bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of APOE ε4/ε4 on Fluid Biomarkers in Patients from the PUMCH Dementia Cohort
Authors: Shang Li , Dong Liling , Huang Xinying , Wang Tianyi , Mao Chenhui , Li Jie , Wang Jie , Liu Caiyan , Gao Jing
Published: December 2023

Background

Apolipoprotein‐E (APOE) ε4 is a major genetic risk factor for Alzheimer’s disease (AD). Current studies, which mainly based on the clinical diagnosis rather than biomarkers, come to inconsistent conclusions regarding the effect of APOE ε4 homozygotes (APOE ε4/ε4) on cerebrospinal fluid (CSF) biomarkers of AD. Additionally, few studies have explored the effect of APOE ε4/ε4 on plasma biomarkers. Therefore, we aimed to investigate the effect of APOE ε4/ε4 on CSF and plasma biomarkers in dementia and biomarker diagnosed AD.

Method

A total of 297 patients were enrolled. They were classified into Alzheimer’s continuum, AD and non‐AD according to CSF biomarkers and/or β amyloid PET results. Plasma Aβ40, Aβ42, glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL) and P‐tau181 were quantified in 144 of the total population using an ultra‐sensitive Simoa technology. We analyzed the effect of APOE ε4/ε4 on CSF and plasma biomarkers in dementia and biomarker‐diagnosed AD.

Result

Based on the biomarker diagnostic criteria, 169 participants were diagnosed with Alzheimer’s continuum, 120 patients with AD and 128 individuals with non‐AD. The APOE ε4/ε4 frequencies were 14.2% (17/120) in AD, 11.8% (20/169) in Alzheimer’s continuum and 0.8% (1/128) in non‐AD. Only CSF Aβ42 was shown to be decreased in APOE ε4/ε4 carriers than in non‐carriers for patients with AD (P = 0.024). As well, we did not find any effect of APOE ε4 on plasma biomarkers of AD and non‐AD. Interestingly, we found that in non‐AD patients, APOE ε4 carriers had lower CSF Aβ42 (P = 0.018) and higher T‐tau/Aβ42 ratios (P<0.001) and P‐tau181/Aβ42 ratios (P = 0.002) than non‐carriers.

Conclusion

Our data confirmed APOE ɛ4/ɛ4 was most common in biomarker diagnosed AD. The APOE ɛ4/ɛ4 had an effect on CSF levels of Aβ42 but not tau for AD and non‐AD, suggesting that APOE ɛ4/ɛ4 affected the Aβ metabolism of both. APOE ε4/ɛ4 had no effect on plasma biomarkers of AD and non‐AD.
Views Of Experienced Physiotherapists About Excellence In Dementia Care: A Qualitative Study
Authors: Quick Stephen M , Lawler Katherine , Shannon Michelle M , Soh Sze_Ee , McGinley Jennifer L , Snowdon David A , Callisaya Michele L
Published: December 2023

Background

Physiotherapy interventions can improve mobility and prevent falls in people with dementia. However, physiotherapists have been found to have low knowledge and confidence in working with people with dementia. Excellence in dementia physiotherapy has not been described in the literature, and it is important to establish with dementia considered a global health priority. Therefore, the aims of this study were to determine 1) what is excellence in physiotherapy dementia care and 2) how can excellence be achieved.

Methods

This was a qualitative study using an interpretive description approach. Participants were 16 physiotherapists from around Australia considered to be experienced in the field of dementia care. Snowball sampling was utilised from the starting group of physiotherapists practicing in Australia, who were recognised by the National Gerontology Committee of the Australian Physiotherapy Association as experienced experts in dementia care. Physiotherapists participated in semi‐structured interviews. Thematic analysis was undertaken, with themes/subthemes derived and a qualitative thematic framework generated.

Results

The four themes (and subthemes) were: 1) engaging the person with dementia (knowing the person, using knowledge to adapt the approach to successfully deliver physiotherapy interventions, optimising the physical environment), 2) collaborative care (working with care partners, working as an interdisciplinary team), 3) development of clinical skills and expertise on the job and 4) advocating for the role of physiotherapy in dementia care.

Discussion/Conclusion

Physiotherapists believe that excellence in dementia care involves being able to effectively engage the person with dementia in therapy, training and supporting care partners, and providing interdisciplinary care. Excellence in care was less about the application of evidence‐based practice, but more about providing patient‐centred care, achieved mainly through on‐the‐job learning from both physiotherapy and other health professional peers.
Visual scanning of faces with neutral expression in patients with Alzheimer’s disease and amnestic mild cognitive impairment
Authors: Boz Hatice Eraslan , Koçoğlu Koray , Akkoyun Müge , Tüfekci Işıl Yağmur , Ekin Merve , Akdal Gülden
Published: December 2023

Background

Deficits in face perception and face processing have been reported in Alzheimer’s disease (AD) (Kawagoe et al., 2017). However, conflicting findings were presented in these functions in amnestic mild cognitive impairment (aMCI) compared to older adults (Lim et al., 2011). This study aimed to examine eye movement patterns during visual scanning of faces with neutral expressions in AD, aMCI, and healthy controls (HC).

Method

Ninety‐five participants, including 29 patients with AD (mean age 72.5±7.9), 34 patients with aMCI (mean age 70.6±6.7 years), and 32 HC (mean age 68.5±6.2 years) were participated in the study. Eye movements were recorded from the right eye with the EyeLink 1000 Plus video‐based eye tracker. In the face scanning task, neutral face images without emotional expressions produced by artificial intelligence were used. In this task, which consists of a practical trial and 20 trials, each stimulus was shown for 3000 ms. Participants were instructed to examine the neutral face images presented. Number of saccade, fixation counts, mean fixation duration, and first fixation duration were analysed separately on the regions of eyes, mouth, nose, and face.

Result

The mean number of fixation, the number of saccades, and mean fixation duration across the face were significantly reduced in AD patients compared to HC. The mean number of fixation and fixation durations in the eye were significantly reduced in AD compared to HC. No significant difference was observed in all groups in eye movements in the nose and mouth. In addition, aMCI and HC exhibited similar eye movement patterns in the face‐scanning task.

Conclusion

Studies with healthy individuals have reported typical eye movement patterns focusing primarily on the eyes, but also on the nose and mouth regions. It is stated that the decrease in the gaze towards the face and eye region in AD patients may be related to face processing difficulties. To our knowledge, this is the first study to examine eye movement patterns during neutral face scanning in AD and aMCI.

This work was supported by the TUBITAK project number 119S560.
GM1 modulates amyloid‐beta activation of NLRP3 inflammasome in microglia through Akt/mTOR‐mediated regulation of autophagy
Authors: Wang Wenxuan , Zhao Lin , Whitehead Shawn N
Published: December 2023

Background

Microglia are cellular players underlying neuroinflammation, a major driver of Alzheimer’s Disease (AD) pathogenesis. In the AD brain, microglia are observed surrounding beta‐amyloid (Aβ) plaque and are responsible for amyloid clearance. However, chronic microglia activation by amyloid leads to microglia dysfunction, including autophagy dysregulation, degradative impairment, and a prominent pro‐inflammatory response that exacerbates plaque deposition and neurodegeneration (Hickman et al., 2008). The key to targeting neuroinflammation may be GM1 ganglioside. Gangliosides are glycosphingolipids highly enriched in the central nervous system and play a critical role in membrane organization and signal transduction. Notably, Ganglioside dysregulation has been observed in pre‐clinical and clinical models of AD (Svennerholm et al., 2008). GM1, the most abundant ganglioside in the adult brain, serves a neuroprotective and anti‐inflammatory role, but the mechanism remains unknown (Galleguillos et al., 2022). This study aims to interrogate the cell‐specific mechanism and therapeutic potential of GM1 to alleviate microglia inflammation in response to amyloid. We hypothesize that GM1 ganglioside is protective against neuroinflammation by upregulating microglia autophagy in AD.

Method

BV‐2 microglia culture was activated by oligomeric Aβ (Aβo) exposure with or without GM1 pre‐treatment. Cells were treated with rapamycin, an mTORC1 inhibitor and autophagy modulation. NLRP3 inflammasome activation was assessed by pro‐inflammatory gene transcription and cleaved caspase‐1 and IL1β release. Autophagy was assessed by p62 and LC3 II/I protein expression. Microglia ganglioside abundance was measured using electrospray‐ionization mass spectrometry.

Result

Aβo significantly increased microglial NLRP3 inflammasome priming, suppressed autophagy flux, and increased GM1 degradation compared to control. GM1 pre‐treatment attenuated Aβo inflammasome activation and promoted autophagy initiation by downregulating Akt and mTOR phosphorylation. The protective effect of GM1 involves membrane signalling receptors such as Trem2.

Conclusion

GM1 ganglioside is protective against amyloid‐mediated microglia inflammation by suppressing NLRP3 inflammasome priming and restoring autophagy via Akt/mTOR signalling pathways. GM1 upregulation of autophagy demonstrates a promising therapeutic target to resolve neuroinflammation and halt the accelerated progression of AD.
The impact of gender‐specific survival on the incidence of dementia in Parkinson’s disease ‐ A cohort analysis of Parkinson’s disease patients in German health claims data for the years 2006 to 2017
Authors: Fink Anne , Dodel Richard , Georges Danieal , Doblhammer Gabriele
Published: December 2023

Background

The aim of our study is to analyze gender‐specific patterns of Parkinson’s disease dementia (PDD) incidence. In addition, we are investigating the extent to which gender differences in survival after initial Parkinson’s disease (PD) diagnosis influence differences in PDD risk among PD patients.

Method

We used a random sample of German longitudinal health claims data of persons at ages 65 years or older (2006‐2017). We identified incident PD cases who were followed‐up for a PDD diagnosis or death. We computed age‐ and gender‐specific PDD incidence rates, death rates, and cumulative PDD incidence functions with death as competing risk. In addition, we performed Cox regression models and Fine and Gray competing‐risk regression models, considering death as a competing event, to calculate PDD hazard ratios (HR), adjusted for important risk factors such as age at PD onset, PD severity in terms of modified Hoehn&Yahr (HY) scale, comorbidities, and medications.

Result

Of 2,195 incident PD cases, 602 people died and 750 people received a dementia diagnosis by the end of 2017. 44% of PD men and 45% of PD women had received a dementia diagnosis, 45% of PD men and 32% of PD women had died, and only 11% of PD men but 23% of PD women had survived without a PDD diagnosis. PDD risk among PD patients differs by gender when controlled for age at onset, severity of PD, comorbidities and medications, with men having a higher PDD risk than women (HR = 1.18, p = 0.029). When accounting for death, men and women do not differ regarding their PDD risk (HR = 1.02, p = 0.770). Gender‐specific analyses showed significant age and severity effects in women (Age: HR = 1.05, p<0.001, HY 0‐2.5: reference, HY 3‐5: HR = 1.46, p = 0.011), but not in men.

Conclusion

We found that older age at first PD diagnosis and higher disease severity increase PDD risk, but this association is attenuated for PD men when we consider death as a competing risk. This implies that the most frail PD men die rapidly before receiving a dementia diagnosis, whereas women with PD survive at higher rates than men, regardless of their age at onset and disease severity.
Transcriptomic profile across different brain areas in Alzheimer’s disease
Authors: Ferrari Riccardo Rocco , Fantini Valentina , Garofalo Maria , Francesca Dragoni , Gerlando Rosalinda Di , Cattaneo Valentina , Davin Annalisa , Profka Xhulja , Medici Valentina , Guaita Antonio , Gagliardi Stella , Poloni Tino Emanuele
Published: December 2023

Background

Aging is often characterized by a progressive loss of cognitive abilities due to the onset of Alzheimer Disease (AD). In recent years, ‐omic sciences have allowed us to begin to shed light on its molecular pathways in order to speculate about new and attractive hypothesis on AD pathogenesis.

Method

In this study, a whole transcriptome analysis and a Gene Set Enrichment Analysis (GSEA) have been carried out on brain samples from hippocampus (HI), temporal and parietal cortex (TC, PC), cingulate cortex (CG), and substantia nigra (SN) from the Abbiategrasso Brain Bank (ABB) of 6 subjects with clinical and neuropathological diagnosis of AD and 3 healthy age‐matched controls in duplicate. Clinical and neuropsychological profile were obtained through serial evaluations, made at the baseline and in the following years. According to the ABB protocol, the neuropathological diagnosis was based on a complete histological characterization, including all the main proteinopathies and vascular scoring.

Result

Transcriptomic results showed a greater number of differentially expressed genes (DEGs) in TC (1571) and CG (1210) and a least amount of DEGs in HI (206), PC (109) and SN (60). Furthermore, the GSEA showed a difference between the group of early affected brain areas (HI, TC) and the group of the subsequently involved areas (PC, CG, SN). Notably, in HI and TC there was a significant down‐regulation of shared DEGs primarily involved in the synaptic transmission and in the development of the central nervous system (CDK5R1, KCNC1, KCNC2, BSN), while in PC, CG and SN there was a significant down‐regulation of genes primarily involved in the proper protein folding and trafficking and inflammation (HSPA1B, HSPA1A, DNAJB1, FKBP4, CHORDC1, STIP1).

Conclusion

The course of AD could follow a definite time and severity‐related pattern that arises from inflammatory processes and protein misfolding, observed in PC, CG and SN, and leads to synaptic impairment, observed in HI and TC. Therefore, we can relate neurobiological processes to clinical manifestations and outline a clearer picture of AD neuropathology and pathogenesis. This could help to discover novel biological targets in order to develop effective and well‐timed therapeutical approaches.
Voice Quality Monitoring in Dementia Households
Authors: Jouaiti Melanie , Vaidyanathan Ravi
Published: December 2023

Background

Voice disorders are common in People Living with Dementia (PLwD) and a decrease in voice quality can be an indicator of cognitive deterioration. Previous computational works have successfully employed voice to detect or predict dementia. Voice quality can be assessed by a speech therapist, or computationally when subjects periodically repeat the same sentences. There is, however, to our knowledge, no research on monitoring voice to track dementia progress from unconstrained data collected in the wild.

Method

In this work, we employ a dataset containing audio recordings of 14 households (a carer, a PLwD and visitors) interacting with Alexa. We identify several voice features, such as speech rate and OpenSmile features that differ between healthy users and PLwD. We create a voice footprint for each PLwD using a Gaussian distribution and identify audio recordings that significantly differ from this baseline over time by combining Expectation‐Minimisation and Mahalanolis distance outliers detection.

Result

The voice features selected are significantly different between our two user groups (p‐value < 0.0001). Training a classifier on those features, allows us to identify healthy subjects and PLwD with over 90% accuracy. We are also able to quality how much the voice differs from its baseline over time.

Conclusion

While we can computationally identify voice variations that are out the ordinary, in the future, we will compare our results to a clinical assessment of voice quality. We will also integrate a semantics analysis to identify grammar errors or the use of wrong words. This will allow us to design an objective index measure for monitoring of speech quality.
POORANA CHANDROTHAYA CHENTHURAM (PCC), A SIDDHA SYSTEM OF MEDICINE PROTECTS AGAINST SCOPOLAMINE‐INDUCED COGNITIVE IMPAIRMENTS IN EXPERIMENTAL RATS
Authors: George Sugin Lal Jabaris Sobhana , B Chitra , Pullaiah Chitikela P , Krishnamoorthy Bhavani , A Manoj
Published: December 2023

Background

Indian Systems of Medicine (ISM) are considered to be of native medical systems which were assimilated into Indian culture. ISM comprising of Ayurveda, Yoga, and Naturopathy, Unani and Siddha which are in practice since time immemorial much before the recognized health system came into existence. In Siddha system, higher order pharmaceutical forms of medicine called PCC are predominantly prepared with metals and minerals through well‐coined pharmaceutical procedures and techniques that have been inscribed in the Siddha literature. The methods which convert the toxic metals/ minerals into compatible form that fits for human consumption. It has the privilege that these drug forms can cure many chronic diseases, in precise dosage. PCC is an imperative medicine which contains gold, mercury and sulphur in defined quantity. As given in Siddha vaithiyathirattu PCC is prepared from Gold, Mercury, and Sulphur in a ratio of 1:8:16 and processed with the required amount of red cotton flower juice and plantain stem pith juice. It is well known for its effectiveness in respiratory disorders especially bronchitis, hepatic disorders, renal diseases, neurological disorders, and skin diseases. However, there are no reports on whether PCC may improve cognitive dysfunction.

Methods

We used RAM and NORT models to evaluate cognitive improvement. In addition, the acetylcholinesterase enzyme was assessed in the brain tissues. Further, protein expression of BDNF was also assessed in hippocampus tissues after the behavioral tasks.

Result

Repeated administration of PCC (2.5, 5 and 10 mg/kg., p.o) before the acquisition trial (T1) explored the object significantly more than the familiar one during the discrimination trial (T2) respectively, showing an increase in memory retention. In the radial arm‐maze task, scopolamine‐treated rats with PCC showed decreased working memory errors as compared to scopolamine‐alone treated rats. Treatment with different doses of PCC showed up‐regulation of BDNF with a significant effect by inhibiting the elevation of acetylcholinesterase activity when compared to the vehicle‐treated group.

Conclusions

These results suggest that the PCC ameliorates scopolamine‐induced impairment of cognitive functions in rats. These data further support that the anti‐amnestic effect of PCC recommends it as a promising candidate for clinical trials in patients with cognitive impairment.
Lifestyle, biological and genetic determinants of brain iron accumulation in aging
Authors: Gustavsson Jonatan , Ištvánfyová Zuzana , Falahati Farshad , Papenberg Goran , Mangialasche Francesca , Kalpouzos Grégoria
Published: December 2023

Background

Optimal iron levels are crucial for brain cells’ functioning. However, brain iron overload occurs in both normal aging and neurodegenerative disorders, including Alzheimer’s disease (AD). High iron concentration triggers oxidative stress and neuroinflammation, both involved the AD pathophysiology. Despite growing evidence of the toxicity of iron overload, why iron accumulates remains unknown. A few studies have linked higher brain iron content to alcohol use, body mass index, cardiovascular health, and smoking. However, no study has investigated the factors behind iron accumulation longitudinally.

Method

We investigated the associations between potential determinants such as blood markers of iron metabolism, cardiovascular health (Framingham’s risk score; FRS), lifestyle factors (smoking, alcohol use, physical activity), ApoE (any e4) status, and iron content and iron accumulation using longitudinal data (n = 208 healthy volunteers, age = 20‐79, mean follow‐up time = 2.75 years) from the IronAge study. Iron was assessed with Magnetic Resonance Imaging using quantitative susceptibility mapping for iron‐rich or age‐sensitive regions (caudate (CA), putamen (PU), pallidum (PA), dorsolateral prefrontal cortex (DLPFC)). We used structural equation modelling to assess the relationships between determinants and iron accumulation.

Result

Higher blood ferritin was related to higher iron content and iron accumulation in DLPFC (B = 0.181 and 0.173), CA (B = 0.158 and 0.225) and PU (B = 0.127 and 0.263). Higher blood haemoglobin was related to higher iron content in DLPFC (β = 0.177) and CA (β = 0.178), as well as to iron accumulation in PA (β = 0.220). Higher blood transferrin was related to lower iron content and iron accumulation in CA (B = ‐0.131 and ‐0.147) and PU (B = ‐0.160 and ‐0.232). Lower FRS was related to greater iron accumulation in DLPFC among younger adults (β = ‐0.379, age<40). Increased FRS was related to greater iron accumulation (β = 0.194). More physical activity was related to higher iron content in PA among younger adults (β = 0.231, age<40). Lastly, older (age>40) ApoE e4 carriers had higher iron content in PA (β = 0.219). No associations were found with alcohol or smoking. These results were independent of, sex, education, atrophy, white‐matter lesions, and age unless age‐stratified results.

Conclusion

Our study identified modifiable and non‐modifiable factors of brain iron accumulation in adulthood. The former can be targeted to prevent accelerated iron accumulation.
Influence of APOE on the Alzheimer’s disease polygenic risk scores based on hippocampal subfield volumes
Authors: Balaji Kannappan , Nijenhuis Jan , Lee Kun Ho
Published: December 2023

Background

Numerous studies have shown the association between Alzheimer’s disease, hippocampal subfield volume atrophy, and the role of APOE. In our previous study, we showed the differential atrophy in the hippocampal subfield volumes (HSV) identified using Alzheimer’s disease polygenic risk scores (AD PGRS). Here, we evaluate the influence of the APOE 𝛆4 on the AD PGRS of the HSV.

Method

We calculated the AD PGRS for HSV atrophy in 1,086 individuals (319 cognitively normal (CN), 591 mild cognitively impaired (MCI), and 176 Alzheimer’s disease dementia (ADD)). We then stratified the samples based on the APOE 𝛆4 carriers and non‐carriers. We studied the AD PGRS for the HSV for the left‐right hemispheres.

Result

The analysis was performed for the left and right hemispheres separately. The effects of APOE 𝛆4 were larger on the left hemisphere than on the right hemisphere. The effects of the APOE 𝛆4 were severe on most of the subfield volumes. Although, certain subfield volumes showed larger effects for 𝛆4 non‐carriers and certain subfield volumes showed no effect between 𝛆4 carriers and non‐carriers.

Conclusion

The APOE 𝛆4 carriers showed a higher AD PGRS for hippocampal subfield volume atrophy than the APOE 𝛆4 non‐carriers. The AD PGRS and the APOE 𝛆4 showed the differential risk for the subfield volumes bilaterally. These risk scores can be used in preclinical Alzheimer’s risk modeling. We also hypothesize that hippocampal subfield volume atrophy occurs in both normal and pathological aging. However, atrophy is intense in pathological aging due to the underlying processes and the functioning of the risk genes. A clear understanding of this will enhance the specificity and sensitivity for the early diagnosis of Alzheimer’s disease.
Intravenously administered gadolinium based contrast agent as a novel approach to longitudinally measure ventricular brain clearance with magnetic resonance imaging in an Alzheimer´s disease model
Authors: Müller Luisa , Lindner Tobias , Polei Stefan , Deike‐Hofmann Katerina , Radbruch Alexander , Kuhla Angela , Teipel Stefan
Published: December 2023

Background

Amyloidopathy, one pathological hallmark of Alzheimer’s disease (AD), results from dysbalanced amyloid‐β production and clearance. Therefore, disruptions in brain clearance may have a pivotal role as pathogenic drivers. Transgenic mice models of AD may serve to develop and establish minimally invasive in vivo measurement methods to observe brain clearance longitudinally.

Method

We used magnetic resonance imaging (MRI) with intravenously administered gadolinium‐based contrast agent (GBCA) on a 7T small animal ultrahighfield MRI scanner to determine brain clearance efficacy. Imaging sessions were performed longitudinally in n = 9 APPswe/PS1dE9 (tg) mice and n = 9 wild type (wt) littermates at 6, 9 and 12 months of age with a scan protocol consisting of a highly T2w Inv. Rec. RARE (FLAIR) sequence. For a subsample of n = 6 wt and n = 6 tg at 9 and 12 months we used an additional T1w RARE sequence for evaluation of parenchymal changes. Both protocols were carried out every 5‐6.5 minutes for a total of 180 minutes. We determined mean voxel values in manually delineated volumes of interest in ventricles (in T2w images) and brain parenchyma (T1w images) using PMOD software.

Result

We created intensity‐time‐curves and measured slopes for signal increase and decrease, derived from fitting with a model consisting of an exponential convoluted with another exponential and used to normalize area under the curve (AUC) values (Figure 1A‐C). Repeated measurements ANOVA revealed no differences in normalized AUC values regarding age in both lateral (p = 0.568, F(2, 28) = 0.577), 3rd (p = 0.306, F(1.903, 26.64) = 1.232) and 4th ventricles (p = 0.181, F(1.345, 18.83) = 1.924) and also no differences regarding genotype in both lateral (p = 0.684, F(1,16) = 0.172), 3rd (p = 0.737, F(1,16) = 0.117) and 4th ventricle (p = 0.186, F(1,16) = 1.910). Measurements of parenchymal clearance capacity are still ongoing and first results will be presented at the conference.

Conclusion

Our first results showed no measurable difference in the brain clearance efficacy. This could have two possible reasons. Either ventricular clearance measurements are not sensitive enough to measure AD related changes in brain clearance or the used pathogenetic model shows no changes in clearance efficacy. Our still ongoing analyses of parenchymal brain could help to elucidate further on this question.
Seed‐competent, high‐molecular‐weight Aβ species is abundantly extracted in the cerebrovasculature and meninges in Alzheimer’s disease
Authors: Uchigami Hirokazu , Kashiwagi‐Hakozaki Mayu , Matsubara Tomoyasu , Murayama Shigeo , Saito Yuko , Toda Tatsushi , Hashimoto Tadafumi , Iwatsubo Takeshi
Published: December 2023

Background

Soluble high‐molecular‐weight (HMW) amyloid β (Aβ) species extracted from autopsied brains of patients with Alzheimer’s disease (AD) have been demonstrated to exhibit a seeding potency to induce cerebral β‐amyloidosis. However, it remains unknown where Aβ seed species resides and how it propagates throughout human AD brains. Our objective is to detect Aβ seed in human AD brain cerebrovasculature and meninges that are enriched with cerebral amyloid angiopathy (CAA).

Method

We examined eight autopsied human AD brains with abundant CAA and eight AD brains without immunohistochemically detectable CAA. Tris‐buffered saline (TBS)‐soluble fractions from the brain parenchyma or meningeal tissues were separated by size‐exclusion chromatography (SEC) with Superdex 75 column, and the concentrations of Aβ in each SEC‐separated fraction were measured by enzyme‐linked immunosorbent assay (ELISA). The TBS‐soluble, high‐molecular‐weight Aβ‐positive fractions were stereotaxically injected into the unilateral hippocampus or cisterna magna of 3‐month‐old amyloid precursor protein (APP) transgenic (tg) mice, and Aβ deposition in the hippocampus was assessed after four months.

Result

HMW Aβ species were detected in TBS‐soluble fractions of the meninges and cerebrovasculature isolated from human AD brains. The concentration of HMW Aβ species extracted from meninges and cerebrovasculature was significantly higher than that from brain parenchyma in the same cases. Meningeal HMW Aβ species induced a robust Aβ deposition in the hippocampus, the area of which was significantly higher than that from the same weight of brain parenchyma. Moreover, the concentration of HMW Aβ species in CAA‐rich AD brains with meninges removed was significantly higher than those of CAA‐minimal AD brains. Intracisternal injection of HMW Aβ species derived from human AD brains induced not only CAA but also Aβ plaque.

Conclusion

Seed competent Aβ species are more abundant in cerebrovasculature and meninges than in brain parenchyma, and may accumulate in CAA in human AD brains. The possibility that HMW Aβ species in CAA contributes to Aβ plaque formation warrants further investigation in future studies.
Combining speech biomarkers for cognition and mood improves diagnostic accuracy between MCI and subjective cognitive decliners in a memory clinic sample
Authors: Ramakers Inez H.G.B. , ter Huurne Daphne B.G. , König Alexandra , Mallick Elisa , Linz Nicklas , Tröger Johannes
Published: December 2023

Introduction

Depressive symptoms are a common comorbidity in an old age memory clinic population. Cognitive and affective syndromes coexist, and supposedly modulate each other. While, there have been separate research streams on analysing speech to infer cognitive performance, as well as mood related symptoms, they are seldom investigated side‐by‐side. We present results from a small sub sample of a larger MCI and dementia cohort indicating that modelling both depressive symptoms and cognitive problems from speech can improve the diagnostic accuracy for MCI above speech biomarkers for cognition alone.

Methods

The ki:e Speech Biomarker for cognition (ki:e SB‐C; Tröger et al., 2022) and a free speech task were collected from 35 memory clinic participants (12F) with 10 of them having an MCI diagnosis (compare Table 1). From the free speech tasks (“Tell me about your upcoming vacation plans.”) we extracted speech features using ki:elements proprietary speech analysis engine SIGMA. Free speech features were corrected for cognitive performance, sex and age and then combined into a mood speech biomarker. To benchmark the diagnostic utility of both cognitive and mood speech biomarker side by side, we trained two groups of simple classifiers (tree based classifiers with leave one participant out cross validation) once with SB‐C alone and once with both SB‐C and the newly‐composed mood speech biomarker.

Results

By combining the speech biomarker for cognition and mood diagnostic performance was significantly improved (AUC of 88%) as compared to classification with the SB‐C alone (AUC of 74%). The mood biomarker correlates significantly with the Geriatric Depression Scale (r = 0.39, p < 0.05). Most important free speech features were jitter, number or pauses, mean pause duration or pronoun rate.

Conclusion

Overall we present rare evidences that combining speech‐based digital biomarkers tapping both into cognition but also mood‐related symptoms helps to improve diagnostic accuracy in MCI patients. Though just a small feasibility study, the results are clearly encouraging and point towards potential application in both clinical practice as well as clinical research.

References: Tröger, J., et al. (2022). Digital biomarkers,30;6(3):107‐116. https://doi.org/10.1159/000526471.
Levels of Mitophagy Biomarkers Differ Between Individuals With Alzheimer’s disease and Frontotemporal Lobar Degeneration
Authors: Katonova Alzbeta , Veverova Katerina , Horakova Hana , Angelucci Francesco , Laczó Jan , Hort Jakub , Shi Liu , Fang Evandro Fei , Vyhnalek Martin
Published: December 2023

Background

Reduced removal of dysfunctional mitochondria has been implicated in the pathogenesis of many neurodegenerative diseases, including Alzheimer’s disease (AD) and Frontotemporal lobar degeneration (FTLD). Mitophagy is the main cellular pathway through which aberrant and aged mitochondria are removed. Impaired neuronal mitophagy triggers the accumulation of damaged mitochondria, leading to cell death and neurodegeneration. While recent evidence suggests that levels of various mitophagy‐associated proteins are altered in AD, whether and in which direction mitophagy biomarkers are altered in non‐AD pathologies remains unclear. Therefore, we aimed to compare the levels of mitophagy markers between biomarker‐defined patients in various stages of AD and FTLD and cognitively unimpaired individuals (CU).

Method

We included 253 biomarker‐defined individuals from Czech Brain Aging Study: 86 AD dementia (ADD), 86 mild cognitive impairment due to AD (AD‐MCI) 21 FTLD dementia (FTLDD), 21 MCI due to FTLD (FTLD‐MCI), and 39 CU individuals. They underwent clinical examination, complex neuropsychological assessment, and brain MRI. Commercial ELISA kits were used to measure standard AD biomarkers in CSF (Aß42, Aß40, pTau, tTau), and mitophagy biomarkers in CSF (ULK1‐ autophagy factor essential for mitophagy initiation) and in serum (TFEB‐ transcription factor critical for mitophagic flux).

Result

We found a significant increase in ULK1 CSF levels in MCI‐FTLD compared to MCI‐AD (p<.01), ADD (p<.001), and CU (p<.01). There was also a significant increase in TFEB serum levels in FTLDD compared to MCI‐AD (p<.01) and CU (p<.01). Similarly, TFEB serum levels were elevated in FTLD‐MCI compared to ADD (p<.001), but were not elevated compared to CU.

Conclusion

There is an upregulation in the key mitophagy activator (ULK1) and in the mitochondrial quality control protein (TFEB) in FTLD compared to AD in various stages of disease (MCI vs dementia). Our data suggest that mitophagy plays different roles in the sub‐types of neurocognitive disorders, with a significant increase in the levels of mitophagy markers in patients with FTLD compared to healthy controls and patients with AD. Further research is needed to elucidate the role of mitophagy in the pathophysiology of different sub‐types of neurocognitive disorders.
Concept for the combination of blood and digital markers: ideas from the PROSPECT‐AD study
Authors: König Alexandra , Linz Nicklas
Published: December 2023

While knowledge about dementia and its causes is progressing rapidly, it remains challenging in clinical practice to detect accurately cognitive decline in the early stages of neurodegenerative diseases such as Alzheimer’s disease (AD). Improving the identification of early changes in the population is a prerequisite for dementia prevention and offering future disease‐modifying treatments to individuals most likely to benefit. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present major limitations for clinical practice (i.e., cost, accessibility).

Thus, the importance to find cost‐effective, and easily accessible tools for early detection has resulted in the development of innovative solutions that are specifically geared towards facilitating the population wide screening of at‐risk individuals.

Emerging blood‐based markers have the potential for widespread clinical use, and could facilitate timely diagnosis. However, several limitations must be overcome such as finding standardized techniques for measurements of blood biomarkers, establishing reliable cutoff values for individual biomarkers, or addressing the impact of confounding factors.

Recently speech analysis has become mature enough to automate speech‐based testing procedures and capture clinically fine‐grained features that are highly sensitive to early cognitive changes. Hence, speech can be utilized to indicate potential candidates to advance in the screening funnel for an on‐site more comprehensive assessment stage.

Supplementing the assessment of subjective complaints by automatized speech based analysis of cognitive tests and blood‐based AD biomarkers may offer a feasible approach for effective and cost‐efficient community‐based screening programs.

PROSPECT‐AD aims to scale up and to validate a novel, digital, and solely speech‐based biomarker extracted from an ordinary telephone to enable remote screening of early AD subjects. Within the PROSPECT‐AD project, novel speech features extracted during remote cognitive testing, and blood AD biomarker measurements will be compared to gold standard AD biomarker such as CSF‐amyloid‐β 1‐42 and CSF p‐Tau to assess value of a combinational approach. For this, the project collaborates with already ongoing cohorts such as EPAD (UK), DESCRIBE and DELCODE (Germany), BioFINDER Primary Care (Sweden) and Beta‐AARC (Spain) by adding the collection of speech data to existing protocols or as follow‐up assessments over the telephone.
Decreased Retinal Microvasculature in Mild Cognitive Impairment: An Optical Coherence Tomography Angiography Study
Authors: Velavarajan Goutham , Mallikarjun Divya N , M L Abhishek , Narayanasamy Rajitha , Malo Palash Kumar , Hameed Shafeeq K Shahul , Stezin Albert , R Meghana , Menon Meenakshi , Partha Ajith , C M Amitha , Singh Sadhana , HS Sunitha , Arvind Prathima , Kommaddi Reddy Peera , Diwakar Latha , Sundarakumar Jonas S. , Issac Thomas Gregor
Published: December 2023

Background

Eye are the extension of brain, any vascular abnormalities in the brain might reflect in ocular structures. The retinal microcirculation of an individual is similar to the small blood vessels found in the brain. The changes to the retina that result from neurodegenerative diseases can be observed through the eye. Studies have shown reduced retinal thickness in MCI when compared to healthy controls (HC). Therefore, OCT plays an important role in neurodegenerative diseases, and also in the MCI (Dudekova et al., 2016) (Sefton et al., 2022).

Method

This is a case‐control study. Total of 19 eyes from 11 MCI subjects, and 20 eyes from 15 HC were taken for analysis from Tata Longitudinal Study on Aging (TLSA) cohort (Sundarakumar et al., 2020). Clinical dementia rating (CDR) score was used to group the participants as having normal cognition and MCI. A score of 0 and 0.5 was considered as subjects having normal cognition and MCI respectively. Macular and radial peripapillary angiography were done using SD OCT‐A to compare foveal avascular zone (FAZ), Superficial capillary plexus (SCP) vessel density VD and SCP perfusion density (PD), and radial peripapillary capillary perfusion (CPD) and radial peripapillary capillary flux index (CFI) between both the MCI and HC groups.

Result

Table 1 shows demographic details, and Table 2 shows comparison of SD OCT‐A data between MCI and HC. MCI subjects showed significant decrease in mean CPD compared to HC (44.19% ± 1.59% vs 45.05% ± 2.03%; p < 0.05). Also, MCI group showed significant decrease in mean CFI (0.42 ± 0.03 vs 0.43 ± 0.02; p <0.05) compared to HC.

Conclusion

We demonstrated that there is decreased radial peripapillary perfusion and flux index in MCI subjects. By using SD OCT‐A, microvascular changes in early stage of dementia offers as a new way of detecting ocular biomarkers.
Is a dementia diagnosis predictive for palliative care? ‐ A machine learning approach
Authors: Rakusa Elena , Reinke Constantin , Doblhammer Gabriele , Schmid Matthias , Welchowski Thomas
Published: December 2023

Background

Palliative care (PC) aims to provide dignified and self‐determined life for dying individuals. While the integration of PC for tumor diseases in health care is established in case of progressive course and unfavorable prognosis, PC is surprisingly not mentioned in the German S3‐guideline for dementia. PC is mainly used by older people, with proximity to death rather than age being the determining factor. However, more people are dying at older ages. Moreover, as the elderly population increases, the number of dementia patients also increases. The aim of this paper is to examine the utilization of PC at the end of life and to explore whether a dementia diagnosis is among the top factors that predict PC utilization.

Method

We developed predictive models using discrete survival conditional inference trees (ctrees) and discrete survival conditional inference forests (cforests). We used randomly drawn claims data from a German health insurer from 2014 aged 50+ (N = 250.000), and followed them quarterly until 2019. We analyzed the last eight quarters of life of 13,628 individuals who had died in the observation period and used outpatient (OPC) and inpatient (IPC) PC as outcomes. We included medical history, care measures, medications, comorbidities and patient status (diagnosis of dementia or cancer, combinations of both diagnoses, and diagnosis‐free patients) as possible predictors. Dementia was defined by ICD‐10 codes F00‐F03,F05.1,G23.1,G30,G31.0 and G31.82 and cancer by C00‐C26,C30‐C41,C45‐C58,C60‐C97 and D00‐D09. For evaluation we used concordance‐index (C‐Index) and calibration plots. We identified the most important predictors by using a permutation variable importance approach.

Result

The models for OPC and IPC had a discriminatory power of more than 0.7 (C‐Index) on the test data. The calibration plots showed well calibrated ctrees, but the cforests require further tuning (Figure 1). Among the top 20 predictors of OPC were proximity to death as well as cancer and dementia diagnoses, and their combinations. Neither cancer nor dementia diagnoses were important predictors of IPC.

Conclusion

We found that a dementia diagnosis has comparably predictive power for OPC as a cancer diagnosis. This issue should be addressed by including appropriate measures in dementia care guidelines.
Neuropsychological and biomarker predictors of conversion to dementia in young‐onset Mild Cognitive Impairment
Authors: Carbone Chiara , Urbano Teresa , Beltrami Daniela , Tondelli Manuela , Gasparini Federico , Balboni Erica , Vinceti Giulia , Molinari Maria Angela , Marti Alessandro , Chiari Annalisa , Zamboni Giovanna
Published: December 2023

Background

Mild Cognitive Impairment (MCI) is a clinical condition that captures the stage between normal aging and dementia along the continuum of cognitive impairment. While it is usually thought to be precursor of Alzheimer’s Disease, when occurring at young ages (i.e., before 65 years old) it may increase the risk of all forms of neurodegenerative dementing diseases. We studied which neuropsychological and biomarker characteristics are predictors of conversion to dementia in a sample of patients with young‐onset MCI.

Method

Subjects with a diagnosis of MCI and early‐onset of cognitive symptoms (< 65 yo) were recruited in a prospective longitudinal study. They underwent extended neuropsychological assessment, Magnetic Resonance Imaging with measurement of hippocampal volume, and lumbar puncture with measurements of cerebrospinal fluid (CSF) light‐chain neurofilaments (NFL), beta‐amyloid 1‐42, total‐ and phosphorylated‐tau. They were followed‐up clinically and repeated the neuropsychological evaluation at 18 months from the baseline. Statistical analyses were performed with Stata15. Each biomarker and neuropsychological variable were added in multivariate Cox regression models with age, sex, and education.

Result

84 young‐onset MCI patients were recruited. After 18 months, 26 converted to dementia while 58 remained stable (i.e., MCI). Preliminary analyses showed that baseline smaller bilateral hippocampal volumes, lower baseline MMSE scores, baseline worst performances in tests of language, verbal long‐term memory, and executive functions, as well as baseline elevated levels of CSF NFLs increased the risk of conversion to dementia. Among them, the higher risk was given by the Free and Cued Selective Reminding Test (FCSRT), the Corsi Supraspan, the Frontal Assessment Battery, and the CSF NFLs levels, as shown by spline regression analyses (Figure 1). Of note, the FCSRT delayed recall showed a U‐shaped relationship with the risk of conversion (i.e., not only low/bad performance but also high/good performance were both related to a higher risk of conversion) suggesting that the types of predicted conversion may be different.

Conclusion

Our results suggest that, in young‐onset MCI, a combination of CSF‐NFLs levels and baseline performance at long‐term memory tests may be predictive of conversion to dementia, either AD or FTD.
A compound that specifically recognises patient‐derived Alzheimer fibrils
Authors: Pedrola Júlia Aragonès , Dekker Françoise A , Mayer Guy , Garfagnini Tommaso , Friedler Assaf , Rüdiger Stefan G.D.
Published: December 2023

Background

Protein aggregation is highly related to the development of Alzheimer’s Disease. The formation of extracellular beta‐amyloid plaques and intracellular neurofibrillary tangles, composed by Tau fibrils, leads to neuronal dysfunction and degeneration. Current diagnosis techniques, such as brain imaging and cerebrospinal fluid tests, can only determine the formation of the protein deposits, which happens to be too late. It is of great importance to visualize initial aggregation steps, which is a prerequisite for early diagnosis.

Method

Tau fibrils were extracted from AD patient‐derived brains or generated in vitro, and analysed by Flow Induced Dispersion Analysis with WH peptide.

Results

Here we present a method to monitor Tau fibrils size from the first aggregation steps. We designed WH peptide as a biocompatible, fluorescence‐labelled compound that specifically recognizes protein fibrils but not non‐amyloidic monomers, based on specific chemical properties, so called π‐stacking and H‐bonding interactions. These interactions are crucial for the recognition of aggregated species. In combination with Flow Induced Dispersion Analysis, a novel microfluidics technology, we determined the size of the aggregated species with sub‐microliter sample volumes. It is a key challenge in the field to study patient derived fibril. WH peptide labels Alzheimer’s Disease patient‐derived fibrils, which structurally differ from the in vitro generated ones, which allowed us to determine the size of the ex vivo fibrils.

Conclusion

WH peptide fluorescently labels Alzheimer’s Disease patient‐derived fibrils. WH peptide is biocompatible and could be further functionalized for imaging applications, which could be a basis for early‐stage diagnosis of Alzheimer’s Disease.