bluuebunny/crossref_metadata_2025 huggingface dataset:
Corticobasal syndrome in a 23‐year‐old female
Authors: Castro‐Suarez Sheila , Lopez Lucia , Lanata Serggio
Published: December 2020

Background

The Corticobasal Syndrome (CBS) is characterized by unilateral parkinsonism and higher cortical dysfunction including apraxia, cortical sensory loss, agnosia, and alien limb phenomena. The underlying neurodegenerative causes of CBS include tauopathies (Corticobasal degeneration [CBD], progressive supranuclear palsy), Alzheimer disease, Lewy body disease, and prion disease, with CBD being most common (CBS‐CBD). Disease onset is typically in the fifth to sixth decade of life. Here we present a case of a woman with sporadic CBS due to underlying tauopathy with first signs and symptoms of disease noted at the age 23 years

Method

The patient is a participant of the University of California, San Francisco (UCSF) Memory and Aging Center (MAC) observational, longitudinal research program. The patient underwent structured neurological history and examination, neuropsychological testing, brain MRI, and neurodegenerative disease biomarker studies

Result

The patient is 28‐year‐old, right‐handed, bilingual (Spanish and English) woman with 12 years education. She presented with a 5 year history of slowly progressive left upper and lower extremity sensorimotor deficits, involuntary movements of the left upper extremity, and imbalance. There was no family history of progressive neurological or psychiatric illness. Her neurological examination was notable for left upper and lower extremity rigidity, myoclonic jerks, and dystonic posturing of the left hand. She demonstrated ideomotor apraxia, agraphesthesia, astereognosis, and finger agnosia of the left hand. Neuropsychological examination revealed mild deficits in frontal‐executive functions. Serological and cerebrospinal fluid analyses were unrevealing. Brain MRI with and without gadolinium enhancement showed severe right‐sided peri‐rolandic atrophy. Tau PET imaging showed asymmetric moderate tracer uptake over the dorsal fronto‐parietal cortices. Genetic testing was negative for MAPT, C9orf72, GRN, TARDBP, FUS, PSEN1, PSEN2, and APP mutations/expansions.

Conclusion

CBS is rare before the age of 50 years. We present a case of a 28‐year‐old woman who meets research criteria for CBS, with brain MRI and tau PET imaging findings suggestive of underlying tauopathy, most likely CBD (CBS – CBD). To our knowledge, this is the youngest case of CBS – CBD ever reported.
The effects of Orengedokuto for decreasing behavioral deviation and the rejection of care by patients with dementia
Authors: Urabe Shinji , Tsuchida Hideto , Tamura Junichi , Nabika Toumei , Shirakikawa Shinsuke , Yoshikawa Yoshimi , Moritoki Yukihiro , Matsuo Koji , Tsunemi Teppei , Wada Takatosi , Shiomoto Takayuki , Urabe Mie
Published: December 2020

Background

Behavioral and psychological symptoms of dementia (BPSD) increase the distress of patients with dementia and the burden for care givers and they are the symptoms that need to be solved immediately. In particular, behavioral deviation and rejection cause a high possibility of harming others, they are important problems to be solved to increase the quality of life for patients and caregivers. But effective treatment for BPSD has not been established yet. Antipsychotics are not recommended for the treatment of agitation and aggression in BPSD, because they increase the risk of death of the elderly according to the Food and Drug Administration.(FDA, 2005) So, as a medicine with fewer side effects and gives the expected effect, herbal medicine is used often for BPSD in Japan. Based on the clinical effects on these symptoms in our clinical practices, we focused on Orengedokuto within Japanese herbal medicine. In previous research of Orengedokuto, we reported that Orengedokuto decreased the aggression in the patients with dementia. (Urabe et al.,AAIC2019) The purpose of this research is to clarify the effect of Orengedokuto on deviation and rejection behavior of patients with dementia.

Method

The subjects were 33 patients with dementia admitted to a psychiatric hospital in Japan. The groups were a group of patients with dementia who were administered with Orengedokuto (ODG;23 patients, average age ; 84 years old) and a control group of patients with dementia who did not take Orengedokuto (NODG; 10 patients, average age ; 82 years old). We evaluated the patients with Behavioral Pathology in Alzheimer’s disease (Behave‐AD), Mini Mental State Examination, the reduction of effects of deviation and rejection were compared with the changes before and after administration between ODG and NODG.

Result

The average score of deviation, was 5.9 before administration but decreased to 1.2 at the time of discharge in ODG (p<0.05). In NODG, the average score of deviation, was 5.8 before administration, was 3.6 t at the time of discharge.

Conclusion

In ODG, deviation and rejection behavior was improved and the burden for caregivers was reduced.
A cost‐efficient model for predicting cerebral Aβ burden using MRI and neuropsychological markers in the ADNI‐2 cohort
Authors: Ko Hyunwoong , Ihm Jungjoon
Published: December 2020

Background

Detecting cerebral Aβ is still expensive, invasive, and have limited accessibility. In this respect, the current study aims to identify and compare predictability of MRI markers with neuropsychological markers for accurate prediction of cerebral Aβ status in AD cohort through machine learning (ML) approaches.

Methods

Predictability of the candidate markers for cerebral Aβ status was examined by analyzing 724 participants from the ADNI‐2 cohort at baseline visit (170 control subjects, 95 with SMC, 324 with MCI and 135 with AD; mean age 73.2 years, range 55–90). Demographic variables (age, gender, education, and APOE status), structural MRI markers (cortical thickness and volume), and neuropsychological test scores were used as input in several ML algorithms. Cerebral Aβ burden was measured using florbetapir PET images. We first calculated the predictability of each ML model, and the adaptive LASSO algorithm with 10‐fold cross validation was implemented to identify the relative predictability of predictors in the selected model.

Results

ML models with MRI markers predicted cerebral Aβ status with the 85% predictability. Out of five combination of candidate markers, neuropsychological markers with demographics showed the most cost‐efficient result compared to MRI methods. The adaptive LASSO model with out‐of‐sample classification was able to distinguish abnormal levels of Aβ based on significantly predictable features. The AUC was 0.85 in the ADNI‐2 cohort, indicating the same performance with MRI‐based models.

Conclusions

Our results are twofold: the result has first identified the predictability in MRI markers using ML approaches, and secondly demonstrated the neuropsychological model with demographics could predict Aβ positivity, suggesting a more cost‐efficient method for detecting cerebral Aβ status compared to MRI markers. More specifically, with advantages in cost and its non‐invasive procedure, the method could be utilized as a brief screening tool in AD risk population for clinical trials or AD therapy. To this end, This research was supported by the MSIT (Ministry of Science and ICT), Korea, under the ITRC(Information Technology Research Center) support program(IITP‐2020‐2017‐0‐01630) supervised by the IITP(Institute for Information & communications Technology Promotion).
Role of vitamin D mediated signaling in iron‐induced neurodegeneration: Implications in the pathogenesis of Alzheimer's disease
Authors: Banerjee Anindita , Ganguly Upasana , Chakrabarti Sasanka
Published: December 2020

Background

The neurodegeneration of sporadic Alzheimer's disease (AD) has several environmental, metabolic and endocrine components. Results of post‐mortem analysis of increased iron accumulation in AD brain and various epidemiological studies indicating association of AD with vitamin D insufficiency, prompted us to examine the role of vitamin D signaling in an experimental model of neurodegeneration induced by iron on undifferentiated SHSY5Y cells.

Method

SHSY5Y cells were exposed to ferric ammonium citrate (FAC, 25‐ 400 μM) with or without 1,25 dihydroxyvitamin D for 24 ‐ 48 h followed by the measurements of oxidative damage markers, mitochondrial functional status, APP, BACE expressions and cell death parameters. Separately similar parameters were assessed in SHHSY5Y cells where vitamin D receptor VDR expression was knocked down by specific siRNA.

Result

We observed that vitamin D ameliorated various features of FAC induced cytotoxicity such as oxidative damage, mitochondrial membrane depolarization, impaired ATP synthesis and loss of cell viability. Exposure of SHSY5Y cells to FAC resulted in elevated APP and BACE mRNA levels which could be prevented by 1,25 dihydroxyvitamin D. Iron caused differential effects on VDR mRNA and protein expression levels in SHSY5Y cells; an increase in mRNA but a decrease in protein expressions. The iron effects were significantly prevented by co‐treatment with 1,25 dihydroxyvitamin D. The effects of VDR knock‐down on both control and FAC‐ treated cells showed augmented cell death with significant mitochondrial dysfunction, lipid peroxidation and oxidative damage.

Conclusion

Our experimental data suggest that vitamin D and VDR mediated signaling is integral in cell survival under basal condition as well as during iron‐induced cytotoxicity. The results have implications in the context of NBIA in aging and the pathogenesis of AD.
Sitting time, physical activity, and cognitive impairment in mid‐life adults: Findings from the Cooper Center Longitudinal Study
Authors: Gafni Tal , Weinstein Galit , Shuval Kerem , Carolyn Barlow E , Gabriel Kelley Pettee , Willis Benjamin L , David Leonard , Haskell William L , DeFina Laura F
Published: December 2020

Background

Evidence suggests that prolonged sedentary time (i.e., daily sitting or reclining during waking hours) is independently related to metabolic syndrome and type 2 diabetes, which are risk factors for cognitive impairment. In the current study, we examined the independent and joint association of sedentary time and physical activity (PA) on the odds for cognitive impairment among community dwelling mid‐to‐later life adults.

Method

This cross‐sectional study included 3,780 individuals aged ≥55y, who came to the Cooper Clinic (Dallas, Texas) for preventive medicine visits (2010‐2019), and enrolled in the Cooper Center Longitudinal Study. Participants provided detailed information on their sitting habits and PA levels. Cognitive function was assessed through the Montreal Cognitive Assessment (MoCA). The independent and joint relations of reported sitting time (≤25%, 50% and ≥75% of the time) and PA levels (not meeting, meeting and exceeding guidelines) with cognitive impairment (MoCA score<26) was examined using multivariable logistic regression, while adjusting for potential confounders.

Result

Of the total analytic sample (mean age 61±6y; 71% men), 22.5% were classified as cognitively impaired. Participants sitting ≥75% of the time had significantly higher odds (OR=1.60; 95% CI 1.19‐2.17) for cognitive impairment compared to those sitting almost none of the time, irrespective of PA levels. Joint association analysis with sedentary time ≤25% and exceeding physical activity guidelines (>1000 MET min/week) as referent, showed that the highest odds for cognitive impairment were in those sitting ≥75% of the time while meeting or not meeting PA guidelines (OR=1.71 [1.14‐2.56] and 1.70 [1.22‐2.37], respectively). However, those who reported sitting 75% of the time or more had lower odds of cognitive impairment when in the exceeding physical activity strata (OR=1.48; 95%CI 1.10‐2.00; see figure).

Conclusion

Prolonged sitting time and insufficient physical activity might each independently increase the likelihood of cognitive impairment. Yet, engaging in extensive PA might attenuate the risk associated with prolonged sitting.
Chitotriosidase attenuates microglia‐associated inflammation via HDAC3/NF‐κB pathway in D‐galactose and aluminum‐induced rat model with cognitive impairments
Authors: Yu Xingyan , Yu Weihua , Wu Lihua , Yang Wenkai , Lü Yang
Published: December 2020

Background

Chitotriosidase (CHIT1, chitinase 1) is elevated in the cerebrospinal fluid and peripheral blood of Alzheimer’s disease (AD) patients. Our previous study has shown that CHIT1 provides potential protection through microglial polarization and reduction of β‐amyloid (Aβ) oligomers on rats models of AD. Histone deacetylase 3 (HDAC3) plays an important regulatory role in the expression and regulation of proteins associated with AD pathophysiology. In addition, nuclear factor‐kappa B (NF‐κB) signaling pathway activation in neurons is involved in the development and progression of AD. NF‐κB activation is regulated by HDAC3 deacetylation. In this study, we investigated the role of CHIT1 in HDAC3/NF‐κB signaling in D‐galactose and aluminum‐induced rat model with cognitive impairments.

Method

Rats in each group were euthanized and transcardial perfusion was performed with 0.9% saline. Brain tissues (cortex and hippocampus) from these rats were quickly removed. The prepared samples were used for western blotting (WB), and real‐time polymerase chain reaction (RT‐PCR). For paraffin sections, rats were anesthetized and perfused with 4% paraformaldehyde following normal saline infusion. Once the limbs became stiff, the brains were removed for dehydration, embedding and sectioning.

Result

We found that the protein and mRNA levels of HDAC3 and NF‐κB were reduced after CHIT1 treatment, and the expression level of IκBα increased after CHIT1 treatment. Anti‐inflammatory factors (Arg‐1, IL‐10, and CD206) were increased while pro‐inflammatory factors (TNF‐a, IL‐1β, and iNOS) were decreased in D‐galactose/aluminum‐induced AD rats with CHIT1 treatment.

Conclusion

These results indicate that CHIT1 can regulate microglial polarization via HDAC3/NF‐κB p65 pathway in D‐galactose and aluminum‐induced rat model with cognitive impairments.
Toronto dementia research alliance (TDRA) dementia clinical‐research platform: An example of research embedded into clinical care
Authors: Tang‐Wai David F. , Strother Stephen C. , Pugh Bradley , Spring Robyn , Vica Carmina , Nourhaghighi Nima , Gee Tom , Pisterzi Luca , Greenberg Barry , Coahran Margaret , Apatsidou Areti , Ding Jane , Kumar Sanjeev , Black Sandra E. , Freedman Morris
Published: December 2020

Background

Dementia is arguably the greatest looming global public health challenge facing today’s society and represents an international crisis as the number of affected persons will triple by 2050. Contributing to morbidity of dementia is the presence of combined pathologies, such as Alzheimer’s disease (AD), cerebrovascular disease (CVD) and Parkinson’s disease (PD). To address this challenge, the TDRA ‐ a collaboration of the University of Toronto’s Faculty of Medicine with four University‐affiliated tertiary memory clinics ‐ created an electronic platform for research studies embedded in clinical care through development of a unified approach for diagnosis and charting of the natural history of pure and mixed dementias, along with the impact of co‐occurring disorders.

Method

A detailed clinical intake form and cognitive testing (for mild‐to‐severe impairment) were created through a collaboration among behavioural neurologists, geriatricians and geriatric psychiatrists. These measures are captured electronically at point‐of‐care and, simultaneously, the deidentified information uploaded to a central research server (see Figure 1).

Result

After approximately 1 year since collecting information, 1182 new patients (622 women; 560 men) have been evaluated – 119 AD; 76 concussion; 20 CBS; 8 delirium; 2 MBI, 278 MCI, 42 mixed AD and CVD; 16 PSP; 1 MSA‐P, 16 PD, 17 PD‐MCI, 21 PDD; 32 DLB; 24 bvFTD; 7 lvPPA, 13 nfPPA; 12 svPPA, 136 with primary and/or co‐morbid psychiatric disease; 165 subjective cognitive impairment; 93 VCI; 18 normal cognition; and 18 dementia NYD. Each of these patients have some demographic and clinical details, such as comorbid psychiatric and/or medical disorders, and cognitive testing obtained for research.

Conclusion

The TDRA Dementia Clinical‐Research Platform is a practising example of research embedded into clinical care with over 1000 new patients with diverse diagnoses evaluated in 1 year and may represent the types of dementia seen in Toronto and surrounding areas. A letter, based on the clinical intake form, is being programmed to send back to the referring physician and will enhance clinical care, along with scores and graphic display of the cognitive testing results.
Serum adiponectin and methylation of adiponectin gene promoter in peripheral blood of the patients with Alzheimer’s disease and vascular dementia
Authors: Kaiyrlykyzy Aiym , Tsoy Andrey , Umbayev Bauyrzhan , Olzhayev Farkhad , Alzhanova Dinara , Zhussupova Alma , Zhumalin Aibek , Masoud Abdul‐Razak , Askarova Sholpan
Published: December 2020

Background

There is increasing body of evidence indicating that adiponectin (APN), a protein hormone produced mainly by white adipose tissue, may be an independent risk factor for all‐cause dementias and Alzheimer’s disease (AD). A number of studies demonstrated that concentration of APN was increased in plasma of patients with mild cognitive impairment (MCI) and AD compared to healthy individuals. In contrast, some studies did not find significant changes in plasma adiponectin in AD patients, or even demonstrated lower plasma level of APN in MCI and AD compared to controls. These controversial data indicate that more studies are needed to reveal an association between plasma adiponectin and dementia. In the present study we have evaluated APN level in blood and analyzed APN gene methylation in patients with AD and vascular dementia (VD).

Method

Blood samples were obtained from the patients with AD (n =26), VD (n=31) and cognitively normal individuals (n =44). We measured serum adiponectin level using ELISA kit; APN gene methylation in blood was analyzed using bisulfite modification of DNA protocol followed by methylation specific PCR.

Result

Analysis of serum adiponectin levels showed a 3‐fold increase in participants with AD (p<0.001) and VD (p<0.001) compared to the control group. 15 out of 57 (26.3%) of the samples in dementia group vs 1 out of 44 (2.3%) of the control samples had a methylated adiponectin gene promoter (p=0.001). Methylation of the adiponectin gene promoter in peripheral blood occurred with relatively same frequency in individuals with AD and VD, 23% and 29%, respectively (p=0.765). In AD patients serum adiponectin level was almost twice as high in samples in which methylation was observed (p=0.0294).

Conclusion

Our data demonstrated that in people suffering from AD and VD there was an increase in the levels of serum adiponectin and amplified methylation of adiponectin gene promoter in peripheral blood. These findings may serve as a basis for the development of prognostic biomarkers of AD and VD. Nevertheless, more data collection is necessary for further analysis and interpretation.
Cerebral hemodynamic responses of subjective cognitive decline evoked by loaded N‐back tasks
Authors: Du Wenying , Zhang Yaoyu , Gao Jiahong , Han Ying
Published: December 2020

Background

Subjective cognitive decline (SCD) is a high risk for Alzheimer’s disease. The physiological mechanisms of SCD is largely unknown. Most of the existing studies made their observations during the resting state of the brain. How the SCD group performs differently from the normal controls (NC) during functional tasks is less studied. This study compared the responses of SCD and NC evoked by loaded working memory tasks. The results of this study help clarify the underlying hemodynamic mechanisms of SCD.

Methods

15 NC (8 females) and 23 SCD subjects (14 females) participated in the study. Table 1 shows the biographical and behavioral data of the two groups. All subjects participated block‐designed 0‐back, 1‐back, 2‐back and 3‐back working memory tasks. Followed by the N‐back tasks, each subject underwent a hypercapnic challenge during which the subject breathed a gas mixture (5% CO2, 20% O2, 75%N2) through a non‐rebreather mask. A pulse sequence which simultaneously acquires cerebral blood volume (CBV), cerebral blood flow (CBF), blood oxygen‐level dependent (BOLD)‐weighted signals was implemented on a 3.0 T GE MR750 system. At the group level, holding sex, age and education as covariates, a general linear model was applied to compare the above parameters between the two groups, and a partial correlation test was performed to relate the imaging results with the behavior data. P < 0.05 was considered statistically significant.

Results

The group averages of δCBV, δCBF, δBOLD and δCMRO2 evoked by 1‐, 2‐ and 3‐back, with respect to 0‐back, in the frontal cortex were displayed in Figure 1. In general, all parameters show a load‐dependent effect, where 1‐back caused minimum signal changes. Among all parameters, δCBF evoked by 3‐back, with respect to 0‐back, was significantly lower (p = 0.04) in the SCD group compared to the NC group. None of the other parameters showed statistical differences between the two groups. In addition, δCBF at 3‐back was found to be significantly correlated with the MoCA (p = 0.04) and AFT (p 0.03) scores of the subjects.

Conclusion

This study may help understand the physiological mechanisms and develop early diagnostic strategies of SCD.
Plasma amyloid‐β dynamics are regulated by the sleep‐wake cycle
Authors: Zhao Beiyu , Liu Chenyu , Wang Liang , Wei Meng , Dang Jingxia , Qu Qiumin
Published: December 2020

Background

It has been reported that sleep is an important physiological process and conducive to the elimination of brain metabolites and the recovery of brain function. Growing evidence suggested that sleep disorders were related to increased risk of AD and Aβ accumulation in the brain. Although peripheral Aβ clearance is associated with brain Aβ deposition, but the relationship between sleep‐wake cycle and plasma Aβ levels is unclear.

Method

Thirty cognitively normal healthy adults (aged 29.07 ± 8.12), sixteen males (53.33%), were recruited. Participants underwent normal sleep and peripheral blood samples were collected every three hours between 20:00 and 8:00 the next day. Plasma Aβ40, Aβ42, total tau, phosphorylated tau 181 (P‐tau), soluble low‐density lipoprotein receptor‐related protein (sLRP1) and soluble receptors for advanced glycation end products (sRAGE) levels were measured using ELISA kits.

Result

Plasma Aβ40 concentration at 5:00 decreased significantly compared with plasma level at 23:00 (p=0.041), and there is a dynamic tendency of decreasing after sleep onset and increasing after awake, which is in accordance with the sleep‐wake cycle. Furthermore, Aβ40 and Aβ42 levels were positively correlated with plasma sLRP1 (Aβ40: r=0.1791, p=0.0283; Aβ42: r=0.1780, p=0.0293). However, there was no significant dynamic change in Aβ42, Tau, P‐tau, Tau, sLRP1 and sRAGE levels in twelve hours.

Conclusion

Plasma Aβ40 dynamics are regulated by the sleep‐wake cycle, and it may play a positive feedback regulating role in sLRP1 level.
The effect of digital reminiscence therapy on the verbal communication of people with dementia
Authors: Park Kyongok , Moon SeolHwa
Published: December 2020

Background

Verbal communication is the basic function for social interaction. People with dementia (PWDs) experience a deterioration in verbal communication function, and this restricts social engagement, and could lead to social isolation. Reminiscence therapy is known to affect emotion, cognition, and behavioral disturbance for PWDs. The effect of digital reminiscence using digital material or equipment for PWDs has also been reported recently. However, it is not clear whether there is an effect of digital reminiscence therapy on verbal communication function for PWDs. Therefore, this study aims to test the effectiveness of digital reminiscence therapy on verbal communication for PWDs.

Method

This study was a randomized, controlled trial that was conducted at nine daycare centers from January to June 2019 (registration number: KCT0003446). The Android application was developed for digital reminiscence therapy. Digital reminiscence or storytelling therapy was performed in each group for eight sessions for four weeks. Out of the 49 female participants, 25 were randomly assigned to the digital reminiscence therapy group, and 24 were randomly assigned to the storytelling (control) group, without using digital materials. The video files of the sessions were analyzed with Noldus Observer XT 14.0 software. The Holden communication scale, verbal engagement, and the number of words used during the therapy session were measured to evaluate the verbal communication function of PWDs at the first session (T1), and the last session (T2). A paired T test analyzed differences in outcomes between the sessions and groups.

Result

The mean value of the Holden communication scale was significantly decreased in the digital therapy group at the last session (t = 2.663, p = .015). However, there was not a significant decreasing of the variable in the control group at the last session (t= ‐ .042, p = .967).

Conclusion

The results of this study showed that digital reminiscence therapy had an effect on the verbal communication function of PWDs. Therefore, the verbal communication function maintained or increased by the digital reminiscence therapy will assist PWDs in interacting with others and help to decrease social isolation. Eventually, digital reminiscence therapy will contribute to increasing the quality of life of PWDs.
Longitudinal flortaucipir accumulation is spatially distinct across baseline tau burden stages: Summary from three phase 2/3 interventional trials in Alzheimer’s disease
Authors: Shcherbinin Sergey , Higgins Ixavier A. , Lu Ming , Pontecorvo Michael J. , Lo Albert C. , Sims John R.
Published: December 2020

Background

To date, regional patterns of the longitudinal tau accumulation in Alzheimer’s Disease (AD) have been examined in very few studies with limited sample sizes. We combined data from three phase 2 or 3 interventional trials to illustrate regional patterns of longitudinal flortaucipir accumulation.

Method

EXPEDITION3 (NCT01900665), NAVIGATE‐AD (NCT02791191) and AMARANTH (NCT02245737) were double‐blind, placebo‐controlled multi‐center trials that enrolled amyloid‐positive patients with early or mild AD dementia. Longitudinal changes for flortaucipir were examined for N=208 placebo participants who underwent 8‐16 month follow‐up (scheduled or early discontinuation) flortaucipir scans. Flortaucipir scans were pooled across the three trials and divided into four stages corresponding to very low, low, medium, and high baseline global neocortical tau SUVR using pre‐determined cut‐points (Pontecorvo et al, 2019). A stage‐wise annualized percent change (APC) and mean‐standard deviation (SD) ratio (MSDR) of longitudinal tau accumulation were examined for 17 Automated Anatomical Labeling (AAL) atlas‐based bilateral cortical regions and a composite neocortical region of interest (ROI).

Result

Our analysis suggested a dependence of the regional longitudinal tau accumulation profile on the global baseline tau burden at a group level. In the lowest baseline SUVR group (N=36), minimal accumulation was observed in the composite ROI (APC=0.04%, MSDR=0.01) and the inferior temporal region (APC=1.00%, MSDR=0.41) showed the strongest tau signal increase. At low (N=42) and medium (N=63) baseline levels, we found a relatively wide‐spread and spatially uniform accumulation with an APC of 2‐3% in the majority of the cortical regions and composite ROI. For patients with a high global baseline burden (N=67), tau increased in all considered frontal regions (APC ≥ 3.95%, MSDR>0.42) which exceeded accumulations in the composite ROI (APC=2.82%, MSDR=0.32).

Conclusion

For the amyloid positive early‐to‐mild AD population, we found different cross‐sectional tau deposition and different regional longitudinal profiles across four baseline tau stages. Performing tau‐based screening might enroll more pathologically homogeneous populations in interventional trials and permit utilization of optimal measures of tau change as outcomes.
Longitudinal aortic stiffness is associated with brain microstructure and cognition: A voxel‐wise magnetic resonance imaging study
Authors: Suri Sana , Chiesa Scott T , Zsoldos Enikő , Filippini Nicola , Mackay Clare , Griffanti Ludovica , Mahmood Abda , Singh‐Manoux Archana , Shipley Martin J , Brunner Eric , Kivimaki Mika , Deanfield John , Ebmeier Klaus P
Published: December 2020

Background

Aortic stiffness, assessed by carotid‐femoral pulse wave velocity (PWV), is closely linked with hypertension, heart disease and stroke. Recent research has suggested that rapid aortic stiffening may also be a risk factor for cognitive decline and dementia. However, the age of onset of this risk and its underlying brain physiology is unknown. We examined whether aortic stiffening over a 5‐year period in mid‐life affects later‐life brain structure and cognition in community‐dwelling adults.

Method

Data from 544 participants from the Whitehall II Imaging Sub‐study were analysed. Aortic PWV was measured at baseline in 2007‐09 (mean age 63.92±5.23) and at a 5‐year follow‐up visit in 2012‐13 (mean age 67.99±5.25) using applanation tonometry (SphygmoCor, AtCor Medical, Australia). After the latter visit, they also received cognitive tests and a 3T brain MRI scan (2012‐2016, mean age 69.82±5.23). Voxel‐based morphometry and tract‐based spatial statistics were used to extract grey matter (GM) volume, fractional anisotropy (FA), mean diffusivity (MD), and white matter hyperintensity (WMH) volumes. Baseline and follow‐up arterial stiffness were entered as predictors of MRI and cognitive outcomes in two separate general linear models, each adjusting for age, sex, education, mean arterial pressure, body mass index, socio‐economic status, scanner model, and follow‐up time interval.

Result

Higher aortic stiffness at baseline was associated with significantly poor performance in semantic fluency (category ‘animals’, B(SE)=‐0.42(0.15), Bonferroni‐corrected p<0.008) and short‐term verbal memory (immediate recall on the Hopkins Verbal Learning Test‐R, B(SE)=‐0.36, (0.12), Bonferroni‐corrected p<0.008) at the time of the scan. Follow‐up aortic stiffness was associated with significantly lower FA and higher MD in widespread brain areas including the corpus callosum, corona radiata, cingulum, and superior longitudinal fasciculus (p<0.05, corrected for voxel‐wise comparisons). No significant associations with GM or WMH were observed.

Conclusion

Elevated aortic stiffness after age 60 is associated with poor WM microstructural integrity and cognitive performance in older age independently of standard vascular risk factors, likely due to increased transmission of pulsatile energy to the delicate cerebral microvasculature. To offer cognitive benefit in older age, strategies to prevent arterial stiffening may be more effective in midlife than in later‐life.
Cerebrospinal fluid tau biomarkers in the prediction and concordance of neurofibrillary tangle and amyloid pathology
Authors: Ashton Nicholas J , Benedet Andréa Lessa , Pascoal Tharick A , Kvartsberg Hlin , Karikari Thomas K , Schöll Michael , Stoops Erik , Francois Cindy , Vanmechelen Eugeen , Mathotaarachchi Sulantha , Savard Melissa , Therriault Joseph , Chamoun Mira , Zetterberg Henrik , Rosa‐Neto Pedro , Blennow Kaj
Published: December 2020

Background

Cerebrospinal fluid (CSF) measures of tau (p‐tau181 and t‐tau) are central to the research diagnostic criteria for Alzheimer’s disease (AD). Nevertheless, alternative tau phosphorylation sites or tau fragments merit further evaluation to better index neurofibrillary tangle (NFT) and amyloid‐β (Aβ) pathology.

Method

We evaluated 168 participants from the TRIAD cohort (young controls, cognitively normal controls (CN), mild cognitive impairment, frontotemporal dementia and AD patients). LUMIPULSE® G1200 (Fujirebio) was used to measure CSF p‐tau181 and t‐tau. CSF p‐tau231 was quantified using a prototype ELISA assay (ADx NeuroSciences). CSF p‐tau217 and tau368 was measured using an in‐house Simoa assay (University of Gothenburg). For PET ([18F]MK6240 and [18F]AZD4694), standard uptake value ratios (SUVR) were determined using the cerebellar and cerebellar cortex as reference tissue, respectively. Finally, ROC curves were generated to investigate the predictive power of the CSF biomarkers.

Result

All CSF p‐tau biomarkers equally associated with [18F]MK6240 (r>0.51), while CSF p‐tau231 correlated more to [18F]AZD4694 (r=0.815) than other tau biomarkers. ROC curves revealed p‐tau biomarkers accurately detected Braak I‐II (AUC>0.905) and III‐IV positivity (AUC>0.940), with p‐tau217 significantly out performing p‐tau231 and p‐tau181 at both stages. Tau368/t‐tau ratio was the superior biomarker in the prediction of Braak V‐VI positivity. P‐tau217 and p‐tau231 demonstrated high accuracy in predicting Aβ positivity (ROC>0.950). This was significantly better than p‐tau181 (p‐tau217, P<0.01; p‐tau231, P<0.001). Prediction of Aβ positivity was also high at the pre‐symptomatic stage for p‐tau231 (ROC>0.9) and again was significantly superior to p‐tau181 (P<0.01). All p‐tau biomarkers demonstrated full concordance (CSF‐/PET‐) with [18F]MK6240 and [18F]AZD4694 for young controls and FTD subjects. P‐tau217 and p‐tau231 demonstrated high concordance with [18F]MK6240 and discordant cases were restricted to the CSF+/PET‐ quadrant (Figure 1). In the same manner, CSF p‐tau217 and p‐tau231 demonstrated the highest concordance with [18F]AZD4694, although subjects were observed in both discordant quadrants (Figure 2).

Conclusion

All CSF p‐tau biomarkers relate to NFT pathology to the same degree, however, tau368/t‐tau seemingly characterises NFT pathology at an advanced stage. CSF p‐tau217 and p‐tau231 are better predictors of Aβ pathology, with p‐tau231 a stronger predictor of Aβ pathology at the pre‐symptomatic stage.
A video feedback intervention for cognitively impaired older drivers
Authors: Ott Brian R , Papandonatos George D , Burke Erin M , Erdman Donna , Carr David B , Davis Jennifer D
Published: December 2020

Background

The goals of this study were to demonstrate that in‐car video technology can effectively detect unsafe driving events in cognitively impaired older adults, and that providing feedback about these events to the drivers and their family members can lead to a reduction in the frequency and severity of unsafe driving behaviors.

Methods

Unsafe driving events (UDE) were triggered by g‐forces leading to capture of a video record that was then transmitted wirelessly to a remote office where each event was analyzed, categorized, and scored for safety demerit points. During the baseline phase (3 months), all participants were monitored with no feedback. During the intervention phase (4‐6 months), half of the participants and their family members were randomly assigned to receive a weekly progress report in the mail along with a DVD of recorded unsafe driving events with recommendations. They also had continuous access to the videos and scores on a web site. The other half of the participants continued with monitoring only. During the post‐intervention monitoring phase (7‐12 months), there was continued monitoring of all participants, but no further feedback.

Results

Of 51 drivers enrolled at baseline (34 with CDR 0.5 and 17 with CDR 1; mean MMSE = 24.35±3.03), 50 drivers completed baseline monitoring and were randomized to monitoring or intervention. During the intervention, UDE frequency per 1,000 miles was reduced by 21% from baseline in the feedback group (Rate Ratio= 0.79, 95% CI=.53‐1.17), while remaining approximately constant in the monitoring group (Rate Ratio=1.02, 95% CI=.69‐1.52). UDE severity score per 1,000 miles was reduced by 48% from baseline in the feedback group (Rate Ratio=0.52, 95% CI=.21‐1.27), but increased by 37% in the monitoring group (Rate Ratio=1.37, 95% CI=.67‐2.83). No major accidents or injuries occurred throughout the course of the study.

Conclusions

These results suggest the potential to improve driving safety among older drivers with cognitive impairment using a behavior modification approach aimed directly at problem behaviors detected in their natural driving environment using g‐force triggered video technology.
The association between an early diagnosis of dementia and secondary health service use: A retrospective cohort study using electronic health records
Authors: Couch Elyse , Mueller Christoph , Perera Gayan , Lawrence Vanessa , Prina Matthew
Published: December 2020

Background

The frequent use of emergency services and unplanned hospitalisations is reflective of fractured dementia care. People living with dementia have a higher risk of hospitalisation and are more likely to use Accident and Emergency (A&E) services more than people of the same age without dementia. It has been proposed that diagnosing dementia early can reduce the risk of harmful hospital admissions or A&E attendances, however there is very little evidence to support this. A diagnosis of Mild Cognitive Impairment (MCI) before dementia can be a helpful proxy to explore early diagnosis. Therefore, the aim of this study was to investigate the association between an early diagnosis of MCI and hospitalisations and A&E attendances.

Method

This study is a retrospective cohort study of electronic health care records from 15,836 patients from a large secondary care database in South London, UK. Participants were divided into two groups: those with a diagnosis of MCI before dementia, to represent an early diagnosis, and those without. Cox regression models were used to compare risk of hospitalisation and A&E attendances after dementia diagnosis. Finally, negative binomial regression models were used to compare the average length of stay and average number of A&E attendances. All models were adjusted for age at diagnosis, gender, ethnicity, levels of comorbid physical conditions, prescription of acetylcholinesterase inhibitors (AChEIs) and, mini‐mental state exam (MMSE) scores at dementia diagnosis.

Results

Participants with an early diagnosis were more likely to attend A&E after their diagnosis of dementia (HR=1.13), however they did not visit A&E more frequently compared to participants without an early diagnosis (IRR=1.01). There was no difference the risk of hospitalisation or length of stay between the groups.

Conclusion

The findings of this study demonstrate that despite the widely held belief that an early diagnosis reduces the likelihood of potentially harmful A&E attendances, patients with an early diagnosis were more likely to visit A&E after their diagnosis. It is possible this may reflect their use of A&E services before dementia. An early diagnosis does not impact the risk of hospitalisation or the length of time spent in hospital.
Association of Apolipoprotein E genetic variation in Alzheimer's disease in a Korean population
Authors: Van Vo Giau , Bagyinszky Eva , An Seong Soo , Kim SangYun
Published: December 2020

Background

Alzheimer’s disease (AD) is one of the most devastating neurodegenerative diseases. The relationship between Apolipoprotein E (ApoE) genotype and the risk of AD is well described in Caucasians, but less established in other ethnicities.

Method

To examine the association between ApoE polymorphism and the onset of AD in Korean population, we enrolled and examined a total of 1000 Korean patients using polymerase chain reaction. The patients were assessed using the criteria of the National Institute of Neurological and Communicative Disorders and Stroke Alzheimer’ Disease and Related Disorders Association.

Result

The frequency of alleles ε2, ε3 and ε4 were 0.076, 0.784 and 0.292, respectively, in Koreans with AD. Furthermore, we compared our allele frequency data with that from other studies of Asian populations using cluster analysis. APOE genotype was closely related to AD in the Japanese population, which was entirely consistent with results previously reported from Korea.

Conclusion

This study confirmed that the subject with at least one ApoE ε4 allele has higher risk suffering from AD than controls in Korean population.
MAPT rs242557 variant is associated with hippocampus tau uptake on 18F‐AV‐1451 PET in non‐demented elders
Authors: Shen Xue‐Ning , Miao Dan , Li Jie‐Qiong , Tan Chen‐Chen , Cao Xi‐Peng , Tan Lan , Yu Jin‐Tai
Published: December 2020

Background

The microtubule‐associated protein tau gene rs242557 variant is associated with multiple tauopathies and dementia. This study investigated whether it was correlated with brain tau‐PET uptake in non‐demented elders.

Method

Ninety non‐demented elders were identified from the Alzheimer's Disease Neuroimaging Initiative cohort. We compared standardized uptake value ratios of tau‐PET tracer 18F‐AV‐1451 between rs242557 variant carriers and non‐carriers in 25 regions of interest.

Result

The minor allele A was associated with increased hippocampus 18F‐AV‐1451 uptake in non‐demented elders (left: β = 0.111, Bonferroni corrected p = 0.035; right: β = 0.103, Bonferroni corrected p = 0.031). Aβ‐positive participants (left: β = 0.206, Bonferroni corrected p = 0.029; right: β = 0.198, Bonferroni corrected p = 0.035) and APOE ε4 non‐carriers (left: β = 0.140, Bonferroni corrected p = 0.006; right: β = 0.134, Bonferroni corrected p = 0.004) exhibited approximately the same findings in hippocampus.

Conclusion

Considering no obvious associations in other regions, we confirmed the significant correlation of MAPT rs242557 risk variant with increased hippocampus tau deposition in non‐demented elders. With higher magnitude signals in the hippocampus that is more likely to be uniquely affected in AD, the tau PET ligand 18F‐AV‐1451 seemed to possess a specific binding property for AD‐like tau pathology.
Image‐based modeling of biomechanical factors for risk assessment of developing periventricular white matter hyperintensities
Authors: Tong Yunjie , Diorio Tyler C , Yang Ho‐ching Shawn , Zhou Xiaopeng , Wu Yu‐Chien , Saykin Andrew J. , Rayz Vitaliy
Published: December 2020

Background

White matter lesions, visible as white matter hyperintensities (WMH) on T2‐weighted MR images, have been associated with aging and with cognitive decline. Among WMHs, periventricular WMHs (adjacent to the ventricular system) have preferential associations with cognitive decline/impairment. Despite the prevalence and potential significance in cognitive declines, there is little to no in‐depth knowledge regarding the underlying causes of WMH, except that it is related to small vessel disease. We hypothesize that the development of periventricular WMH is caused by pulsatile stresses exerted on the lateral wall of the ventricles. Elevated stress in regions adjacent to the ventricular wall, coupled with the weakening of the ependymal layer, may trigger the early changes in white‐matter microstructure and surrounding small vessels, eventually causing WMH.

Method

We developed a method to predict stress distribution in the periventricular white matter using patient‐specific brain anatomy and ventricular movement, obtained through MR imaging techniques. Utilizing established tools for image‐based segmentation (ITK Snap), pre‐processing (3D Systems–Geomagic; Altair–Hypermesh), and finite element modeling (ANSYS Workbench), we tested this pipeline on a healthy volunteer. Patient‐specific ventricular wall movement was assessed over the cardiac cycle using fast EPI MRI and utilized as a boundary condition driving displacement on the ventricular walls in the computational model.

Result

As shown in Figure 1, the stress distribution around the lateral ventricles was calculated based on subject specific ventricular geometry. The stress distribution is not uniform, but changes with the curvature of the ventricular wall. Peak stress concentrations were detected around the anterior and posterior horns of the lateral ventricles, where WMHs are commonly found. Initial results provide support for our hypothesis of biomechanical contributions to lesion development.

Conclusion

We developed a computational modeling framework based on the ventricular anatomy obtained with structural MR images, and material properties from relevant literature and fast EPI MRI. The periventricular locations with high stresses were correlated with the common WMH topography. In the next step, we will apply the model to patient data to further determine the role of biomechanical factors in forming WMH.
Analyzing the correlation of vitamin D and cognitive function in community elders over 60 years old
Authors: LI Zheng , Yang Yanrong , Hu Tingting , Gao Jing , Wang Yao , Chen Shanping
Published: December 2020

Background

Dementia is a syndrome which describes a decline about cognition severe enough to affect daily living ability. The treatment for dementia is limited; Looking for factors related to cognitive dysfunction, controlling or reducing these factors will help delay the disease.

Method

We collected 190 community elders over 60 years old, used Montreal cognitive assessment (MOCA) to evaluated cognition, and divided into normal cognitive function group and abnormal cognitive function group. And the same time blood samples were collected to measure vitamin D. Compared the vitamin D between the two groups, P<0.05 was significant difference .Pearson's index was used to further compare the vitamin D and a single cognitive domain, P<0.05 was significant statistically.

Result

The incidence of cognition impairment was 77.9%, Comparing to normal cognitive function group and cognitive impairment group, the Vitamin D was significant differences(P<0.05).Further Pearson correlation analysis found that multiple cognitive domains such as executive, calculation, abstraction, visual space, naming, and attention were Positively correlated with vitamin D(P<0.05).

Conclusion

Cognitive function is closely related to vitamin D, especially executive, orientation, calculation, abstraction, visual space, naming, and attention, adequate vitamin D may delay cognitive decline.