bluuebunny/crossref_metadata_2025 huggingface dataset:
Taxifolin is a novel therapeutic agent for Alzheimer’s disease and cerebral amyloid angiopathy
Authors: Saito Satoshi , Tanaka Masashi , Satoh‐Asahara Noriko , Carare Roxana O. , Weller Roy O. , Ihara Masafumi
Published: December 2020

Background

Impaired amyloid‐β clearance from brain along intramural periarterial drainage (IPAD) is key in the pathogenesis of Alzheimer’s disease (AD). Facilitating IPAD would delay or prevent cerebral amyloid angiopathy (CAA). Taxifolin, a flavonol with strong anti‐oxidative and anti‐glycation activities, has been reported to disassemble amyloid‐β. Here, we test the hypothesis that taxifolin has therapeutic potential in reducing AD and CAA.

Method

Tg‐SwDI mice, as a model of AD and CAA, were treated with either taxifolin or vehicle alone from the age of one month. Wild type and Tg‐SwDI mice aged eight to thirteen months were used for the investigation of the amyloid‐β metabolism in vivo, amyloid‐β pathology, cerebral blood flow, cerebrovascular reactivity and cognitive function. Cerebral blood flow and cerebrovascular reactivity were evaluated by using laser speckle flowmetry. Cognitive function was assessed by Morris water maze. Thioflavin‐T fluorescence assay and transmission electron microscope were to examine the effect of taxifolin on amyloid‐β disaggregation.

Result

There was reduced accumulation of amyloid‐β in the cerebrovasculature in the hippocampus in taxifolin‐treated Tg‐SwDI mice compared to the mice treated with vehicle alone (n = 5). Tg‐SwDI mice treated with taxifolin exhibited decreased expression of amyloid‐β precursor protein in the hippocampus, suppressed oligomerization of amyloid‐β in the brain and increased levels of amyloid‐β40 in the blood (n = 4‐6). Taxifolin completely restored the cerebral blood flow and cerebrovascular reactivity in Tg‐SwDI mice (n = 4‐6). Spatial reference memory returned to normal levels following treatment with taxifolin (n = 10‐17). Amyloid‐β aggregation was suppressed by taxifolin treatment in vitro.

Conclusion

Taxifolin prevents overproduction and oligomerization of amyloid‐β and facilitates its clearance into the blood. Taxifolin thus appears to be a promising therapeutic agent for AD and CAA.
A case study of frontal variant of Alzheimer disease
Authors: Jia Ziyan , Xu Jun , Shi Jiong , Chen Qidong , Zhang Qian
Published: December 2020

Background

With the further understanding of AD, we found that it has heterogeneous clinical presentations. It is typical of early and progressive impairment of episodic memory, but we also recognized a special type—fv‐AD,which shows obvious executive cognitive impairment. We report a male patient, aged 60 years, who was clinically diagnosed with fv‐AD. He had memory impairment in the early stage of the disease, but had executive dysfunction that did not match with memory impairment, resulting in the early loss of social function. He had a history of personality change, stubbornness, delusion and hallucination.

Method

Chose an fv‐AD patient and collect his clinical manifestation, neuroimaging data and cognitive assessment.

Result

In clinical manifestations, it coincides with behavioral‐variant frontotemporal dementia (bvFTD), and has difficulties in differential diagnosis. Positron emission tomography(PET) with fluorodeoxyglucose showed marked hypometabolism in frontotemporal and parietal regions. The PIB‐PET showed hypermetabolism in frontotemporal, parietal and occipital regions, which was consistent with in vivo amyloid deposition neuroimaging evidence of AD pathology.

Conclusion

This report mainly discusses the similarities and differences between fv‐AD and bvFTD, which is helpful for clinical differential diagnosis, enriching the clinical manifestations of this kind of patients and improving our understanding.
Associations between cognition and neuropsychiatric symptoms in people with dementia: Protocol for a systematic review and multilevel meta‐analysis
Authors: Sabates Julieta M. , Lampit Amit , Malmberg Gavelin Hanna , Loi Samantha M. , Brodtmann Amy , Chong Terence W.H. , Goh Anita M.Y. , Lautenschlager Nicola T. , Bahar‐Fuchs Alex
Published: December 2020

Background

Neuropsychiatric symptoms (NPS), including depression, anxiety, apathy, aggression and agitation, among others, are highly prevalent in people with dementia (PWD), and are associated with lower quality of life and greater caregiver distress1.

Over recent years there has been a proliferation of research aimed at exploring the cause of NPS and the relationships between them and impairment in specific cognitive abilities. Despite this interest, previous work has been limited mostly to cross‐sectional and longitudinal studies and, until now, systematic reviews on this topic have tended to focus on one symptom or type of dementia. The specific associations between cognitive impairment and NPS in PWD regardless of aetiology are, therefore, still poorly understood. Furthermore, no previous study has investigated whether these associations vary between younger and late‐onset dementia. The aim of our research is to investigate the specific links between cognition and NPS in PWD, and explore the moderators of these relationships, including dementia aetiology and age of onset. This review forms a first step in the design of a novel mHealth intervention for NPS in PWD which will be informed by its findings.

Method

We will search relevant databases for observational and interventional studies investigating these associations. We will convert outcome data from studies to standardised mean difference (SMD, calculated as Hedges’ g)2 with 95% confidence interval of difference in cognitive performance between the exposure groups, correlation coefficient or odds ratios. We will synthesise the data by conducting multilevel random effects analyses.

Results

The findings from this review will make an important contribution to research by improving the knowledge about the correlates of NPS.

Conclusion

Results are likely to have important implications for the management and treatment of NPS. Appelhof, B., Bakker, C., Zwijsen, SA., Smalbrugge, M., Verhey, F. R., de Vugt, M. E., … & Koopmans, R. T. (2017). The determinants of quality of life of nursing home residents with young‐onset dementia and the differences between dementia subtypes. Dementia and geriatric cognitive disorders, 43(5‐6), 320‐329. Rosenthal, Robert, H. Cooper, and L. Hedges. “Parametric measures of effect size.” The handbook of research synthesis 621 (1994): 231‐244.
Amyloidogenic nanoplaque levels are increased in the cerebrospinal fluid in Alzheimer’s disease
Authors: Aksnes Mari , Tiiman Ann , Edwin Trine Holt , Terenius Lars , Bogdanovic Nenad , Vukojevic Vladana , Knapskog Anne‐Brita
Published: December 2020

Background

The aggregation of amyloid β (Aβ) is a central step in Alzheimer’s disease (AD) pathogenesis according to the amyloid cascade hypothesis. Measures of misfolded or aggregated Aβ are attractive biomarkers for AD, as they could potential reflect an important disease step. Newly, a Thioflavin‐T Fluorescence Correlation Spectroscopy (ThT‐FCS) assay has been developed that allows the quantification of amyloidogenic aggregates, hereby nanoplaques, with single‐molecule sensitivity. Thus far, no study has evaluated the association between cerebrospinal fluid (CSF) nanoplaque levels and core CSF biomarkers of AD.

Method

CSF was collected from 118 individuals assessed for cognitive complaints at the Oslo University Hospital Memory Clinic. Levels of CSF core biomarkers: Aβ42, total tau (T‐tau) and phosphorylated tau (P‐tau) were evaluated with ELISA assays (Innotest kits). The CSF nanoplaque concentration was quantified using the ThT‐FCS analysis. All patients received research diagnoses, and were AT(N)‐classified based on all available biomarkers (fluid‐ and imaging biomarkers).

Result

Sixty‐eight patients were clinically diagnosed with possible or probable AD, and 50 patients were diagnosed with other cognitive disorders. Sixty‐five patients were classified as A+ (on the Alzheimer’s continuum) and 53 patients were classified as A‐ (normal AD biomarkers or non‐AD pathologic changes). Nanoplaque levels were significantly increased in patients with clinically diagnosed possible or probable AD as compared to memory clinic patients with other cognitive disorders, P = .02. Nanoplaque concentration was also significantly increased in A+ patients as compared to A‐, P = .04. CSF nanoplaque levels were inversely correlated with CSF Aβ42 levels (r = − 0.2, P = .03), but did not correlate with CSF T‐ or P‐tau levels.

Conclusion

CSF concentrations of nanoplaques can be quantified with single‐molecule sensitivity using the ThT‐FCS assay. Increased nanoplaque levels are related to the Alzheimer’s continuum and clinical AD, and correlate inversely with levels of Aβ42 monomers/small oligomers determined by immunoassays. The association between this potential biomarker and disease stage should be further explored.
QEEG: The tentative biomarker for early screening of preclinical Alzheimer’s disease or progressiveness of subjective cognitive decline
Authors: Ho SeongHee , Yang Dong Won , Hong Yun Jeong , Jeong Jee Hyang , Park Kee Hyung , Kim SangYun , Wang Minjung , Choi Seong Hye , Han SeungHyun , Kang Seung Wan , Lee Hannah , Kim Seon Myeong
Published: December 2020

Background

Early screening biomarker has been required to discriminate higher risk of progressive subgroup in subjective cognitive decline(SCD) at preclinical stage. Study purpose was to identify quantitative EEG patterns among different condition of amnestic SCD

Method

From 6 dementia clinics in Korea, we enrolled participants aged over 60 years with complaining of persistent cognitive decline, performance range of 7% to 50% of the verbal memory tests and over 7% of the rest subtests of comprehensive neuropsychological battery. Both 18F‐Florbetaben brain amyloid‐beta PET and genetic test for APOE ε4 allele were conducted. EEG was measured at 19 channels of international 10‐20 system under resting state, and spectrum power and power ratio were calculated. Source cortical activity was mathematically estimated by standardized low resolution brain electromagnetic tomography(sLORETA)

Result

120 SCD subjects (male 53, female 67) were included. Amyloid PET(+) was 25 (20.8%) and APOE ε4 allele (+) was 26(21.6%) independently. Amyloid PET (+) SCD had higher frequency of APOE e4 (48%) compared to amyloid PET (‐) SCD (14%). We selected 67 amyloid PET (‐) SCD older than 65 years to escape age differences between 2 groups. Amyloid PET (+) SCD showed significant increase of relative theta power at left frontotemporal(Fp1, F7, T5), both occipital(O1,2) and right parietal(P4) channels. Similarly, significant enhancement of theta was observed at left superior and transverse temporal, fusiform and cuneus at sLORETA in amyloid PET (+) SCD. Among amyloid PET (+) SCD, APOE ε4 (+) subgroup showed significant increase of theta/beta ratio at both superior frontal and anterior cingulate, right parietal and occipital area

Conclusion

Amnestic SCD with amyloid (+) showed relative enhancement of slow wave in resting EEG, which have been similarly reported about amnestic MCI or AD dementia. QEEG could be tentative biomarker to screen AD or to predict progressiveness of SCD at preclinical stage. Longitudinal study and development of single quantitative index of QEEG to evaluate individual subject will be needed to confirm its clinical significance.
Effectiveness of lifestyle and psychosocial interventions in reducing cognitive decline in older people: Systematic review
Authors: Mansour Hassan , Whitty Emma , Aguirre Elisa , Palomo Marina , Charlesworth Georgina , Ramjee Serena , Poppe Michaela , Brodaty Henry , Kales Helen C , Morgan‐Trimmer Sarah , Nyman Samuel , Lang Iain A , Walters Kate , Petersen Irene , Wenborn Jennifer , Minihane Anne‐Maire , Ritchie Karen , Huntley Jonathan D , Walker Zuzana , Cooper Claudia
Published: December 2020

Background

Observational findings suggest that a third of dementia cases are attributable to modifiable risk factors (Livingston et al, 2017). However, we are still unclear on what non‐pharmacological interventions should look like or what a manualised dementia prevention programme might include.

Method

PubMed, EMBASE (Ovid), PsycINFO, CINAHL, Web of Science, and reference lists of included studies were systematically searched and screened by two independent reviewers. We included lifestyle and psychosocial interventions that aimed to reduce cognitive decline in healthy people aged 50+, and people of any age with Subjective Cognitive Decline or Mild Cognitive Impairment. We narratively synthesised evidence, prioritising results from studies rated at lower Risk of Bias (ROB) and used Centre for Evidence Based Medicine guidelines to grade levels of evidence. These findings were used to inform co‐production of an internationally collaborated APPLE‐Tree (Active Prevention in People at risk of dementia: Lifestyle, bEhaviour change and Technology to REducE cognitive and functional decline) programme.

Result

A total of 64 studies were included describing psychosocial (n=12), multi‐domain (n=10), exercise (n=36) and dietary (n=6) interventions. We found Grade A evidence that 4+ months of aerobic exercise twice weekly had a moderate effect on global cognition. With interventions that integrate, cognitive and motor challenges (e.ge. dance or dumb bell training) had small to moderate effects on memory or global cognition. We also found Grade B evidence that 4+ months of creative art or storytelling groups; 6 months of resistance training and a two‐year, dietary, exercise, cognitive training and social intervention had small but positive effect on global cognition. Conflicting evidence was observed for interventions solely focusing on increasing Mediterranean diet adherence. With effects for some interventions remaining up to a year beyond facilitated sessions. Only two lower ROB studies measured impact of non‐pharmacological interventions onto dementia incidence with neither finding significant effects.

Conclusion

Based on current published findings an evidence‐based intervention strategy to improve global cognition, memory and executive functioning should include group therapy carried out for 4+ months, promoting engagement in regular (at least weekly) activity, involving aerobic or resistance exercise, and cognitively demanding (visuospatial/memory) or creative tasks.
Long‐term treatment with cholinesterase inhibitors in Alzheimer's disease is associated with modest but persisting benefits on cognition and reduced mortality
Authors: Eriksdotter Maria , Xu Hong , Jönsson Linus , Wimo Anders , Nordström Peter , Garcia‐Ptacek Sara
Published: December 2020

Background

Cholinesterase inhibitors (ChEIs) are the mainstay treatment of Alzheimer’s dementia (AD) and are considered symptomatic. However, their long‐term effectiveness is not well studied. This study aims to investigate whether ChEIs are associated with less cognitive decline in AD, and decreased risk of severe dementia or death.

Method

AD patients from the Swedish Dementia Registry (SveDem) starting on ChEIs within three months of the dementia diagnosis were included and compared to non‐treated AD patients. In a propensity score matched cohort, the association between ChEI use and cognitive trajectories assessed by MMSE scores were examined with a mixed model, and severe dementia (MMSE<10) or death as outcomes with Cox proportional hazards models.

Result

The matched cohort included 11,652 ChEI‐users and 5,826 non‐users. ChEI use was associated with higher MMSE at each visit (0.13 MMSE points/year; 95% confidence interval‐CI 0.06, 0.20). Moreover, ChEI users had a 27% lower risk of death (0.73; CI 0.69, 0.77) compared with non‐users. Galantamine was associated with lower risk of death (0.71; CI 0.65, 0.76), lower risk of severe dementia (0.69; CI 0.47‐1.00), and had the strongest effect on cognitive decline of all the ChEIs (0.18 MMSE points/year, CI 0.07, 0.28).

Conclusion

ChEIs are associated with cognitive benefits which are modest but persist over time. An association with reduced mortality partly explained by their cognitive effects was found. A significant reduction in the risk of developing severe dementia was demonstrated by the ChEI galantamine.
Gray matter atrophy, but not vascular brain injury is related to cognitive impairment in patients with heart failure
Authors: Leeuwis Anna E. , Amier Raquel P. , Marcks Nick , Nijveldt Robin , Hooghiemstra Astrid M. , Rocca Hans‐Peter Brunner‐La , Roos Albert , de Bresser Jeroen , Bron Esther E. , Niessen Wiro J. , Buijs Mathijs , Barkhof Frederik , van Rossum Albert , van Der Flier Wiesje ,   Heart‐Brain Connection Consortium
Published: December 2020

Background

Cognitive impairment in heart failure (HF) interferes with the capacity to self‐care and is associated with adverse health outcomes. This underlines the importance of detecting the extent and nature of cognitive impairment in HF. We report on the presence and mutual association of neuroimaging markers and cognitive impairment in patients with HF.

Method

We included 147 patients with HF (69±10yrs; 32%F; MMSE 29±1) and 121 reference participants (66±8yrs; 46%F; MMSE 29±1) from the Dutch multicenter Heart‐Brain study. Brain MRI scans were rated for (lacunar) infarcts and microbleeds. Total grey and white matter volume, hippocampal volume and white matter hyperintensity (WMH) volume were calculated. We used a standardized neuropsychological test battery to measure cognition and calculated compound z‐scores for each cognitive domain. Associations between neuroimaging markers and cognitive functioning were investigated using linear regression analyses, with separate models for each cognitive domain. We adjusted for participant group, age, sex and education. To investigate whether associations differed according to participant group, interaction terms were included in our analyses.

Result

Patients with HF had lower total grey matter volume and more vascular brain injury compared to the reference group, including WMH (median (interquartile range) 1.7(40) versus 0.6(1.8), p<0.001), (sub‐)cortical infarcts (13% versus 3%, p<0.01) and lacunar infarcts (28% versus 10%, p<0.001). Cognitive impairment was found in 18% of HF, most often in the domains of memory and attention/psychomotor speed. Overall, we found associations between smaller total grey matter volume and worse global cognition, more cortical and lacunar infarcts (standardized beta [stβ]=‐0.14‐0.56, p<0.05). Stratification for participant group showed associations between worse global cognition and smaller total (stβ=0.43, p<0.01) and hippocampal (stβ=0.22, p<0.05) grey matter volumes in HF. We found no association between cognition and vascular brain injury.

Conclusion

Patients with HF exhibit cognitive deficits more pronounced in the domains of memory and attention/psychomotor speed. Grey matter atrophy, but not vascular brain injury seems to be related to cognitive impairment in HF.
Predicting factors of cognitive progression in preclinical AD: A five‐year follow‐up of the insight‐study
Authors: Bombois Stephanie , Villain Nicolas , Genthon Remy , Younsi Nadjia , Levy Marcel , Houot Marion , Colliot Olivier , Lamari Foudil , Epelbaum Stéphane , Habert Marie‐Odile , Dubois Bruno
Published: December 2020

Background

As not all the asymptomatic Alzheimer Disease (AD) subjects will progress to symptomatic stages, targeting those individuals at high risk of progression to prodromal AD is relevant, especially for disease‐modifier therapeutic trials. The aim of this study is to determine markers of progression to prodromal AD in cognitively normal individuals.

Method

INSIGHT‐preAD study is a cohort of 318 cognitively normal individuals, over 70 years, with subjective memory complaints, followed‐up for 5 years. Subjects were stratified by brain amyloid status (A(+) or A(‐)) according to the uptake of 18F‐Florbetapir. Demographic, cognitive, ApoE status and imaging (MRI and FDG‐PET) were performed at baseline. Clinical and cognitive assessments were repeated every 6 months, MRI, FDG‐PET and amyloid‐PET scans every 2 years. Definition of progressors: MMSE and FCSRT scores below the threshold for inclusion in the study was indicative of a possible progression to prodromal AD. An independent and blinded committee using adjudicated prodromal AD using the IWG‐2 criteria. Statistical analysis: Comparisons between A(+) progressors and A(+) non‐progressors were performed using Wilcoxon test for continuous variables and Fisher’s exact tests for qualitative variables.

Result

After 5 years, 13 subjects progress to a mild cognitive impairment: 12 prodromal AD (11 typical phenotype; 1 atypical phenotype with a logopenic presentation) and 1 with a Lewy body phenotype. All the progressors were A(+), with a rate of progression of 14% among A(+) individuals. When compared to A(+) non‐progressors, the progressors had lower performance in each FCRST sub‐scores, lower total hippocampal volume (Median [Q1, Q3]: 2.43 [2.24, 2.56] versus 2.65 [2.45, 2.87]) and higher AV45 SUVr (1.23 [0.99, 1.32] versus 0.95 [0.84, 1.10], for a threshold of 0.79).

Conclusion

As expected, the predicting factors from cognitively normal individuals to prodromal AD are the co‐occurrence of amyloid burden and tau pathology (represented by hippocampal volume loss and memory deficit). However, only 14% of A(+) subjects progress to prodromal AD after 5 years follow‐up. This result suggests protective and compensatory mechanisms that should be investigated to open up to innovative treatment.
Automatic detection of Alzheimer’s disease and mild cognitive impairment from spontaneous speech collected during tablet‐based interviews: A preliminary result
Authors: Shinkawa Kaoru , Kosugi Akihiro , Kobayashi Masatomo , Nishimura Masafumi , Nemoto Miyuki , Tsukada Eriko , Ota Miho , Nemoto Kiyotaka , Arai Tetsuaki , Yamada Yasunori
Published: December 2020

Background

As the world’s elderly population increases, health monitoring technologies that can automatically detect subtle changes resulting from Alzheimer’s disease (AD) have become increasingly important. In this respect, speech is one of the promising clues due to the expansion of voice‐based interaction systems such as smartphones and tablets. Indeed, previous studies have succeeded in quantifying language dysfunctions and identifying AD and mild cognitive impairment (MCI) from speech data collected during neuropsychological tests conducted by clinicians. Conducting such assessments in an automated fashion by using computer devices would extend opportunities for assessments and help with the early detection of AD. In particular, if we can detect language dysfunctions related to AD from various types of speech data (e.g., question answering and daily conversations), it would extend the scope of application and help improve the current worldwide low‐diagnosis coverage.

Method

In this study, we developed a tablet‐based application and collected spontaneous speech data during interview tasks from 106 Japanese seniors consisting of 48 healthy controls (HC), 33 MCI, and 25 AD.

Participants answered nine questions relating to their current condition, yesterday’s dinner, games played as a child, and future travel plans. For comparison, we also collected speech data during neuropsychological tests (e.g., verbal fluency and picture description tasks) using the tablet. We extracted vocal and prosodic features from both speech data and then built binary classification models for differentiating MCI or AD from HC using a support vector machine with a feature selection method. We evaluated the models by leave‐one‐subject‐out cross‐validation.

Result

We found that the models using speech data during neuropsychological tests achieved the accuracy of 86.3% for HC vs. AD and 80.2% for HC vs. MCI. The models using spontaneous speech data from interview tasks achieved comparable accuracies: 87.7% for HC vs. AD and 81.6% for HC vs. MCI.

Conclusion

We demonstrated the possibility of using tablet‐based automatic assessments for detecting patients with both MCI and AD. In addition, our results suggest that speech data from not only neuropsychological tasks but also when answering everyday questions might contain useful information to help early detection of AD.
Unfolded P53 as a novel lead biomarker for Alzheimer’s disease diagnosis
Authors: Abate Giulia , Fowler Christopher J , Martins Ralph N , Memo Maurizio , Uberti Daniela
Published: December 2020

Background

Blood‐based biomarkers represent a promising choice for early Alzheimer’s disease (AD) diagnosis and for evaluating the efficacy of novel disease‐modifying therapeutics.

The complexity of the disease, where multiple pathogenetic mechanisms are involved, would require a pragmatic approach that includes a biomarkers panel for an individually‐tailored AD diagnosis. Oxidative stress, reactive oxygen and nitrogen species have been well documented in AD, however the potential use in the clinic of the metalloprotein p53 as a lead biomarker for this devastating neurodegenerative disorder has not yet been thoroughly investigated. Thus, the aim of this study was to evaluate the role of a conformational variant of p53 as a lead biomarker (Up532D3A8+) in plasma samples from AD at the pre‐clinical and prodromal stages.

Method

Plasma samples from Australian Imaging, Biomarkers and Lifestyle cohort (AIBL) biobank were used to evaluate the concentration of Up532D3A8+ through immunoprecipitation with the 2D3A8 antibody followed by SRM‐MS. A total of 102 plasma samples was studied, which includes at baseline samples from (a) AD patients, (b) Mild Cognitive Impairments (MCI) patients and (c) cognitive normal (CN) individuals, in addition to samples at a later time‐point from (d) individuals that converted to AD in a period of 18‐72 months, (e) MCI patients that converted to AD in a period of 18‐36 months and (f) MCI patients at baseline that have not declined to AD for a period of 36 months. Through using a standard heavy isotype labelled peptide spiked into clinical sample before the assay such as plasma, the absolute abundance of Up532D3A8+ protein isoform or its partial degradation products was measured accurately with a high sensitivity.

Result

A specific peptide of Up532D3A8+ as signature of clinical AD progression was detected by 2D3A8 immunoprecipitation and quantified by SRM‐MS. This peptide showed a prognostic value with a sensitivity >90%, specificity >85%, PPV around 80%, NPV >95%.

Conclusion

The study presented here strongly supports Up532D3A8+ as a promising lead AD biomarker, in particular for disease prognosis in its asymptomatic stage. Consequently it may become an indispensable tool for patient stratification for clinical trials that aim for the prevention of dementia stage in AD progression.
A co‐creation approach to design the implementation of a multimodal intervention in patients with subjective cognitive decline (PENSA study)
Authors: Forcano Laura , Soldevila‐Domenech Natalia , Rodriguez‐Arjona Maria Dolores , Puig‐Pijoan Albert , Pizarro Nieves , Knezevic Iva , Fauria Karine , Minguillón Carolina , Molinuevo Jose Luis ,   PENSA Study Group
Published: December 2020

Background

In recent years, there has been a growing concern about the hierarchical relationship between researchers and patients. A change of paradigm has been promoted by recent initiatives supporting an active citizenship involvement in research. The combination of patients’ views together with the expertise of clinicians and researchers may lead to a change on how research actions are identified, designed, conducted and disseminated. Following this approach, we introduced a co‐creation action in the intervention design process of the project Prevention of cognitive decline in APOE‐ɛ4 carriers with SCD after epigallocatechin‐gallate and a multimodal intervention (PENSA study). We aimed to assess participants’ opinion about the multimodal intervention and its viability, and to identify aspects of improvement.

Methods

We performed a qualitative descriptive study in a focus group composed by 10 participants (5 women and 5 men) between 60 and 80 years. Two researchers and a qualitative methodology specialist planned the content of a 2‐hour group session, that was guided by the specialist and audio recorded. Subsequently, an analysis of the thematic content was performed to extract the participants’ global comprehension of the phenomenon.

Results

The qualitative analysis revealed that participants positively rated the intervention and found it as a useful tool to implement a healthy lifestyle. Facilitators and barriers for the implementation of the multimodal intervention were identified. The former related to the great support received by the health professionals and the opportunity of acquiring reliable knowledge about Alzheimer’s disease and its management. The later were mostly related with time availability and a general worry about the return and dissemination of the study results. Moreover, alternatives and changes were proposed to improve the intervention, such as the possibility of adapting the proposed activities to participants’ preferences. The research team has implemented a number of actions to adequate the multimodal intervention to the participants needs.

Conclusions

Our study shows that co‐creation actions considering patients experience represents a rich source of information for designing effective health interventions. The co‐creation process represents an exercise of public commitment in responsible research and innovation.
25‐Hydroxycholesterol amplifies microglial IL‐1beta production in an APOE isoform‐dependent manner
Authors: Wong Man Ying , Lewis Michael , Doherty Jim , Shi Yang , Gong Shiaoching , Qian Mingxing , Cashikar Anil G. , Sullivan Patrick M. , Petsko Gregory A. , Covey Douglas , Gan Li , Holtzman David M. , Paul Steven M. , Luo Wenjie
Published: December 2020

Background

Genome‐wide association studies of Alzheimer’s disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25‐hydroxycholesterol (25‐HC) is an important immunomodulator produced by peripheral macrophages with wide‐ranging effects on cell signaling and innate immunity. Genetic variants of the enzyme responsible for 25‐HC production, cholesterol 25‐hydroxylase (CH25H), have been found to be associated with AD.

Method

In the present study, we measured CH25H expression in human AD brain and AD transgenic mouse brains. We also investigated the activity of 25‐HC in LPS‐induced innate immune responses including cytokine production in primary mouse microglia and human iPSC‐derived microglia‐like cells.

Results

we found that CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue bearing amyloid‐bplaques or tau pathology. Treatment with the toll‐like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain and stimulates CH25H expression and 25‐HC secretion in mouse primary microglia. We found that LPS‐induced microglial production of the pro‐inflammatory cytokine IL‐1bis markedly potentiated by 25‐HC and attenuated by deletion of CH25H.The upregulation of LPS‐induced IL‐1bby 25‐HC was validated in human microglia‐like cells derived from iPSCs. Through a 42‐multiplex human cytokine assay, we further found that 25‐HC specifically induces IL‐1beta and IL‐1alpha, with little effects on other cytokines in human microglia‐like cells. Interestingly, microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25‐HC than apoE3‐expressing microglia following treatment with LPS. Remarkably, 25‐HC treatment results in a greater level of IL‐1bsecretion in LPS‐activated apoE4‐expressing microglia than in apoE2‐ or apoE3‐expressing microglia. Blocking potassium efflux or inhibiting caspase‐1 prevents 25‐HC‐potentiated IL‐1brelease in apoE4‐expressing microglia, indicating the involvement of caspase‐1/NLRP3 inflammasome activity.

Conclusion

25‐HC may function as a microglial secreted inflammatory mediator in brain, promoting IL‐1b‐mediated neuroinflammation in an apoE isoform‐dependent manner (E4>>E2/E3) and thus may be an important mediator of neuroinflammation in AD.
LDL cholesterol and uridine levels in blood are potential nutritional biomarkers of AD progression: The NUDAD project
Authors: de Leeuw Francisca A. , Tijms Betty M. , Doorduijn Astrid S , Hendriksen Heleen M.A. , van de Rest Ondine , de van der Schueren Marian , Visser Marjolein , van den Heuvel Ellen G.H.M. , van Wijk Nick , Bierau Jörgen , Scheltens Philip , Kester Maartje I. , van Der Flier Wiesje , Teunissen Charlotte E.
Published: December 2020

Background

Suboptimal nutritional status is considered a modifiable risk factor for Alzheimer’s disease (AD). Identification of nutritional biomarker levels that are related to clinical progression might provide targets for dietary intervention studies. Therefore, we examined associations between nutritional biomarkers and clinical progression in a prospective study with individuals with subjective cognitive decline (SCD), mild cognitive impairment (MCI) and AD‐type dementia.

Method

We included 551 participants: 219 patients with SCD (age 61±8y, F47%), 135 patients with MCI (age 66±8 y, F40%) and 197 patients with AD (age 67±8y, F50%). Mean follow‐up was 2±1 years. Main outcome was time to clinical event operationalized as presence of at least one of the following: 1) in SCD, progression to MCI or dementia; in MCI, progression to dementia; in AD an increase of ≥1 point on clinical dementia rating scale; or 2) admission to a nursing home or deceased; or 3) self‐reported progression of cognitive symptoms. Baseline levels of cholesterol, triglycerides, glucose, homocysteine, folate, vitamin A, B12, E, and uridine were measured in blood and those of S‐adenosylmethionine and S‐adenosylhomocysteine in cerebrospinal fluid. Cox proportional hazard models adjusted for sex, age, diagnosis, BMI and lipid lowering medication were used to assess associations of baseline nutritional biomarker levels with time to clinical progression, in the total cohort and stratified for baseline diagnosis (SCD/MCI/AD). We repeated analyses in the total cohort restricted to amyloid positive patients.

Result

Clinical progression was observed in 25 (11%) patients with SCD, 45 (33%) with MCI and 100 (51%) with AD. None of the nutritional biomarkers was associated with clinical progression in the total cohort. Higher levels of LDL cholesterol in SCD (HR (95%CI) 1.92 (1.05‐3.52)), and lower uridine levels in AD were associated with clinical progression (HR (95%CI) 0.78 (0.62‐0.99)) (Table 1). In amyloid positive patients, lower uridine levels were associated with clinical progression.

Conclusion

In this large prospective memory‐clinic study, we found that higher LDL cholesterol and lower uridine levels were associated with clinical progression in SCD and AD dementia respectively. Our findings suggest that nutritional interventions should take into account clinical stage, and target uridine and cholesterol levels.
Enlightening behavioral disturbances in myotonic dystrophy type 1 through neuropsychology and imaging correlations: Insights from the frontal and temporal lobe functions
Authors: Morin Alexandre , Funkiewiez Aurélie , Routier Alexandre , Colliot Olivier , Eymard Bruno , Dubois Bruno , Stojkovic Tanja , Azuar Carole
Published: December 2020

Background

Myotonic Dystrophy Type 1 (MD1) is a neuromuscular disease in which subtle behavioral disturbance is often described. Few studies evaluated frontal lobe function and behavioral scales in relation with brain pathology.

Method

27 MD1 adult patients (mean age 46), were included. All patients performed an exhaustive neuropsychological assessment with a specific focus on cognitive and behavioral frontal functions. 18 MD1 patients and 18 healthy controls had a brain MRI with T1 and T2 Flair sequences. We performed a voxel‐based analysis with SPM12 via Clinica Software. The normalized data were smoothed with an isotropic Gaussian kernel of 8 mm. Statistical analysis was performed using general linear model with age sex and total intra cranial volume as covariates. Statistics were corrected for multiple comparisons with family‐wise error (FWE) correction at the cluster level with a height threshold of 0.001. T2 white matter lesions were segmented with VolBrain software.

Result

More than 60 % of the patients showed significant impairment in executive frontal functions (inhibition, mental flexibility, contextualization and theory of mind) with relative sparing of motivation, emotion recognition and initiation/planification.

MD1 patients MRI compared to healthy controls showed grey matter atrophy in medial temporal lobe, (parahippocampus mostly) and in a smaller extent in the middle frontal gyrus and the right caudate nucleus and excessive white matter hyperintensities, mostly in temporal lobes.

Frontal cognitive and behavioral impairment on neuropsychological testing was correlated with medial temporal and in a smaller extent frontal localization.

Conclusion

Behavioral disturbance in MD1 might be related to cognitive impairment in mental flexibility and contextualization rather than a specific social cognition deficit. This impairment might be related to white matter lesions or grey matter disease (including frontal‐subcortical network or parahippocampus, known to apprehend contextualization in emotion detection). Altogether, these findings confirm the hypothesis of a specific central nervous system involvement in MD1 patients.
Cardiovascular health metrics from mid‐ to late‐life and risk of dementia: A population‐based study
Authors: Liang Yajun , Ngandu Tiia , Laatikainen Tiina , Soininen Hilkka , Tuomilehto Jaakko , Kivipelto Miia , Qiu Chengxuan
Published: December 2020

Background

Cardiometabolic risk factors in middle age have been associated with late‐life risk of dementia. The associations of cardiovascular health (CVH) metrics in midlife and old age with late‐life risk of dementia need to be clarified in cohort studies. We sought to examine the associations of CVH metrics from mid‐ to late‐life with risk of incident dementia in late‐life.

Method

This population‐based cohort study used data from the Finnish Cardiovascular Risk Factors, Aging and Dementia study. A total of 1449 participants were followed from midlife (1972 to 1987, mean baseline age 50.4 years) to late‐life (1998 to 2005‐2009, mean baseline age 70.2 years, N=744). We defined six CVH metrics (smoking, blood pressure, physical activity, body mass index, fasting plasma glucose, and serum total cholesterol) following the modified American Heart Association’s recommendations. Dementia diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria. Data were analysed with Cox regression models.

Result

During the follow‐up examinations, dementia was diagnosed in 61 persons in 1998 and additional 47 persons during 2005 to 2008. The incidence of dementia (per 1000 person‐years) was 7.27, 3.76, and 2.00 for those with poor (score ≤5), intermediate (6‐7), and ideal (≥8) levels of CVH metrics in midlife, respectively. Compared with people with poor CVH metrics, those with ideal CVH metrics in midlife had a 48% lower risk of dementia in late‐life (fully‐adjusted hazard ratios, 0.52; 95% CI, 0.20‐0.92). The incidence rate of dementia (per 1000 person‐years) was 9.5, 5.5, and 8.7 for those with poor, intermediate, and ideal levels of CVH metrics in late‐life, respectively. No significant association was found between late‐life CVH metrics and risk of dementia. Compared with poor CVH metrics in both midlife and late‐life, the fully‐adjusted hazard ratio of dementia was 0.24 (95% CI, 0.06‐0.94) for having intermediate or ideal CVH metrics in either midlife or late‐life and 0.29 (0.10‐0.86) for intermediate or ideal CVH metrics in both midlife and late‐life.

Conclusion

Having an intermediate or ideal level of CVH metrics in either midlife or late‐life is associated with a decreased risk of dementia.
Cognitive frailty: A pre‐dementia syndrome or a branch of healthy ageing?
Authors: Kocagoncu Ece , Nesbitt David , Hughes Laura , Henson Richard N , Can Cam , Rowe James B
Published: December 2020

Background

There is a pressing need for new therapeutic strategies to arrest Alzheimer’s disease (AD) at its prodromal stage. MTL pathology at this stage causes widespread synaptic dysfunction, before any cognitive decline and atrophy. We propose that neurophysiological biomarkers sensitive to this early synaptic dysfunction could be recorded using electro‐magnetoencephalography (E/MEG). Cam‐CAN Frail study, investigates neurophysiological changes that occur in cognitively frail individuals, who show cognitive decline in the absence of a clinical diagnosis.

Method

We collected E/MEG data from healthy controls, cognitively frail, MCI and early AD patients (N=90). Frail and MCI groups performed similarly on MMSE or ACER. Frail group had lower education levels than the other groups. Participants were presented fractals followed by sounds. The stimuli consisted of standard and deviant pairs. Deviants were pairs with shuffled sounds (associative deviants) or novel sounds (novelty deviants). We extracted the signal from inferior frontal (IFG), superior temporal (STG) and Heschl’s gyri (HG). We tested the relationship between the mismatch response, hippocampal grey matter volumes (GMV), neuropsychological scores and education.

Result

Novelty response was found in control and frail groups, with larger clusters in bilateral IFG. MCI and AD groups showed weaker novelty effects only in the RHG and RSTG respectively. The associative deviant response was observed only in the bilateral IFG across the groups. Novelty deviant response in LHG negatively correlated with MMSE and ACER. Education level was not significant correlated with mismatch responses. Hippocampal and entorhinal GMVs of the controls and the cognitively frail were significantly higher than the MCI/AD groups. The difference in GMVs between controls and the frail was not significant. Hippocampal, entorhinal GMV and education levels positively correlated with MMSE and ACER scores.

Conclusion

Cognitively frail do not show the neurophysiological or structural profile, characteristic of AD. Cognitive frailty might be reflecting an extreme of the normal spectrum of cognition, but not AD. The underperformance could instead be explained by lower education levels. Secondly, we showed that E/MEG identifies the loss of response to novelty deviance in MCI and AD; and E/MEG tasks that are automatic, easy and require minimal training can be used to develop biomarkers in AD.
Slowed processing speed contributes to cognitive deficits in amnestic and non‐amnestic mild cognitive impairment
Authors: Daugherty Ana M. , Shair Sarah , Kavcic Voyko , Giordani Bruno
Published: December 2020

Background

Mild cognitive impairment (MCI) is characterized by deficits across functional domains, with pronounced memory impairment among amnestic (aMCI) patients. The mixture of cognitive complaints is a challenge in diagnosis and is further complicated by interactions between cognitive domains that are typical for neuropsychological performance.

Method

We aim to examine if slow processing speed may convey MCI‐related deficits across cognitive domains in a sample of African American adults (ages 56‐90): 61 cognitively typical, 28 aMCI, and 14 non‐amnestic MCI. Working memory, executive function, declarative memory and processing speed indices were estimated in structural equation modeling, including indirect effects with bootstrapped 95% confidence intervals (CI).

Result

MCI diagnosis predicted deficits in processing speed (b=‐0.53, p=0.02), executive function (b=‐0.37, p=0.03), working memory (b=‐0.62, p=0.001), and episodic memory (b=‐0.61, p<0.001). Slow processing speed predicted low function across domains and in turn partially accounted for effects of diagnosis on executive function (‐0.21, CI:‐0.37/‐0.10), working memory (‐0.12, CI: ‐0.24/‐0.05) and a non‐significant trend for declarative memory (‐0.05, CI: ‐0.15/0.01). Slow processing speed explained approximately 36% of MCI‐related deficits in executive function, 16% in working memory and 8% in declarative memory. In comparison between typical aging and specifically aMCI, processing speed explained deficits in executive function (‐0.19, CI: ‐0.39/‐0.06; 37% indirect) and working memory (‐0.09, CI: ‐0.22/‐0.01; 13%), and a non‐significant trend in declarative memory (‐0.06, CI: ‐0.19/0.00; 8%).

Conclusion

Slowed processing speed contributes to typical cognitive aging and conveys MCI‐related deficits across domains. Identification of deficits in processing speed may provide insight into MCI progression and opportunities for clinical intervention.
Neuropsychiatric symptoms and cognitive trajectories in older adults free of dementia: The Mayo Clinic Study of Aging
Authors: Krell‐Roesch Janina , Vassilaki Maria , Syrjanen Jeremy , Machulda Mary M. , Christianson Teresa J. , Kremers Walter K. , Mielke Michelle M. , Knopman David S. , Petersen Ronald C. , Geda Yonas E.
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) are associated with the risk of incident mild cognitive impairment (MCI) and dementia. However, the association between NPS and global and domain‐specific cognitive trajectories among older adults free of dementia remains unclear.

Method

We conducted a longitudinal study derived from the population‐based Mayo Clinic Study of Aging, including individuals aged ≥ 50 years who were free of dementia. Participants completed the Neuropsychiatric Inventory Questionnaire at baseline and underwent neuropsychological testing assessing four cognitive domains (i.e., memory, language, attention, visuospatial skills) every 15 months. We calculated linear mixed‐effect models with random subject‐specific intercepts and slopes to examine the association between presence of twelve different NPS (i.e., delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, motor behavior, nighttime behavior, appetite) at baseline and trajectories for individual yearly change in global and domain‐specific cognitive z‐scores. The models were adjusted for age, sex, education, and whether or not this was the first time the cognitive battery had been administered.

Result

The sample included 5081 persons (51% males; 4439 cognitively unimpaired, 642 with MCI). The median [IQR] age was 74 [67, 81] years, and the median [IQR] education was 14 [12, 16] years. Regardless of NPS status, participants declined in cognition over time, on average. However, presence of NPS was significantly associated with an increased decline in cognition, i.e., the annualized change in global cognition z‐scores for participants with compared to without the given NPS ranged from ‐0.018 (p = 0.011) for irritability to ‐0.16 (p = 0.001) for hallucinations. These associations between NPS and annual decline in global cognition were significant for all NPS except euphoria and disinhibition. Similar results were seen for the individual cognitive domains, e.g., participants with depression, apathy and nighttime behavior had a greater longitudinal decline in all domain specific z‐scores, whereas presence of delusions and anxiety was associated with a more pronounced decline in language, attention and visuospatial skills.

Conclusion

Neuropsychiatric symptoms are associated with greater longitudinal decline of both global and domain‐specific cognitive functions in community‐dwelling older adults free of dementia. More research is needed to confirm these preliminary findings.