini-Hochberg corrected with q < 0.05).

Discussion: Local functional brain activities decayed in the early stage of the disease, and long-range communications were impacted in the later stage. Our study demonstrated longitudinal changes in AD-related rsfMRI complexity, indicating its potential as an imaging biomarker of AD.

Highlights: We conducted longitudinal resting state functional magnetic resonance imaging (rsfMRI) complexity analyses using the Alzheimer's Disease Neuroimaging Initiative dataset.Higher-frequency complexity in the CNtoMCI group (those transitioning from cognitively normal [CN] to mild cognitive impairment [MCI]) was found to decay faster over time compared to CN, specifically in the prefrontal and lateral occipital cortex.Lower-frequency complexity was found to decay faster in AD versus CN in various frontal and temporal regions.This study demonstrated that longitudinal changes in rsfMRI complexity could serve as a potential imaging biomarker for Alzheimer's disease.

Introduction: Melanopsin is a photopigment with roles in mediating sleep and circadian-related processes, which are often disrupted in Alzheimer's disease (AD). Melanopsin also impacts cognition and synaptogenesis. This study investigated the associations between melanopsin genetic variants, sleep, and markers of brain health.

Methods: Linear regression analyses examined the relationship of single-nucleotide polymorphisms (SNPs) within the melanopsin gene (OPN4), with cortical amyloid beta (Aβ), cognition, brain volumes, and self-reported sleep traits in cognitively unimpaired older adults. Further analyses assessed whether sleep traits x OPN4 SNP interactions were associated with markers of brain health.

Results: OPN4 SNPs rs2355009 and rs3740334 were associated with attention and processing speed and ventricular volume and language, respectively. Furthermore, rs3740334 and rs1079610 showed significant interactions with sleep traits in association with language.

Discussion: This study shows associations of OPN4 genetic variants with markers of brain health, and suggests that these variants interact with sleep to exacerbate cognitive effects.

Highlights: The relationships between melanopsin gene (OPN4) variants and markers of brain health were examined cross-sectionally in cognitively unimpaired older individuals.Variation within OPN4is associated with differences in cognition and ventricular volume.rs2355009 and rs3740334 show small-moderate associations with differences in attention and processing speed. Further to this, rs2355009 and rs3740334 were associated with ventricular volumes and language performance, respectively.The interactions between rs3740334 and rs1079610 and sleep traits also showed small-moderate associations with differences in language performance.

Introduction: Little is known about the factors underpinning discordant cerebrospinal fluid (CSF) amyloid beta (Aβ)₄₂ versus p-tau181/Aβ₄₂ or CSF Aβ₄₂ versus Aβ positron emission tomography (PET).

Methods: We stratified 570 non-demented Alzheimer's Disease Neuroimaging Initiative (ADNI) participants by Aβ PET and further by CSF Aβ₄₂ or p-tau181/Aβ₄₂. We used analysis of covariance testing adjusting for covariates, followed by Tukey post hoc pairwise comparisons, to compare CSF soluble triggering receptor expressed on myeloid cells-2 (sTREM2) across four participant groups: CSF+ _Aβ42 with CSF- _p-tau/Aβ42, CSF- _Aβ42 with CSF+ _p-tau/Aβ42, and concordant CSF_Aβ42/CSF_p-tau/Aβ42. We also compared sTREM2 across discordant and concordant CSF_Aβ42/PET.

Results: Regardless of Aβ PET status, CSF+_Aβ42 with CSF-_p-tau/Aβ42 had lower sTREM2 than CSF-_Aβ42 with CSF+_p-tau/Aβ42. CSF sTREM2 was similarly also associated with discordant CSF Aβ42 /PET.

Discussion: Our study suggests the potential roles of sTREM2 in discordant CSF Aβ₄₂ and p-tau181/Aβ₄₂ and discordant CSF_Aβ42/PET. Low- and high-CSF sTREM2 may affect the accuracy of p-tau181/Aβ₄₂ during the clinical work-up of AD.

Highlights: 17% of non-demented older adults had discordant CSF Aβ₄₂ versus p-tau181/Aβ₄₂.sTREM2 differed between discordant cases of CSF Aβ₄₂ versus p-tau181/Aβ₄₂.20% of non-demented older adults had discordant CSF Aβ₄₂ versus Aβ PET.sTREM2 also differed between discordant cases of CSF Aβ₄₂ versus Aβ PET.p-tau181/Aβ₄₂ may miss 6.7% of PET+ non-demented older adults with low sTREM2.

Introduction: Seed amplification assays (SAAs) demonstrate remarkable diagnostic performance in alpha-synucleinopathies. However, existing protocols lack accessibility in routine laboratories, mainly due to the requirement for in-house production of recombinant alpha-synuclein (aSyn). This study proposes a cerebrospinal fluid (CSF) aSyn-SAA protocol using solely commercial reagents to facilitate its clinical implementation.

Methods: Routine clinical care CSF samples from 126 patients, comprising 47 with Lewy body diseases (LBD) (41 with dementia with Lewy bodies, six with Parkinson's disease), 37 without alpha-synucleinopathy, and 42 with Alzheimer's disease (AD), underwent assessment for aSyn-SAA activity.

Results: CSF aSyn-SAA showed a sensitivity of 72.3% and a specificity of 100% when distinguishing clinically diagnosed LBD patients from those without alpha-synucleinopathy. In AD patients, 14.3% were tested positive for aSyn.

Discussion: The commercial-only CSF aSyn-SAA protocol exhibited excellent specificity when applied to a real-life cohort, signaling progress toward the accessibility of an aSyn biomarker in clinical settings.

Highlights: Diagnosis of LBD through aSyn-SAA lacks accessibility.This commercial-only aSyn-SAA has satisfactory performance in a real-life cohort.A negative aSyn-SAA does not completely exclude a synucleinopathy.Some technical points must be considered when developing aSyn-SAA.aSyn-SAA must be confined to expert laboratories due to prion-like risk management.

Introduction: We examined semantic and phonemic fluency in individuals with subjective cognitive decline (SCD) in relation to amyloid status and clinical progression.

Methods: A total of 490 individuals with SCD (62 ± 8 years, 42% female, 28% amyloid-positive, 17% clinical progression) completed annual fluency assessments (mean ± SD follow-up 4.3 ± 2.9 years). Associations between fluency trajectories, amyloid status, and clinical progression were examined with linear mixed models and joint models.

Results: Amyloid-positive individuals declined faster than amyloid-negative individuals on semantic fluency (B = -0.35, p < 0.001), but not on phonemic fluency (B = -0.06, p = 0.218). An annual decline of one word in semantic and phonemic fluency was associated with 22% (hazard ratio [HR] = 1.22, p < 0.001) and 28% (HR = 1.28, p = 0.004) increased risk of clinical progression.

Discussion: Our results indicate that decline in semantic fluency is an early indicator of cognitive deficits in preclinical Alzheimer's disease.

Highlights: Abnormal amyloid burden is associated with decline in semantic fluency.Fluency trajectories are associated with an increased risk of clinical progression.More refined measures are needed to detect the earliest language deficits.