bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolomics biomarker discovery in cerebrospinal fluid for cerebral amyloid angiopathy
Authors: van den Berg Emma , Kuiperij H. Bea , Van Nostrand William E. , Peters Tessa M.A. , Coene Karlien L.M. , Engelke Udo F.H. , de Boer Siebolt , Verbeek Marcel M.
Published: December 2020

Background

Cerebral amyloid angiopathy (CAA) is a major cause of intracerebral hemorrhages and contributes to cognitive decline. Probable diagnosis is currently determined using the modified Boston criteria. However, these in vivo imaging correlates only represent late‐stage disease manifestations, are unable to set definitive CAA diagnosis, and do not reflect disease progression or track severity. Thus there is an unmet need for an early‐stage CAA biomarker to bypass these limitations. Next to vascular amyloid‐ß accumulation and increased neuroinflammation, metabolite levels may also be altered due to changes induced by amyloid‐ß deposits.

Method

In the Cerebral Amyloid Angiopathy Fluid Biomarker Evaluation (CAFE) study, we aim to discover and validate new CAA‐specific biofluid markers. By using a transgenic rat model for small‐vessel CAA, the rTg‐DI model, we are able to study a genetically homogenous group, housed in an environment equal to wild‐type rats. An unbiased combined liquid chromatography‐mass spectrometry protocol to analyze cerebrospinal fluid (CSF) from these rats will be generated and optimized. With the obtained distinct metabolite profiles, we aim to identify novel CAA‐associated metabolite biomarkers.

Result

Next‐generation metabolic screening (NGMS) is our newly developed methodology to study the metabolome, using high‐resolution liquid chromatography quadrupole time‐of‐flight mass spectrometry. This high‐throughput unbiased NGMS approach enables us to detect >10,000 different features in one plasma sample, defined by their unique combination of accurate mass, specific retention time and intensity. In human CSF, 206 metabolites were annotated using the Human Metabolome Database. Application to rodent models requires only 25µL of CSF for analysis. Currently, we are analyzing CSF from 6‐months old rTg‐DI rats compared to age‐matched wild‐type rats (each n=10); the results will be presented during the conference.

Conclusion

We expect that our powerful innovative technology for untargeted and simultaneous analysis of a large number of metabolites in body fluids will be promising in discovering novel potential biomarkers for CAA. Using a robust animal model allows us to study biomarkers along the trajectory of disease progression. Furthermore, it will gain more insight in underlying processes and metabolic pathways that are involved in the pathophysiology of CAA. After the initial discovery phase, candidate markers will be validated in patient cohorts.
Microglial activation: A process potentially related to Alzheimer's disease and late‐life major depression
Authors: Heslegrave Amanda J. , Foiani Martha S , Bruno Davide , Reichert Chelsea , Zlokovic Berislav V. , Huang Yadong , Zetterberg Henrik , Blennow Kaj , Pomara Nunzio
Published: December 2020

Background

Since genetic findings have implicated microglia and TREM2 in the aetiology of neurodegenerative diseases, particularly Alzheimer's disease (AD), there have been numerous studies indicating changes in the levels of sTREM2 in cerebrospinal fluid (CSF) in sporadic and familial disease. Inflammation has also been implicated in depression and associated with an increased risk for AD. This prompted us to investigate levels of sTREM2 in late life major depression (LLMD).

Method

CSF was obtained from 47 older subjects with intact cognition having an MMSE score of at least 28 and no gross MRI abnormalities other than white matter hyperintensities (22 LLMD, 19 controls). Severity of depression was determined at baseline and screening visits using the HAM‐D. CSF sTREM2 was determined using an electrochemiluminescence immunoassay. We also determined AD biomarker levels and indices of blood brain barrier (BBB) dysfunction.

Result

sTREM2 levels were significantly lower in the CSF of LLMD subjects compared to controls (3476±525.1 pg/mL, 5178±2787 pg/mL p = 0.00351). Levels of sTREM2 were positively correlated with Aβ40 (r = 0.495, p = <0.001), Aβ42 (r = 0.461, p = 0.001) tTau (r = 0.417, p = 0.003) pTau181(r = 0.413, p = 0.004) and IL8 (r = 0.338, p = 0.022), this was driven by controls only. Markers of BBB integrity, the albumin quotient (AQ), cyclophilin A and soluble platelet derived growth factor beta (sPDGFβ) all show a positive correlation with sTREM2 (r = 0.503, p = 0.028; r = 0.479, p = 0.024; r = 0.455, p = 0.017 respectively) but this correlation is only seen in LLMD subjects, apart from sPDGFRβ, where a positive correlation was also seen in the whole cohort (r = 0.0337, p = 0.022).

Conclusion

The correlation of sTREM2 with indices of BBB dysfunction suggests that in LLMD the sTREM2 measured could be peripheral, and that there is a decrease or suppression of microglial activation. It is possible then, that LLMD leads to a higher risk of AD due to an inability of microglia to react appropriately and further studies should focus on investigating this in more detail.
PET imaging of net availability in humans using [11C]MRB: Age, gender and ethnicity effects
Authors: Ding Yu‐Shin , Wang Jiacheng , Chen Jingyun , Babb James , Rusinek Henry ,   Ding Group
Published: December 2020

Background

Understanding the underlying pathological mechanisms of AD is urgently needed to enable the development of effective treatments. Tau pathology emerges decades before amyloid pathology, appearing first in the brainstem (BS); particularly in the locus coeruleus (LC), the source of brain’s norepinephrine (NE). Our preliminary data using [11C]MRB have documented an age‐related decline in NE transporters (NET) starting in middle age, suggesting in vivo NET availability is a sensitive biomarker for aging and preclinical stages of AD. This report investigated the age, gender and ethnicity effects on NET availability

Method

Coregistration of PET (dynamic [11C]MRB), MRI and the FreeSurfer (FS) atlas images of each individual to generate regional time‐activity curves (TAC) using Firevoxel. Binding potential (BPND) were determined using MRTM2 (t2* 20 min and k2’ 0.021 min‐1 with occipital as the reference region). Annual percent change (APC) of BPND was calculated based on linear regression (APC = 100 × (em
– 1), m: slope) and effects of age, gender and ethnicity on tracer binding were evaluated.

Result

For all HC (N=31), with both genders and all races included, the NET availability decline can be observed; e.g., ‐0.4%/yr for BS & ROfac. However, in gender‐separated group analysis [(19M, age 36.2±9.9) vs. (12F, age 36.6±9.0)], there was a significant gender effect for APC (P <0.01) with decline rates faster for M (e.g., ‐0.8%/yr for LTH), starting from mid 30 (p<0.001). Interestingly, out of 16 ROIs, while AA (N=14, age 34±7) had consistently higher regional BPND than white subjects (N=12, age 35±8)(P<0.000), the decline rate was much higher for AA (P<0.00001); e.g., ‐3%/yr in LTH for AA‐M.

Conclusion

In addition to our previously determined age effect on MRB‐NET binding, this report further reveals, for the first time, the role of gender and ethnicity effects on NET availability, in the context of the aging brain. A bigger sample size is warranted to investigate these effects on the NET availability.
Microinfarcts in the deep gray matter on 7 Tesla MRI: Risk factors, MRI correlates and relation to cognitive functioning — the SMART‐MR study
Authors: Ghaznawi Rashid , Zwartbol Maarten H. T. , de Bresser Jeroen , Kuijf Hugo J. , Hendrikse Jeroen , Geerlings Mirjam I.
Published: December 2020

Background

Histopathological studies suggest that microinfarcts in the deep gray matter are associated with ante‐mortem cognitive impairment, however in vivo data on subcortical microinfarcts are lacking. We examined the association of microinfarcts in the deep gray matter on 7T MRI with vascular risk factors, MRI markers of cerebrovascular disease and cognitive functioning in patients with a history of arterial disease.

Method

Within the SMART‐MR study, 213 patients (68 ± 8 years) had risk factor assessment, a 7T and 1.5T brain MRI, and cognitive examination. Microinfarcts in the deep gray matter on 7T MRI were defined as lesions ≤4 mm. Regression models were used to examine the age‐adjusted associations between risk factors, MRI markers and presence of microinfarcts in the deep gray matter. Cognitive function was summarized as composite and domain‐specific z‐scores.

Result

A total of 47 microinfarcts were found in 28 patients (13%). Older age, history of stroke, hypertension and intima‐media thickness were significantly associated with microinfarcts. On 1.5T MRI, cerebellar infarcts (RR = 2.75, 95% CI: 1.42 ‐ 5.33), lacunes in the white (RR = 3.28, 95% CI: 3.28 ‐ 6.04) and deep gray matter (RR = 3.06, 95% CI: 1.75 ‐ 5.35) were associated with microinfarcts, and on 7T MRI cortical microinfarcts (RR = 2.33, 95% CI: 1.32 ‐ 4.13). Microinfarcts were also associated with poorer global cognitive functioning (mean difference in global z‐score between patients with multiple microinfarcts vs. none = ‐0.97, 95% CI: ‐1.66 to ‐0.28, p = 0.006) and across all cognitive domains, independent of age, education level and number of infarcts ≥5 mm in the deep gray matter.

Conclusion

Microinfarcts in the deep gray matter on 7T MRI were associated with MRI markers of small and large vessel disease and worse cognitive functioning. These findings suggest that microinfarcts in the deep gray matter represent a novel imaging marker of vascular brain injury.
Neuropsychiatric symptoms in subjective cognitive complaints (SCC) and mild cognitive impairment (MCI): Detecting changes over time with the Mild Behavioral Impairment Checklist (MBI‐C)
Authors: Mallo Sabela C. , Pereiro Arturo X. , Campos‐Magdaleno Maria , Nieto‐Vieites Ana , Lojo‐Seoane Cristina , Facal David , Ismail Zahinoor , Juncos‐Rabadán Onésimo
Published: December 2020

Background

Neurobehavioral Symptoms (NPS) have been usually measured with the Neuropsychiatric‐Inventory (NPI‐Q) (Kaufer et al., 2000) in pre‐dementia individuals. However, this instrument was designed to dementia states. The Mild Behavioral Impairment Checklist (MBI‐C) (Ismail et al., 2017) is an instrument developed to evaluate NPS in pre‐dementia states, including Mild cognitive impairment (MCI) and people with Subjective Cognitive Complaints (SCC). Evidence of longitudinal behavioral change obtained with the MBI‐C is still scarce. Our objective was to compare NPS scores, measured with the NPI‐Q and the MBI‐C, in MCI and SCC participants, at follow‐up.

Method

Two hundred forty participants from the Compostela Ageing Study recruited from primary care health centers, were classified into two groups, MCI (84) and SCC (166). Socio‐demographic, neuropsychological and NPS measures, including MBI‐C and NPI‐Q total scores on severity, were collected at baseline and at follow‐up (mean interval, 24 months) (Table 1). Instrument (NPI‐Q and MBI‐C) total score differences as a function of measurement Time (baseline vs follow‐up) were analyzed using repeated measure ANOVAs including Group (SCC vs MCI) as inter‐subject factor.

Results

Significant main effects of Time, F(1, 251)=7.68, p = .006, ηp
2=.030, observed power=.789, and Group, F(1, 251)=9.88, p = .002, ηp
2=.038, observed power=.879, were observed for the NPI‐Q total scores (Figure 1). Time*Group interaction was not found. Mixed ANOVA for the MBI‐C total score showed significant main effect of Group, F(1, 248)=13.93, p < .001, ηp
2=.053, observed power=.961, and Time*Group interaction, F(1, 248)=4.89, p = .028, ηp
2=.020, observed power=.596. Post hoc Bonferroni tests for the MBI‐C total score showed (Figure 2) significantly higher behavioral impairment in MCI than in SCC group in both time measurements (baseline and follow‐up).

Conclusions

Time main effect in NPI‐Q total scores showed decreases in severity of behavioral symptoms in the follow‐up measurement in spite of the Group (SCC vs MCI). On the contrary, MBI‐C scores pointed‐out slight increases in the follow‐up measurement and, considering the descriptive trends, particularly in MCI group. Only the MBI‐C was able to detect significant differences between MCI and SCC groups both in baseline and follow‐up measurements.
Cerebroprotective effects of D. triquetrum on sodium nitrite‐induced hypoxia and ethanol‐induced neurodegeneration in animal models relevant to dementia
Authors: Joshi Hanumanthachar , Sandhya P. , Charan C.S.
Published: December 2020

Background

Cognitive impairment is a multidimensional and complicated concept that subsumes the attention, concentration, learning, memory, problem‐solving ability, visuospatial abilities, mental flexibility, psychomotor efficiency and manual dexterity.

Objective

To study the effects of aqueous extracts of roots of Desmodium triquetrum on cognitive deficit mice.

Methods

Aqueous extracts of Desmodium triquetrum (DTE) were screened for Sodium nitrite induced hypoxia and Ethanol induced neurodegeneration using behavioral models such as rotarod, Passive shock avoidance paradigm, special water bottle case model, elevated plus maze and Morris water maze. DTE (5, 2.5 and 1.25 mg/kg p.o.) were administered to the mice. Acquisition, retention, Transfer latency (TLT), Time spent in target quadrant (TSTQ), Step down latency (SDL) and Escape latency (ELT) and biochemical parameters such as AChE, MAOA, TBARS, epinephrine, 5 HT were determined. DNA fragmentation studies were conducted which were compared with Donepezil.

Results

DTE (5, 2.5 and 1.25 mg kg(‐1) p.o.) significantly (p < 0.001) protected the Sodium nitrite induced memory impairment by decreasing the time require to find the water bottle in special water bottle case model. DTE improved acquisition and retention memory significantly (p < 0.001) by decreasing the Transfer Latency Time (TLT), escape latency time, TSTQ and increased the Step Down Latency (SDL. DTE inhibited Acetylcholinestrase (p < 0.01) activity, increased GSH, decreased TBARS and inhibited MAOA activity. Reduced the metabolism of epinephrine, 5‐HT. DTE (5 mg kg‐1) protected the DNA fragmentation of frontotemporal cortex from hypoxic effects.

Conclusion

Desmodium triquetrum are beneficial in the management of Neurodegenerative disorders particularly for Alzheimer’s disease.
A fully automated cognitive screening tool based on assessment of speech and language
Authors: O'Malley Ronan , Walker Traci , Mirheidari Bahman , Christensen Heidi , Reuber Markus , Blackburn Daniel J. , Venneri Annalena
Published: December 2020

Background

The dramatic recent rise in referrals to specialist memory clinics has been associated with an increased proportion of patients referred with Functional Memory Disorder (FMD), i.e. non‐progressive cognitive complaints. These referrals have exerted time and financial pressures on secondary care services, impairing their ability to deliver high‐quality care for patients with neurodegenerative cognitive disorders. We have developed a fully automated system, “CognoSpeak”, which enables risk stratification at the primary‐secondary care interface and ongoing monitoring of patients with memory concerns.

Method

We recruited 15 participants to each of four groups: Alzheimer’s disease (AD), Mild Cognitive Impairment (MCI), FMD and healthy controls. Participants responded to 12 questions posed by a computer‐presented talking head. Automatic analysis of the audio and speech data involved speaker segmentation, automatic speech recognition and machine learning classification.

Result

CognoSpeak could distinguish between participants in the AD or MCI groups and those in the FMD or healthy control groups with a sensitivity of 86.7%. Patients with MCI were identified with a sensitivity of 80%.

Conclusion

Our fully automated system achieved levels of accuracy comparable to currently available, manually administered assessments. Greater accuracy should be achievable through further system training with a greater number of users, the inclusion of verbal fluency tasks and mood assessments. The current data supports CognoSpeak’s promise as a screening and monitoring tool for patients with MCI. Pending confirmation of these findings, it may allow clinicians to offer patients at low risk of dementia earlier reassurance and relieve pressures on specialist memory services.
Show, don't tell: Brain visualisations for neuroimaging studies
Authors: Marinescu Razvan V , Young Alexandra L
Published: December 2020

Background

Efficient visualisation of brain structure, function and pathology is crucial for understanding the mechanisms underlying neurodegenerative diseases such as Alzheimer’s disease (AD). However, visualisation of dynamic brain processes such as pathology spread in AD is difficult due to the slow progression of pathological cascades at multiple scales and over extended periods of time. Current visualisation software (e.g. Freesurfer or SPM) are excellent for interactive visualisation of single brain scans, but for a study population, do not enable easy generation of coloured brain templates or movies showing the temporal progression of pathology.

Method

We present BrainPainter (Fig 1), a recently released brain visualisation software that has two key advantages: (1) it can generate brain templates or movies showing dynamic processes in the brain, e.g. propagation of amyloid or tau pathology and (2) it does not require the input data to be in a specialised format, allowing it to be used in conjunction with any neuroimaging analysis software (e.g. Freesurfer, SPM).

Result

We highlight two use cases of BrainPainter for existing neuroimaging studies: (i) Fig. 2 – visualisation of the progression of pathology in Alzheimer’s disease and (ii) Fig. 3 – visualisation of pathology in subcortical regions in Huntington’s disease. We further present two novel functionalities of BrainPainter: (iii) generation of movies showing progression of atrophy in Alzheimer’s disease (e.g. https://brainpainter.csail.mit.edu/#examples ) and (iv) Fig. 4 – visualisation of individual regions‐of‐interest based on three supported atlases (Desikan‐Killiany, Destrieux and Trourville).

Conclusion

BrainPainter is customisable, easy to use, and runs straight from the web browser: https://brainpainter.csail.mit.edu. It can generate visualisations of imaging data from any modality, which can easily be included as images or videos into neuroimaging studies. Through the design of BrainPainter, we further demonstrate the possibility of turning Blender, the powerful 3D rendering engine, into a useful tool for the neuroscience community.
Occupational burnout‐like syndrome in early‐onset Alzheimer’s disease
Authors: Olivieri Pauline , Lagarde Julien , Hamelin Lorraine , Niel Philippe , Bottlaender Michel , Kas Aurélie , Habert Marie‐Odile , Sarazin Marie
Published: December 2020

Background

Early‐onset Alzheimer’s disease (EOAD) differentiates from late‐onset AD by a predominant and early involvement of the parietal neocortex with hippocampal sparing, leading to non‐amnesic cognitive syndromes (deficits in working memory, visuospatial abilities, praxis, or language). The diagnosis of a neurodegenerative disease is often not the first mentioned in such young patients. We aimed to identify the inaugural symptoms and diagnosis in working age EOAD patients.

Methods

We retrospectively reviewed the files of patients younger than 62 years referred to our memory clinic for cognitive dysfunction during the last year. Among 91 patients, 31 were diagnosed with AD based on clinical and biological criteria (cerebrospinal fluid biomarkers). Their mean age was 55±3.8 years.

Results

Eleven EOAD patients (35%) were initially diagnosed with an occupational burnout syndrome, while logopenic aphasia or visuo‐spatial deficit were observed in the remaining 20 patients (65%). In the burnout syndrome subgroup, the delay between the first symptoms and neurological examination was 2.6±1.1 years. The initial Mini‐Mental State Examination score was 19.6±4.6/30. Neuropsychological assessment showed a severe working memory deficit, associated with mild cognitive cortical parietal syndrome. Visual inspection of brain MRI and FDG‐PET showed bilateral parietal atrophy and a severe focal hypometabolism of associative parietal cortices. No patient had family history of EAOD and the molecular genetic testing of AD mutation was negative.

Conclusion

We describe, for the first time, a new clinical presentation of EOAD mimicking an occupational burnout syndrome. The severe inaugural working memory deficit due to the early cortical parietal damage leads to an inability to carry out concurrent professional tasks, a reduction of professional efficacy and a severe anxiety, in the absence of overt aphasia or episodic memory deficit at the time of initial evaluation. The patient stops working and is often referred to psychiatrists, the diagnosis being delayed until the cognitive deficit worsens, and strongly affects the autonomy at a more advanced stage of the disease. It is crucial to consider this clinical phenotype in the definition of EOAD to avoid delayed diagnosis.
Reducing the sample size in high‐frequency biomarkers RCTs
Authors: Taylor‐Rodriguez Daniel M , Lovitz David M , Mattek Nora , Wu Chao‐Yi , Kaye Jeffrey , Dodge Hiroko H , Jedynak Bruno Michel ,   ORCATECH
Published: December 2020

Background

High‐frequency biomarkers (HFB) are measurements collected weekly, on a daily basis or even more frequently. They are designed to detect early progression from one cognitive state to a later stage. Examples include home‐based measurements, e.g., computer usage and sleep patterns. In randomized controlled trials (RCT), we aim to detect the difference in trajectories of HFB between placebo and experimental group. Current statistical analysis e.g. linear mixed effect with random intercept models detect changes in the mean trajectory but fail to detect changes in the covariance structure, thus requiring longer trials. We examined whether more careful modeling, using historical data, would reduce the sample size needed for a RCT? Objective: (1) to present a novel statistical methodology for analyzing RCTs whose outcomes are HFB based on historical data of cognitively normal subjects, and (2) to evaluate this methodology using simulated data first, then using data from the Oregon Center for Aging and Technology (ORCATECH).

Methods

The statistical methodology proposed proceeds in three phases (Figure 1). Highlights include the use of historical data for cognitively normal subjects and the use of a Gaussian process with parameterized mean function and covariance structure. Examples of results from simulated data are shown in Figure 2, demonstrating the superior power of the methodology compared to the linear mixed‐effects model. ORCATECH’s weekly computer usage data was used (Figure 3). We computed an RCT effect size with 86 cognitively normal subjects and 11 subjects who were cognitively normal at baseline, but would eventually develop MCI within 139 weeks on average (sd=72).

Results

Using this new approach, we found an effect size of W=0.616 (Area Under the curve), outperforming a baseline method which yielded an effect size of W=0.515. Respective total sample sizes for an RCT with alpha=0.05 and power=0.8 are 74 and 1028, for the new versus the conventional approach, respectively.

Conclusions

We have shown that a careful statistical procedure allows for maximally benefiting from HFB by reducing the sample size needed for a 100 week RCT. More experiments will be necessary to validate these findings.
Angiotensin receptor blockers versus angiotensin‐converting enzyme inhibitors: Longitudinal associations with PET amyloid in the Alzheimer's Disease Neuroimaging Initiative
Authors: Ouk Michael , Wu Che‐Yuan , Rabin Jennifer S. , Edwards Jodi D. , Ramirez Joel , Masellis Mario , Swartz Richard H. , Herrmann Nathan , Lanctot Krista L. , Black Sandra E. , Swardfager Walter
Published: December 2020

Background

Evidence suggests that Angiotensin II type‐1 Receptor Blockers (ARBs) and Angiotensin‐Converting Enzyme Inhibitors (ACE‐Is) may be differentially beneficial for cognition, but there is little clinical evidence supporting possible mechanisms. This study examines longitudinal associations between the use of ARBs and ACE‐Is with summary cortical and subregional brain amyloid‐β (Aβ).

Method

This study included participants with hypertension who were using an ACE‐I or ARB with available PET data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1, GO, and 2 databases (years 2010‐2018). Analyses were conducted in subgroups with normal cognition (NC) and with cognitive impairment (amnestic mild cognitive impairment or Alzheimer’s disease [AD/MCI]). The outcome was PET Aβ SUVR in a cortical summary region and subregions involved in early/late stages of Aβ accumulation. Linear mixed‐effects models with inverse probability of treatment weighting were used to compare rates of Aβ accumulation over 48 months between ARB and ACE‐I users. Models were adjusted for demographics, ApoE ε4 status, baseline MMSE, relevant comorbidities, and other concurrent antihypertensive use.

Result

In the NC group (n=124, age=74.8±5.6, 46.3% women), ARB vs. ACE‐I use was associated with a slower rate of Aβ accumulation in the cortex (β=‐0.138 [‐0.062, ‐0.223]), the inferior temporal lobe (β=‐0.165 [‐0.076, ‐0.255]), and precuneus (β=‐0.164 [‐0.075, ‐0.252]). In people with AD/MCI (n=246, age=74.5±7.3, 39.1% women), users of an ARB vs. an ACE‐I did not differ in the rate of Aβ accumulation in the cortex (β=0.019 [‐0.038, 0.075]), in the above regions (inferior temporal lobe β=‐0.027 [‐0.102, 0.048]; precuneus β=0.008 [‐0.051, 0.067]), or in areas associated with later Aβ accumulation (parietal lobes β=0.035 [‐0.027, 0.097]; frontal lobes β=0.014 [‐0.053, 0.081]).

Conclusion

In cognitively‐normal adults, ARB use was associated with a significantly slower rate of Aβ accumulation. This difference may be partially explained by preservation of Aβ‐clearing effects of the angiotensin‐converting enzyme by ARBs. In contrast, there were no significant differences in AD/MCI which could reflect both plateau effects, less impact on more advanced stages, or a relatively small sample size. Prospective analyses and clinical trial evidence are warranted to confirm the potential benefit of ARB use to slow Aβ accumulation and prevent cognitive impairment.
Detecting seizure patterns in patients with Alzheimer’s disease using long‐term EEG monitoring: A feasibility study
Authors: Musaeus Christian Sandøe , Waldemar Gunhild , Larsson Henrik Bo Wiberg , Andersen Birgitte Bo , Høgh Peter , Kidmose Preben , Hasselbalch Steen Gregers , Fabricius Martin , Tøpholm Richard , Rank Mike Lind , Kjær Troels Wesenberg , Frederiksen Kristian Steen
Published: December 2020

Background

Seizure patterns as detected with electroencephalography (EEG) has been suggested to be frequent in patients with Alzheimer’s disease. However, long‐term EEG monitoring to detect seizure patterns requires hospitalization for longer periods of time, which is both expensive and difficult for patients with Alzheimer’s disease.In the current feasibility study, we investigated whether it was possible for patients with Alzheimer’s disease to wear ear‐EEG for long‐term EEG monitoring of seizure patterns at home.

Method

We recruited patients who met the criteria for Alzheimer’s disease and had no previous history of epilepsy. Seizure patterns was assessed using long‐term EEG monitoring with ear‐EEG for 48 hours every three months for half a year. Furthermore, patients and relatives were instructed in the use of a seizure diary, which was used during the ear‐EEG recordings.

Result

So far, we have recruited 9 patients with Alzheimer’s disease, and all patients who underwent ear‐EEG monitoring have been able to wear the ear‐EEG for at least 24 hours including sleep. We are currently in the process of investigating whether the patients with Alzheimer’s disease show seizure patterns as measured with ear‐EEG.

Conclusion

Long‐term EEG monitoring using ear‐EEG seems to be feasible for measuring seizure patterns in patients with Alzheimer’s disease. If any of the patients show seizure patterns using ear‐EEG, we will be able to treat with anti‐epileptic medication, which may improve their symptoms.
Properties of TCR gamma clonotypes in AD brain and peripheral blood
Authors: Aliseychik Maria P. , Patrikeev Anton , Gusev Fedor , Grigorenko Anastasia , Andreeva Tatiana , Biragyn Arya , Rogaev Evgeny I.
Published: December 2020

Background

The immune system contributes to various neurodegenerative pathologies, including Alzheimer’s disease (AD). γδ T cells can mediate different pathological processes in the human brain, such as oncogenesis, autoimmunity, and stroke. However, the role of γδ T cells in AD have not yet been elucidated.

Method

We designed an approach based on multiplex PCR system with following library preparation and deep sequencing of the CDR3 region of TRGs. In total clonotype repertoires from 147 peripheral blood and postmortem brain samples of AD patients and control individuals without dementia were analyzed. Moreover 17 blood repertoires of patients with Parkinson’s disease (PD) were also tested.

Result

Our results showed special features of peripheral blood (PB) and brain TRG repertoires: compared with the PB, the brain showed reduced TRGV9 clonotypes but was enriched in TRGV2/4/8 clonotypes. Age‐related changes were found. The reduced diversity and CDR3 length of human blood TRG repertoires and in the composition of the brain TRG repertoire, in particular, a decrease in the frequency of the TRGV9 segments and an increase in TRGV2/4/8 were identified. We developed a bioinformatic approach based on the physicochemical properties analysis of rare clones that are found in patients with AD but not in healthy individuals. Our findings revealed the enrichment of TRG clonotypes with specific properties in the brain or blood of patients with AD compared to those in controls. (Aliseychik et al. 2020) These AD‐associated clonotypes are not typical for patients with PD, for which accumulation of the AD specific clonotypes was not pronounced.

Conclusion

The pilot study of TCR repertoires in AD revealed disease associated TRGs profile properties in brain and blood and implied putative AD‐associated immunogenic markers. This work was supported by the National Institute on Aging (NIA; R01 AG054712); the Russian Foundation for Basic Research (RFBR, grant no. 18‐29‐13051) and the Russian Science Foundation (RSF, grant no. 19‐75‐30039).
STRONGER 60+ Adaption of the multimodal FINGER model to prevent cognitive decline in a Swedish primary care rehabilitation unit: An effectiveness‐implementation hybrid design
Authors: Thunborg Charlotta , Åkesson Elisabet , Leavy Breiffni , Håkansson Krister , Sindi Shireen , Solomon Alina , Levak Nicholas , Kivipelto Miia
Published: December 2020

Background

Preventing cognitive and physical decline in people >60 is a major public health priority. Evidence‐based programs for promoting healthy lifestyle in people 60+ are sparse. WHO has launched risk reduction guidelines for cognitive decline and dementia focusing on several lifestyle and cardiovascular risk factors. The FINGER trial is the first large RCT indicating that targeting several risk factors simultaneously can reduce cognitive and functional decline among at risk elderly persons. To develop and implement personalized, effective and feasible lifestyle interventions for real life settings, the multimodal FINGER model needs to be adopted and new evidence from recent studies implemented (e.g. importance of psychosocial factors). The aim of STRONGER 60+ is to adapt the FINGER‐model and investigate intervention effectiveness on lifestyle factors in association with cognitive‐ and physical function. By adopting a hybrid‐design, the implementation process will be followed in a real‐world setting.

Method

STRONGER 60+ will include an adapted version of the FINGER‐model, with the components of a brain‐healthy diet, exercise, cognitive training, and stimulating social activity, in addition with careful monitoring of cardiovascular risks. A co‐production design including clinicians and participants will be used. It is a 6‐monh (with 12 month follow‐up) randomized controlled, single blind parallel‐group clinical effectiveness study. Up to 160 persons will be recruited. Participants will receive either the adapted multimodal healthy lifestyle intervention or regular health advice. A measure of psychosocial states will be included to highlight the importance of tailormade interventions in the study. The intervention is designed for community‐dwelling persons ≥ 60 years, with elevated risk for dementia according to the Dementia Risk Tool risk score, MMSE ≥ 24.

Result

We are currently finalizing the resource planning, recruitment start in September 2020. With the hybrid‐design outcome evaluation we will be able to explore the process by examining; facilitators and barriers for the adaption process, the recruitment process of participants, the extent to which the target audience encounter the program, retention rate, fidelity to the FINGER‐model, dose received/delivered.

Conclusion

For people at‐risk of cognitive‐ and physical decline to benefit from multimodal lifestyle intervention research, interventions tested in research settings require adaption and assessment in real‐world clinical practice.
Treatment implementation leads to improved outcomes in patients with dementia in Sweden from 2008‐2017: Experience from the Swedish Dementia Registry
Authors: Xu Hong , Garcia‐Ptacek Sara , Secnik Juraj , Hoang Minh Tuan , Tan Edwin CK , Religa Dorota , Eriksdotter Maria
Published: December 2020

Background

The efficacy of available treatments for dementia remains limited and few randomized clinical trials have been able to demonstrate the benefits of treating comorbidities in improving outcomes of patients with dementia. In this study, we evaluated temporal changes in the management of comorbidities and survival rates in incident dementia over a ten‐year period in Sweden.

Method

We included 40,219 patients with newly diagnosed dementia in memory clinics from the Swedish Dementia Registry (SveDem) during 2008‐2017 and stratified all data by one‐year blocks. We evaluated trends in the use of dementia drug treatments and selected key medications within 1‐year blocks. We then evaluated the incidence of death, major cardiovascular events (MACE), and fracture within one‐year from the diagnosis date using standardized incidence rates to account for differences in patient characteristics over time. Via Cox regression models, we explored whether adjustment for implementation of new treatments modified survival, MACE and fracture risk. Finally, survival trends were also compared against an age‐sex‐calendar year‐matched general Swedish population using standardized incidence ratios (SIR).

Result

Across 1‐year blocks, there was no difference in Mini‐Mental State Examination, and proportion of Alzheimer’s and vascular dementia over time. However, age and proportion of females and unspecified dementia decreased. The use of renin‐angiotensin‐system‐inhibitors, calcium‐channel‐blockers, statins and dementia medication memantine increased while antipsychotics, antidepressants and cholinesterase‐inhibitors decreased. After standardization for demography and comorbidities, the 1‐year risk of mortality, MACE or fracture decreased by 13%, 7% and 19%, respectively, in the year 2016 compared to the year 2008. In multivariable Cox models, per 1‐year increase, the risk of death within 1‐year decreased by 4% (HR 0.96[95% CI 0.95‐0.97]), MACE by 3% (0.97[0.96‐0.98]) and fracture by 3% (0.97[0.95‐0.98]). Compared with general population, the risk of death corresponding to a SIR reduced by 11% in the year 2016 compared to 2008.

Conclusion

Over the last 10 years, a reduction in the short‐term risk of death, MACE and fracture risk in patients with dementia was found in association with changes in drug prescribing practices. This suggests that implementation of established treatments for comorbidities may be beneficial for patients with dementia.
Abstract dementia risk prediction model development in low‐ and middle‐income countries: The 10/66 study
Authors: Worrall Alice Louise , Prina Matthew , Pakpahan Eduwin , Siervo Mario , Terrera Graciela Muniz , Mohan Devi , Acosta Daisy , Pichardo Guillermina Rodriguez , Sosa‐Ortiz Ana Luisa , Acosta‐Castillo Gilberto Isaac , Llibre Juan , Prince Martin J , Robinson Louise , Stephan Blossom CM ,   10/66
Published: December 2020

Background

Most people with dementia live in Low and Middle Income Countries (LMICs), where little research on dementia risk prediction modelling has occurred. This study aimed to develop new models to simply predict all‐cause dementia, suitable for use in LMICs. Country‐specific models were expected, due to different risk profiles.

Method

Data was from the 10/66 cohort study. Individuals aged ≥65 years without dementia at baseline (N=11,143) were recruited from Cuba, the Dominican Republic, Peru, Venezuela, Mexico, Puerto Rico and China. Dementia incidence was assessed over a mean follow‐up of 3.8 years (SD=1.3 years). Variables were selected to be tested that have been associated with dementia previously. Two Cox risk models were produced for each site, with and without objective cognitive variables. Predictive accuracy (c‐statistic) and calibration were tested.

Result

1,069 individuals progressed to dementia during follow‐up. The models had mostly moderate to good predictive accuracy. The models in the total sample performed moderately (cognitive model c‐statistic = 0.74; 95%CI: 0.72‐0.75; non‐cognitive model c‐statistic = 0.71; 95%CI: 0.70‐0.73). In each country, the cognitive models’ c‐statistics ranged from 0.70 (95%CI: 0.67‐0.74) in China to 0.84 (95%CI: 0.80‐0.88) in Peru, and the non‐cognitive models’ c‐statistics ranged from 0.67 (95%CI: 0.63‐0.71) in the Dominican Republic to 0.80 (95%CI: 0.74‐0.85) in Peru. There were no major noticeable patterns of variables included in each country‐specific model. Model calibration was however poor.

Conclusion

Different prediction models were necessary for each country, most of which had moderate to good predictive accuracy. Further research is needed to improve calibration, and to determine whether risk prediction is cost‐effective, ethical and acceptable in LMICs. Dementia risk prediction is important so that individuals at high risk can be identified, and their risk factors addressed, to help decrease the burden of dementia.
Alzheimer’s disease‐associated (hydroxy)methylomic changes in the brain and blood
Authors: Riemens Renzo Jan Maria ,   EPI‐AD Consortium
Published: December 2020

Background

Considerable evidence suggests that epigenetic processes including DNA methylation and hydroxymethylation represent critical factors in the development and course of Alzheimer’s disease (AD).

Method

Within the EPI‐AD project (http://www.epi‐ad.eu/), we performed an epigenome‐wide association study (EWAS), assessing both DNA methylation and hydroxymethylation, using bulk tissues from the dorsal raphe nuclei (DRN), locus coeruleus (LC) and middle temporal gyrus (MTG) derived from AD patients and matched non‐demented controls. We followed up these analyses by exploring methylomic signatures in microdissected serotonergic DRN cells using limiting dilution bisulfite pyrosequencing. In an independent (longitudinal) cohort, we compared the blood methylome of converters to AD dementia and non‐converters at a preclinical stage.

Result

Within the DRN and LC, we revealed overlapping Braak stage‐associated epigenetic abnormalities in TNXB, ANKRD2 and MBP. Interestingly, when comparing methylation levels of TNXB in individually isolated serotonergic neurons with those of non‐serotonergic cells in the DRN, we found a significant interaction between cell‐type and condition. The AD‐associated methylation profiles were opposite in the serotonergic neurons and non‐serotonergic cells, the latter of which resembled the EWAS data. Within the MTG, we revealed epigenetic differences close to or overlapping with genes such as OXT, CHRNB1, RHBDF2 and C3 that were associated with Braak staging. By comparing the blood methylome of converters to AD dementia and non‐converters at a preclinical stage, we found that DNA methylation in the exact same region of the OXT promoter as seen in the MTG was associated with subsequent conversion to AD.

Conclusion

Overall, data on the MTG confirmed previous findings, identifying loci such as RHBDF2 and C3 that have been associated with AD in various EWAS studies on cortical brain regions. Notably, our brainstem work highlighted several novel epigenetic signatures that we hypothesize to play a pivotal role in early AD development. Furthermore, we show that dysregulation in TNXB methylation in the DRN is both dependent on the disease phenotype and the cell type analyzed, which warrants the need for cell‐type specific neuroepigenetic studies in AD. Finally, we demonstrate that the detection of OXT methylation at pre‐dementia stages holds potential relevance as a novel biomarker and therapeutic target.
Beyond aphasia: Natural history of the aphasia onset dementia syndromes
Authors: Erkoyun Hulya Ulugut , Stek Simone , Wagemans Lianne , Jutten Roos J. , Scheltens Philip , Pijnenburg Yolande A.L.
Published: December 2020

Background

Aphasic syndromes caused by neurodegenerative disease are known as Primary Progressive Aphasias (PPA). The most recent consensus criteria have classified PPA into the non‐fluent variant (nfPPA), semantic variant (svPPA) and the logopenic variant (lvPPA). Few longitudinal studies have explored the prognosis of patients with PPA. This study aims to give an overview of the clinical profile divided into different domains, the progression into other diagnoses and mortality of the different subtypes of PPA.

Method

Twenty‐two patients diagnosed with nfPPA, 24 with svPPA and 18 with lvPPA between 2011 and 2019 were retrospectively collected and followed‐up for a maximum of over 6 years. Biomarkers and neuroimaging were acquired at baseline. Reported additional symptoms, neurological signs and outcomes on different neuropsychological tests during follow‐up period were collected and compared for baseline and longitudinal results. Kaplan‐ Meier survival analysis was performed for mortality rate.

Result

As expected, a language disorder was the main problem of all PPA patients at the first assessment. However, over the disease course, the subtypes exhibited a different progression pattern. Behavioural problems were prominent in svPPA whereas patients with lvPPA exhibited a greater executive and visuospatial dysfunction and episodic memory impairment (p<0.05). Unlike svPPA and lvPPA, nfPPA subjects presented a relatively pure aphasia profile initially. However, 50% of the subjects developed extrapyramidal and pyramidal signs within 4 years and progressed into other diagnoses such as corticobasal degeneration, progressive supranuclear palsy, motor neuron disease, behavioural variant frontotemporal dementia and Alzheimer’s disease. Furthermore, in this group the mortality rate was significantly higher in comparison to the other subtypes (median years 3.04 [1.06 – 5.62], p=0.001). By contrast, none of the svPPA patients progressed into another diagnosis whereas 78% of the lvPPA patients progressed to Alzheimer’s disease within 3 years (Figure 1).

Conclusion

To our knowledge, this is the first study to determine the progression profiles and the entire course of the disease from the diagnosis to the death. Our results show that prognosis differs widely per PPA subgroup. Disclosing the risk of developing motor symptoms should be considered in the case of nfPPA.
Relationship between cerebral amyloid angiopathy and plasma homocysteine levels in Alzheimer’s disease
Authors: Kanemaru Kazutomi , Kanemaru Akiko , Murayama Shigeo
Published: December 2020

Background

Cerebral amyloid angiopathy (CAA) is the characteristic vascular pathology in Alzheimer’s disease (AD). The vascular changes including CAA contribute to mental decline in AD. Elevated plasma total homocysteine (tHcy) is reported to be an independent risk factor for Alzheimer’s disease (AD). Elevated tHcy is also reported to result in CAA in mice. Here we investigated the relationship between CAA and plasma tHcy levels in AD.

Method

The subjects of this study consisted of clinically diagnosed 136 patients with AD (83 females, 53 males, age 75.2±8.8 years). The cortical microbleeds shown by T2*‐weighted MRI images could be CAA‐related. We divided the AD patients into two groups; CAA(+) (AD with CAA, n=46) and CAA(‐) (AD without CAA, n=90). We compared the levels of plasma tHcy between the two groups: CAA(+) and CAA(‐). We also compared CSF biomarkers (tau, ptau‐181 and Abeta42) and MMSE scores between the two groups. The CSF samples were obtained by lumbar puncture after informed consent was obtained. The CSF levels of tau, ptau‐181 and Abeta42 were measured by ELISA (Fujirebio, Belgium) according to the manufacturer’s protocol.

Result

The tHcy levels were 14.3±10.5 nmol/ml in the CAA(+) group and 11.6±4.0 in the CAA(‐) group. The tHct levels showed no significant difference between the two groups. The CSF Abeta42 levels were significantly lower in the CAA(+) group (274.2±108.7 pg/ml) than those in the CAA(‐) group (316.8±112.1 pg/ml, p<0.05, t‐test), whereas the CSF tau and ptau levels showed no difference between the two groups. MMSE scores were lower in the CAA(+) group (16.5±7.0) than those in the CAA(‐) group (20.3±6.3) (p<0.005, t‐test). The tHcy levels were not related to any of CSF biomarkers (tau, ptau‐181 or Abeta42) .

Conclusion

Plasma tHct levels showed no significant difference between the two groups: CAA(+) and CAA(‐).CSF levels of Abeta42 and MMSE scores were lower in the CAA(+) group than those in the CAA(‐) group.