Language Network Connectivity Increases in Early Alzheimer’s Disease

Background: Language production deficits occur early in the course of Alzheimer’s disease (AD); however, only a few studies have focused on language network’s functional connectivity in mild cognitive impairment (MCI) due to AD. Objective: The current study aims to uncover the extent of language alteration at the MCI stage, at a behavioral and neural level, using univariate and multivariate analyses of structural MRI and resting-state fMRI. Methods: Twenty-four MCI due to AD participants and 24 matched healthy controls underwent a comprehensive language evaluation, a structural T1-3D MRI, and resting-state fMRI. We performed seed-based analyses, using the left inferior frontal gyrus and left posterior temporal gyrus as seeds. Then, we analyzed connectivity between executive control networks and language network in each group. Finally, we used multivariate pattern analyses to test whether the two groups could be distinguished based on the pattern of atrophy within the language network; within the executive control networks, as well as the pattern of functional connectivity within the language network and within the executive control networks. Results: MCI due to AD participants had language impairment during standardized language tasks and connected-speech production. Regarding functional connectivity, univariate analyses were not able to discriminate participants, while multivariate pattern analyses could significantly predict participants’ group. Language network’s functional connectivity could discriminate MCI due to AD participants better than executive control networks. Most notably, they revealed an increased connectivity at the MCI stage, positively correlated with language performance. Conclusion: Multivariate analyses represent a useful tool for investigating the functional and structural (re-)organization of the neural bases of language.

Serum BDNF as a Potential Biomarker of Alzheimer's Disease: Verification Through Assessment of Serum, Cerebrospinal Fluid, and Medial Temporal Lobe Atrophy

There is an urgent need to establish blood biomarkers for Alzheimer's disease (AD). Although it has been speculated that brain-derived neurotrophic factor (BDNF) is associated with AD, whether it can be used as a blood biomarker has yet to be determined. We used serum, cerebrospinal fluid (CSF), and medial temporal lobe atrophy from patients with AD to evaluate the association of BDNF with AD and assess its severity. For the blood analysis, 66 participants [21 normal controls (NCs) with normal cognitive function, 22 patients with mild cognitive impairment (MCI) due to AD, and 23 patients with AD] were included. For the CSF analysis, 30 participants were included. Magnetic resonance imaging, including a voxel-based specific regional analysis system for AD, and a Mini Mental State Examination were performed. Serum levels of BDNF and CSF levels of amyloid-β42, total tau, and phosphorylated tau were measured using ELISA. Serum BDNF levels were significantly lower in the MCI due to AD group than in the NC group (p = 0.037). Although there was no significant difference in the AD group, there was a downward trend compared to the NC group. Serum BDNF levels were positively correlated with CSF Aβ42 levels (r = 0.49, p = 0.005). There was a significant correlation between serum BDNF levels and medial temporal lobe atrophy. Decreased serum BDNF can potentially be used as a biomarker for early AD detection. Early detection of AD with a less invasive blood test is very beneficial, as it allows for intervention before dementia progresses.

Toxic Amyloid-β42 Conformer May Accelerate the Onset of Alzheimer’s Disease in the Preclinical Stage

Background: Toxic amyloid-β protein (Aβ) conformers play an important role in the progression of Alzheimer’s disease (AD). The ratio of toxic conformer to total Aβ42 in cerebrospinal fluid (CSF) was significantly high in AD and mild cognitive impairment (MCI) due to AD using an enzyme-linked immunosorbent assay kit with a 24B3 antibody. Objective: We compared the toxic Aβ42, conformer at different stages of AD to identify its contribution to AD pathogenesis. Methods: We compared 5 patients with preclinical AD, 11 patients with MCI due to AD, 21 patients with AD, and 5 healthy controls to measure CSF levels of total Aβ42, total tau, tau phosphorylated at threonine 181 (p-tau), and toxic Aβ conformers. All were classified using the Clinical Dementia Rating. Cognitive function was assessed using the Japanese version of the Mini-Mental State Examination (MMSE-J). Results: Toxic Aβ conformer level was insignificant between groups, but its ratio to Aβ42 was significantly higher in AD than in preclinical AD (p < 0.05). Toxic Aβ42 conformer correlated positively with p-tau (r = 0.67, p < 0.01) and p-tau correlated negatively with MMSE-J (r = –0.38, p < 0.05). Conclusion: Toxic Aβ conformer triggers tau accumulation leading to neuronal impairment in AD pathogenesis.

Impact of hearing loss and vestibular decline on cognition in Alzheimer’s disease: a prospective longitudinal study protocol (Gehoor, Evenwicht en Cognitie, GECkO)

IntroductionDementia is a prevalent disease affecting a growing number of the ageing population. Alzheimer’s disease (AD) is the most common cause of dementia. Previous research investigated the link between hearing loss and cognition, and the effect of vestibular dysfunction on cognition. Hearing loss and, to a lesser extent, vestibular decline both result in a decreasing cognitive function. However, their interaction should not be underestimated. The aim of this study is to assess the effect of hearing loss, vestibular decline and their interaction on cognition in people suffering from mild cognitive impairment (MCI) and dementia due to AD (ADD).Methods and analysisWe designed a prospective longitudinal study to assess the effect of hearing loss and vestibular decline on cognition. A total of 100 cognitively impaired elderly (between 55 and 84 years of age), consisting of 60 patients with MCI due to AD and 40 patients with ADD will be included. The control group will consist of individuals with preserved cognition group-matched based on age, hearing level and vestibular function. A comprehensive assessment is performed at baseline, 12-month and 24-month follow-ups. The primary outcome measure is the change in the Repeatable Battery for the Assessment of Neuropsychological Status adjusted for Hearing-impaired individuals total score, a cognitive test battery assessing different cognitive domains. Secondary outcome measures include additional neuropsychological assessments, cortical auditory-evoked potentials, and evaluation of general and disease-specific health-related quality of life. Variables include cognitive, audiological and vestibular evaluation. Variance analyses will assess the effect of hearing loss and vestibular decline on cognition. More precisely, the link between hearing loss and non-spatial cognitive functioning, the effect of vestibular decline on spatial cognition and the impact of both factors on the rate of conversion from MCI due to AD to ADD will be investigated.Ethics and disseminationThe study protocol was approved by the ethical committee of the Antwerp University Hospital on 4 February 2019 with protocol number B300201938949. The findings will be disseminated through peer-reviewed publications and conference presentations.Trial registration numberClinicalTrials.gov Registry (NCT04385225).

A MISSED OPPORTUNITY FOR DEMENTIA PREVENTION? CURRENT CHALLENGES FOR EARLY DETECTION AND MODERN-DAY SOLUTIONS

The path towards developing effective therapeutics to either cure or prevent the onset of Alzheimer’s disease (AD) and related neurodegenerative dementias has been plagued by challenges. Nevertheless, innovative treatments and clinical frameworks that represent our current understanding of the trajectory of disease may help to reduce morbidity, or delay symptom onset, for patients in the pre-dementia stages. Late-life AD dementia develops over an extended period, first as an asymptomatic phase referred to as preclinical AD, which affects an estimated 46 million people in the United States alone (1). Following preclinical AD is the first symptomatic phase known as mild cognitive impairment (MCI) due to AD. Collectively, both stages offer a unique chance for early intervention.

Disease progression modelling from preclinical Alzheimer’s disease (AD) to AD dementia

Background: 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. Methods: We used longitudinal data from 127 participants with preclinical AD and 309 participants with mild cognitive impairments (MCI) due to AD from the Alzheimer’s Disease Neuroimaging Initiative. In order 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 according to the follow-up time for each cohort, determined the time point at which the estimated scores of ADAS-cog 13 for the two cohorts first overlapped, and shifted the ADAS-cog 13 scores for the latter cohort at this time point to connect the two cohorts and to combine the data into a single unified progression course. Results: The estimated years for progression from the median ADAS-cog 13 score in the preclinical AD cohort (9.3 points) to the median ADAS-cog 13 score at the time of progression in the participants who progressed from preclinical AD to MCI due to AD (16.0 points) was 7.8 years. The estimated years for progression from preclinical AD to the median ADAS-cog 13 score at the time of progression in those who progressed from MCI to due AD to AD dementia (26.8 points) was 15.2 years. ADAS-cog 13 scores deteriorated most rapidly in female APOE ε4 carriers and most slowly in male APOE ε4 non-carriers ( p < 0.001). Conclusion: 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.

Verbal memory and hippocampal volume predict subsequent fornix microstructure in those at risk for Alzheimer’s disease

While strong cross-sectional evidence supported the use of fornix microstructure as a marker for detecting Alzheimer’s disease (AD), longitudinal data remains inconclusive on the sequential nature of fornix microstructure abnormalities and AD progression. An unequivocal longitudinal relationship between fornix microstructure and markers of AD progression –memory impairment and hippocampal atrophy, must be established to validate fornix microstructure as a marker of AD progression. We included 115 participants from the Alzheimer’s Disease Neuroimaging Initiative across the non-demented AD spectrum— defined as those who had at least one AD risk marker at baseline (e.g., mild cognitive impairment (MCI) due to AD diagnosis, amyloid or ApoE4 positivity) and/or ‘cognitively normal individuals who converted to MCI due to AD or AD, with structural and diffusion tensor imaging scans at baseline and two years follow-up. Hippocampal volumes (HV), fractional anisotropy (FA) and mean diffusivity (MD) in the fornix were extracted. Memory was indexed via composite scores of verbal memory tests. Structural equation models tested the bidirectional cross-lagged effects of fornix microstructure, memory, and HV. Impaired memory and smaller HV at baseline significantly predicted worse fornix microstructure (decreased FA and increased MD) two years later. Baseline fornix microstructure was not associated with subsequent changes in memory and HV. Fornix microstructure is compromised likely at a later stage, where significant decline in memory and hippocampal atrophy have occurred. This limits the utility of fornix microstructure in the early detection of AD. Our findings inform the possible pathophysiology and refined the use of AD neural markers.

CSF and blood Kallikrein-8: a promising early biomarker for Alzheimer’s disease

ObjectiveThere is still an urgent need for supportive minimally invasive and cost-effective biomarkers for early diagnosis of Alzheimer’s disease (AD). Previous work in our lab has identified Kallikrein-8 (KLK8) as a potential candidate since it shows an excessive increase in human brain in preclinical disease stages. The aim of this study was to evaluate the diagnostic performance of cerebrospinal fluid (CSF) and blood KLK8 for AD and mild cognitive impairment (MCI) due to AD.MethodsIn this multi-centre trans-sectional study, clinical and laboratory data as well as CSF and/or blood serum samples of 237 participants, including 98 patients with mild AD, 21 with MCI due to AD and 118 controls were collected. CSF and/or serum KLK8 levels were analysed by ELISA. The diagnostic accuracy of KLK8 in CSF and blood was determined using receiver operating characteristic (ROC) analyses and compared with that of CSF core biomarkers Aβ42, P-tau and T-tau.ResultsThe diagnostic accuracy of CSF KLK8 was as good as that of core CSF biomarkers for AD (area under the curve (AUC)=0.89) and in case of MCI (AUC=0.97) even superior to CSF Aβ42. Blood KLK8 was a similarly strong discriminator for MCI (AUC=0.94) but slightly weaker for AD (AUC=0.83).ConclusionsThis is the first study to demonstrate the potential clinical utility of blood and CSF KLK8 as a biomarker for incipient AD. Future prospective validation studies are warranted.