bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk assessment for postoperative delirium: Cognitive impairment as major factor
Authors: Klingenhegel Ingo , Ihl Ralf
Published: December 2020

Background

Elderly patients show an increased risk of postoperative delirium. Cognitive impairment constitutes a risk factor for delirium, whereas delirium can also accelerate cognitive decline. To improve prevention and therapy of delirium, planning of surgical and anaesthetic measures could integrate a range of psychiatric, psychosocial and somatic risk factors. Here, the predictive value of risk factors was investigated.

Method

In a longitudinal design, 120 patients aged 65 years and older were included. Risk factors were assessed before surgical interventions with a questionnaire for risk factors, the TE4D as a screening tool for cognitive impairment and depression and Reisberg’s GDS staging of severity of cognitive impairment. Postoperative prevalence of delirium was assessed with the Confusion Assessment Method for the Intensive Care Unit (CAM‐ICU). Pearson correlation was calculated for metric variables. If significant (p<.05), metric variables were transformed into dummy variables by calculating the highest possible odds ratio for delirium. For nominal variables, odds ratio for delirium was calculated. A stepwise binary logistic regression was conducted.

Result

Prevalence of postoperative delirium was 13.3%. Results of the Pearson correlation indicated neither significant association between postoperative delirium and age (r(118) = .089, p > .05) nor education (r(118) = ‐.002, p > .05). Postoperative delirium and duration of general anaesthesia were found to be correlated (r(118) = .33, p < .01). Logistic regression of 20 risk factors (Table 1) resulted in a 6‐factor‐model including preoperative cognitive impairment (OR 33.67), severe disease (OR 23.05), premedication with narcotics or benzodiazepine (OR 9), fracture (OR 5.77), duration of general anaesthesia above 160 minutes (OR 5.56) and male gender (OR 2.29). For the resulting model predictive sensitivity was 1, specificity was .93, Youden index J=.93, accuracy .94.

Conclusion

For the risk of delirium in elderly surgical patients, preoperative cognitive impairment demonstrated the highest odds ratio followed by somatic predisposition. To decrease the risk of delirium, the result of calculating the risk factors will give the chance to adapt anaesthetic and surgical procedures. A screening tool, working title Computation of Risk for Delirium (COR‐D), including a short version based on the presented data will be provided and further validated.
Memory complaints are associated with impaired working memory and reduced frontal cortical thickness in mid‐life surgically menopausal women
Authors: Reuben Rebekah B. , Almey Anne , Gervais Nicole J. , Au April , Duchesne Annie , Gravelsins Laura , Brown Alana , Kannampuzha Courtney , Perovic Mateja , Bernardini Marcus , Eisen Andrea , Meschino Wendy , Foulkes William , Grady Cheryl , Einstein Gillian
Published: December 2020

Background

Alzheimer’s disease (AD)‐related brain pathology is observed in participants within the normal ranges of cognitive assessments (Delacourte et al., 1999). Consequently, there is increased interest in subjective cognitive decline (SCD), a self‐experienced decline in cognition, as an early risk factor (Jessen et al., 2014). SCD is associated with earlier conversion to mild cognitive impairment (MCI) and AD (Jessen et al., 2010; Reisberg et al., 2010), poorer performance on cognitive tasks, and cortical thinning in AD‐related regions (Schultz et al., 2015; Sánchez‐Benavides et al., 2018). Women with surgical menopause prior to age 50 have an increased risk of AD (Rocca et al., 2007). Women with bilateral salpingo‐oophorectomy (BSO) without estradiol (E2) therapy in mid‐life show decreases in WM performance and volumetric declines in the frontal cortex and hippocampus compared to controls (Almey et al., 2018; Gervais et al., 2018).

Method

The current study evaluated the association of memory complaints with WM performance and frontal cortical thickness in a mid‐life cohort of at‐risk women with BSO. Participants with memory complaints (n = 42) and without (n = 30) completed demographics and neuropsychological tasks to assess WM. A subset of these participants with memory complaints (n = 11) and without (n = 14) were scanned using a 3T Siemens scanner, and cortical thickness was obtained from T1‐weighted scans using CIVET 2.1.1 (Ad‐Dab’bagh et al., 2005). Analyses were performed using R 1.1.4 (R Core Team, 2018).

Result

Our analyses revealed participants with memory complaints performed significantly worse on WM tasks than those without. Furthermore, we found participants with memory complaints had significantly thinner cortices within the left ventrolateral prefrontal cortex (vlPFC), a region associated with WM (Badre & Wagner, 2007).

Conclusion

Our preliminary results demonstrate memory complaints are associated with impaired WM performance and frontal cortical thinning in women with BSO. The results suggest that women with surgical menopause and memory complaints show differences associated with SCD in WM function and frontal cortical structure at an early age (Wang et al., 2004). Ongoing research is evaluating effects of memory complaints on cognition and brain structure within spontaneously menopausal women in the COMPASS‐ND database (CCNA, 2020).
Regional distribution of amyloid deposition and grey matter atrophy in late‐life depression
Authors: Takamiya Akihiro , Casteele Thomas Vande , Koole Michel , De Winter François‐Laurent , Bouckaert Filip , Van den Stock Jan , Van Laere Koen , Emsell Louise , Vandenbulcke Mathieu
Published: December 2020

Background

Depression is associated with a risk of developing dementia and is hypothesized to enhance (pathological) brain aging. Previously we reported that amyloid burden in late‐life depression (LLD) did not differ from healthy controls in cortical regions typically associated with Alzheimer’s disease (AD) [1]. Here we extend our analysis beyond hippocampal volume and AD‐specific volumes‐of‐interest, to the whole brain.

Method

Forty‐eight individuals with LLD (age 74.1±7.5 years, 33 female) and 52 healthy controls (72.4±6.4 years, 37 female) underwent static amyloid PET imaging with [18]F‐flutemetamol and 3D T1‐weighted structural MRI. Amyloid deposition was quantified using the standardized uptake value ratio (SUVR) relative to the cerebellar grey matter (GM). Whole‐brain voxel‐wise comparisons of amyloid PET SUVR and GM volume (GMV) between LLD and controls were performed using SPM12, with age as covariate. Total intracranial volume was included as an additional covariate in the GMV analysis. The significance threshold was set to a family‐wise error (FWE) corrected p <0.05 at cluster‐level with an individual voxel height threshold p = 0.001.

Result

There were no statistically significant group differences in amyloid deposition. In contrast, compared to controls, individuals with LLD showed widespread significant GMV reductions, predominantly in the left temporo‐parietal and the right occipital regions (Figure).

Conclusion

Late‐life depression is associated with lower GMV in regions also implicated in AD, but is not associated with increased amyloid burden. Future analysis investigating correlations with neuropsychological measures of mood and cognition, and accounting for the potential effects of regional atrophy and white matter pathology on amyloid quantification, may further extend our knowledge about differences in the underlying neurobiology of LLD and AD.
How much can the Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS‐Cog) tell us? Insights from a latent state‐trait auto‐regressive (LST‐AR) model
Authors: Cogo‐Moreira Hugo , Krance Saffire H. , Rabin Jennifer S. , Lanctot Krista L. , Herrmann Nathan , Macintosh Bradley J. , Black Sandra E. , Eid Michael , Swardfager Walter
Published: December 2020

Background

The ADAS‐Cog assesses several cognitive domains and is the international gold standard for monitoring cognitive decline in clinical trials for Alzheimer’s disease (AD) dementia. These manifold cognitive deficits can progress differently and therefore, individual ADAS‐Cog items may contain different sources of information: some predictable based on the baseline score (i.e. trait), and some based on progression from one occasion to the next (i.e. accumulated or “autoregressive” effects), while some reflects unpredictable “occasion specific” fluctuations in symptoms (i.e state).

Method

Over multiple occasions of measurement, latent state‐trait autoregressive (LST‐AR) models can be used to decompose each item into reliable consistent information (composed of trait information and accumulated effects), reliable occasion‐specific information (i.e. state effects), and unreliable information (i.e. measurement error). Thus, consistency (trait + accumulated effects) and reliability (consistency + occasion specificity) can be determined for each item, at each assessment. The LST‐AR model was fit to four waves of data assessments (baseline, 6, 12 and 24 months) among 341 mild AD patients that participated in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.

Result

The reliabilities of the memory (43.4%‐80.1%) and language (63.8%‐92.5%) items were generally greater than those of the praxis (average of 65.6%) and orientation (average of 60.8%) items. At the last assessment, all of the memory and language items had more consistency (ranging from 63.4% for comprehension of spoken language to 88.2% for word recognition) than occasion specificity. Disentangling the consistency into traits and accumulated effects, the items most reflective of traits were word recognition (79.4%) and commands (64.1%). Word recall, orientation and naming tasks contained roughly equal amounts of trait and accumulated information. Scores on comprehension of spoken language and spoken language ability were mainly related to accumulated effects (71.4% and 64.7%, respectively).

Conclusion

In mild AD, most individual ADAS‐Cog memory and language items were reliable over time. Moreover, the scale captured additional information about the state, trait and accumulated effects of AD; the memory items tended to be more reflective of trait differences between subjects, whereas the language items tended to reflect effects that accumulated from one visit to the next, consistent with the typical progression of AD.
The relationship between cortical microstructural changes and in vivo amyloid‐β and tau in aging and preclinical Alzheimer's disease
Authors: Rodriguez‐Vieitez Elena , Montal Victor , Sepulcre Jorge , Lois Cristina , Hanseeuw Bernard , Vilaplana Eduard , Schultz Aaron P , Properzi Michael J , Scott Matthew R , Fortea Juan , Johnson Keith A , Sperling Reisa A , Vannini Patrizia
Published: December 2020

Background

A novel technique for the analysis of diffusion‐weighted imaging (DWI) has allowed quantifying brain microstructural properties by means of cortical mean diffusivity (cMD) in the grey matter. Using this approach a biphasic trajectory of the cMD signal has been revealed, characterized by an early decline followed by an increase across preclinical stages of Alzheimer's disease (AD), primarily in temporo‐parietal brain regions (Montal et al.,Alz&Dem,2018). The initial cMD reduction has been hypothesized to be due to glial activation (Vilaplana et al.,Neurology,2020), while increased cMD in later stages is thought to reflect breakdown of cortical tissue microstructure and neurodegeneration. However, the pathological underpinnings of the cMD signal, specifically its relationship to in vivo amyloid‐β and tau, remain unknown.

Methods

84 cognitively‐normal participants from the Harvard Aging Brain Study underwent cross‐sectional DWI, T1‐weighted‐MRI, 11C‐PiB‐PET, and 18F‐Flortaucipir (FTP)‐PET imaging (Table 1). 11C‐PiB‐PET was quantified using non‐PVC‐corrected Logan DVR, and individual amyloid‐β burden was extracted from a cortical composite including frontal‐lateral‐retrosplenial (FLR) regions. 18F‐FTP‐PET was quantified using PVC‐corrected SUVR and individual tau burden was extracted from the entorhinal cortex. All PET data were normalized to cerebellar grey matter. First, a whole‐brain surface‐based approach was used to investigate the linear and quadratic (correcting for the linear term) vertex‐wise relationships of cMD to amyloid‐β and tau. Second, cMD signal was extracted from significant regions‐of‐interest to visualize its relationships with amyloid‐β and tau.

Results

Cortical MD was not significantly associated to amyloid‐β using either the linear or quadratic term. The relationship between cMD and tau was best described by a quadratic model across the whole cohort, as seen vertex‐wise (Fig.1) and regionally (Fig.2). Specifically, cMD signal decreased and then increased as both amyloid‐β and tau accumulated.

Conclusions

The novel imaging technique of cMD is a promising approach to measure cortical microstructural changes. Our findings of a non‐linear trajectory of cortical mean diffusivity, particularly in the temporal regions, may indicate an initial phase of reduced cMD due to glial activation followed by increased cMD signal due to breakdown of cortical tissue microstructure as amyloid‐β and tau accumulate. Ongoing longitudinal studies will help elucidate the temporal dynamics of cortical microstructure and protein accumulation.
Neuropsychological factors related to progression of subjective cognitive decline
Authors: Ryoo Nayoung , Suh Jeewon , Son Eunji , Pyun Jung Min , Park Young Ho , Kim SangYun
Published: December 2020

Background

Individual with subjective cognitive decline (SCD) complains of cognitive decline on its own while cognitively normal. Current research suggests that SCD can indicate an at‐risk stage of Alzheimer’s disease (AD). In this study, we analyzed neuropsychological factors in SCD patients at a higher risk of progression to MCI.

Method

This retrospective cohort study included 68 patients who were confirmed with SCD after neuropsychological test. They were classified into progressive SCD group and stable SCD group according to whether they progressed to MCI within the follow‐up period. For both groups, neuropsychological tests including Seoul verbal language test, Boston naming test, Stroop color & word test, Rey complex figure test, and forward and backward digit span test were assessed.

Result

We collected neuropsychological data of 107 SCD individuals retrospectively, and 68 patients were followed up for a mean of 52.93 months (range 11–113 months). At follow‐up, 35.3% of patients showed cognitive decline to a diagnosis of mild cognitive impairment (MCI) and defined as progressive SCD group (N=24), and the other patients (N=44) were as stable SCD group. Patients with progressive SCD were about 4 years older and more likely to have ischemic heart disease. Furthermore, they showed worse performance on a delayed recall and a recognition task from the Seoul Verbal Learning Test, and Boston naming test compared to those with stable SCD.

Conclusion

SCD patients with progression of MCI have a tendency of older age, higher rate of ischemic heart disease, and worse decline in memory and language ability. This study suggest that it is worth to consider SCD subtypes based on memory and language ability so that it is possible to detect a high‐risk group of MCI at the early stage.
Pharmacological treatment of neuropsychiatric symptoms of dementia: A systematic review and network meta‐analysis
Authors: Huang Yu‐Yuan , Dou Kai‐Xin , Zhong Xiao‐Ling , Shen Xue‐Ning , Chen Shi‐Dong , Chen Ke‐Liang , Cui Mei , Dong Yi , Dong Qiang , Yu Jin‐Tai
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) of dementia are a common issue in dementia patients. It generally presents as three disparate symptom clusters—agitation, psychosis, and mood disorders which have different biological and psychosocial triggers. Therefore, a “one size fits all” solution may not exist. Pharmacological treatments are its treatment of choice, but there is controversy about which agent should be used. We aimed to update and expand our previous work to compare and rank drugs for the treatment of neuropsychiatric symptoms of dementia.

Methods

We included all randomized controlled trials reported as double‐blind and comparing one active drug with another or with placebo. Studies searched Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, EMBASE, from database inception to Jun 28, 2019. Our primary outcome was change in overall neuropsychiatric symptoms measured with standardised rating scales. And the secondary outcomes were change in aggressive behavior, psychosis, apathy, and depressive symptoms. Effect size measures were standardised mean differences (SMD) with 95% credible intervals (CrIs). We ranked the comparative effects of all drugs against placebo with surface under the cumulative ranking probabilities. We conducted subgroup analyses to assess the robustness of our findings. Confidence in the evidence was assessed using CINeMA. The study protocol is registered with PROSPERO, number CRD42019132231.

Results

We identified 8175 citations and of these included 114 trials comprising nearly thirty thousand participants. Effect size estimates suggested galantamine was more effective than placebo for reducing overall neuropsychiatric symptoms. SMD compared with placebo for reduction of aggressive behavior found that aripiprazole and risperidone appeared to be more efficacious, citalopram and methylphenidate for reduction of apathy symptoms, memantine and donepezil for reduction of psychosis. While the certainty of evidence was low to very low.

Conclusion

This systematic review synthesized the available evidence on the comparative efficacy of different pharmacological approaches in the management of overall NPS, agitation, psychosis, apathy and depressive symptoms in dementia patients. These results may serve evidence‐based practice and inform patients, physicians, guideline developers. Especially, clinicians should differentiate these disparate symptom clusters since the appreciation of such complexity is vital to determine the appropriate treatment.
Assessments of nutritional status and cognitive function of the elderly in Korea: Cross‐sectional study
Authors: Chang Kyung Ja , Bae Mi‐ae , Lee Go Eun , Kim Sung Hoon
Published: December 2020

Background

Recently Korea has become an aged society and prevalence of dementia in the elderly is increasing rapidly. The purpose of this study was to investigate the nutritional status and cognitive function of the elderly in Korea.

Method

The subjects were 127 elderly(55 males, 72 females) in Korea. The nutritional status was assessed using the Nutrition Quotient for Elderly(NQ‐E) developed by the Korean Nutrition Society and 24‐hour recall method. The cognitive function was assessed using the Mini‐Mental State Examination for Dementia Screening(MMSE‐DS) and Subjective Memory Complaints Questionnaire(SMCQ). Data were collected through the face‐to‐face survey from June to July, 2019 and they were statistically analyzed using SPSS 20.0. The subjects were compared by dividing them into good group(GG) and poor group(PG) according to the NQ‐E criteria score(62 points).

Result

The total score of the NQ‐E in GG(69.1 points) was significantly higher than that of PG(53.6 points) (p<0.001). The elderly of both groups showed less energy, vitamin A, D, C, niacin, calcium, potassium and magnesium than the Dietary Reference Intakes For Koreans(KDRI). The total score of MMSE‐DS did not show a significant difference between GG(26.4 points) and PG(25.2 points), but scores of ‘Time orientation’ and ‘Place orientation’ in GG were significantly higher than those in PG(p<0.05). The SMCQ means that subjective memory complaints is severe when the score is 6 points or more. Both GG(3.4 point) and PG(5.0 points) showed good status, but the score of PG was significantly higher than that of GG(p<0.01). There was a tendency to have a positive correlation between the total score of NQ‐E and MMSE‐DS of the subjects(p=0.056), and there were negative correlations between the total score, balance, and food behavior in NQ‐E and SMCQ. These results indicated that scores of some cognitive function(MMSE‐DS) in the PG were lower than those in the GG, and it showed a more severe degree of subjective memory complaints. Also, it showed that the better nutritional status in the balance and food behavior, the lower subjective memory complaints of the subjects.

Conclusion

Therefore, it is necessary to improve nutritional status through sufficient nutrients intake and systematic management to maintain mental health of the elderly.
7β‐hydroxycholesterol increases amyloidogenic pathway and may serve as a peripheral biomarker of Alzheimer’s disease
Authors: Ha Junghee , Cho So Yeon , Lee Jimin , Kim Hyunjeong , Choi Man Ho , Kim Eosu
Published: December 2020

Background

Oxidized cholesterols have been related to Alzheimer’s disease (AD). However, the role of 7β‐hydroxycholesterol (7β‐OHC) in AD pathogenesis is largely unexplored: There is a lack of understanding of whether the increase in 7β‐OHC levels in AD is a consequence of neurodegeneration process or 7β‐OHC plays a direct role in AD pathogenesis. Thus, we aimed to explore the potential of 7β‐OHC as a biomarker of AD and to observe the direct effect of 7β‐OHC on AD pathologies.

Method

7β‐OHC levels in scalp hairs were assessed by gas chromatography‐mass spectrometry (GC‐MS) methods in persons with normal cognition (NC, n = 82), mild cognitive impairment (MCI, n = 39) and AD (n = 81). Also, we examined the relationship between hair 7β‐OHC levels and various clinical features representing cognitive status. Upon stereotaxic injection of 7β‐OHC into the hippocampus of mice, we investigated AD pathologies such as β‐amyloid, tau, and neuroinflammation. We also assessed the behavioral effects of intracerebroventricular injection of 7β‐OHC using the touchscreen‐based 5‐choice serial reaction time task (5‐CSRTT).

Result

7β‐OHC levels were increased in hairs of persons with AD compared to those with NC (p = 0.001). There was also a significant correlation between hair 7β‐OHC levels and the scores of Mini‐Mental State Examination (MMSE) and Global Deterioration Scale (GDS) after controlling age, gender, education ,and statin use. In the animal experiment, we found that hippocampal 7β‐OHC injection induces microglial and astrocytic activation and increases levels of interleukin (IL)‐1β and IL‐6, suggesting neuroinflammation. It also promoted the amyloidogenic pathway by upregulating BACE 1 while downregulating alpha‐secretase, TACE. In the behavioral assessment, we found that 7β‐OHC treatment increases perseveration, compatible with frontal lobe dysfunction.

Conclusion

Our results suggest that 7β‐OHC in scalp hair could serve as a convenient peripheral biomarker of AD. Given that accumulative levels of steroid molecules in hairs indicate its plasma exposure levels in the past several months, our study also suggests that increased plasma 7β‐OHC may be a preceding factor that can increase AD pathology.
Visit‐to‐visit blood pressure variability is associated with functional decline in older adults: The S.AGES cohort
Authors: Rouch Laure , Vidal Jean‐Sébastien , Hanon Olivier ,   S.AGES Investigators
Published: December 2020

Background

Visit‐to‐visit blood pressure variability (BPV) has been increasingly recognized as a predictor of cardiovascular events, all‐cause mortality and more recently of cognitive decline and dementia. All these associations may be mediated by vascular damage which is a determinant of functional decline in older adults. We aimed to investigate the impact of visit‐to‐visit systolic, diastolic, mean arterial pressure and pulse pressure variability on functional decline in non‐institutionalized patients aged ≥ 65 years.

Method

3042 subjects from the S.AGES (elderly subjects) cohort underwent clinical examinations every 6 months during 3 years. Systolic, diastolic, mean arterial pressure and pulse pressure variability were evaluated using standard deviation, coefficient of variation, average real variability, successive variation, variation independent of mean and residual standard deviation. Functional decline was assessed using the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales and defined over time as any help required to perform at least one task. Cox proportional hazards models were used for the analyses.

Result

Among the 3042 subjects, 527 (17.3%) had functional decline (ADL) over time. After adjustment for demographics, systolic blood pressure, antihypertensive drugs, coronary artery disease, diabetes mellitus, chronic heart failure, atrial fibrillation, transient ischemic attack or stroke, smoking, dyslipidemia and Mini Mental State Examination at baseline, higher systolic blood pressure variability was associated with greater risk of functional decline (ADL) (adjusted HR per 1‐SD increase of coefficient of variation = 1.12, 95% CI [1.03‐1.22], p<0.01). Similar results were observed for diastolic blood pressure variability (adjusted HR = 1.11, 95% CI [1.01‐1.22], p=0.03) and mean arterial pressure variability (adjusted HR = 1.15, 95% CI 1.05‐1.25, p<0.01). Higher pulse pressure variability was no longer significantly associated with functional decline after adjustment for age (p=0.6). Similar patterns were found with all indicators of variability and loss of autonomy defined using IADL.

Conclusion

Higher blood pressure variability could be a novel risk factor for functional decline and controlling blood pressure instability a promising interventional target in preserving autonomy in older adults.
The effect of child‐centered play therapy and person‐centered therapy consultation on behavioral and psychological symptoms of dementia in people with dementia of Alzheimer's type
Authors: Kuo Ching‐Yi
Published: December 2020

Background

Behavioral and psychological symptoms of dementia (BPSD) is highly correlated with early nursing home placement, caregiver burden, and cognitive and functional decline. Non‐pharmacological interventions should be first‐line used given the side‐effect of medication. Child‐centered play therapy (CCPT) is a proven scientifically and culturally responsive psychotherapy modality that is widely used with children and a variety of problematic behaviors, including individual with brain injury. Person‐centered therapy consultation (PCTC) is a recognized form of psychotherapy with an emphasis on self‐actualization and therapeutic relationships that facilitate psychological changes. This pilot study of people with dementia of Alzheimer's type who exhibit BPSD in Taiwan examines a combination of CCPT and PCTC an effective non‐pharmacological intervention for people with dementia and their caregivers.

Method

A single‐case research design will be employed. Three PWD receive 40‐minute weekly CCPT sessions for 8 weeks. Three family caregivers receive 50‐minute weekly person‐centered therapy consultations over 8 weeks. PWD will enter a follow‐up phase for 2 weeks after the last CCPT session. Measures: Neuropsychiatric Inventory (NPI), Neuropsychiatric Inventory Distress Scale (NPI‐D), Geriatric Depression Scale (GDS), Clinical Dementia Rating (CDR), and Alzheimer’s Disease Assessment Scale‐cognitive subscale (ADAS‐cog) are used to measure the effectiveness of CCPT on alleviating BPSD.

Result

The research process is on‐going.

Conclusion

The research process is on‐going.
Increased functional connectivity of anterior insula to anterior cingulate cortex in amnestic mild cognitive impairment: A longitudinal resting‐state fMRI study
Authors: Fan Xiang , Li Hui , Li Kuncheng
Published: December 2020

Background

The insula has been reported as a crucial role in Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). However, the mechanism and functional connectivity (FC) changes of insula in follow‐up remain unclear. Exploring specific insula network interaction can contribute to a better understanding of integration and segregation patterns of aMCI.

Method

Twenty aMCI and twenty healthy controls (HC) participants were recruited and underwent resting‐state functional magnetic resonance imaging (rs‐fMRI) and neuropsychological assessment at baseline and 15 months afterward. Rs‐fMRI data were preprocessed using SPM 12 and CONN software. FC of two insular subregions in each hemisphere were defined as anterior insula connectivity (AIC) and posterior insula connectivity (PIC). Using data driven clustering technique, the insular lobe was subdivided based on whole brain functional connectivity. Two‐way analysis of covariance was used with covariates of gender, age, education, follow‐up interval, volume of gray matter and global correlation (GCOR).

Result

Within group FC maps of HC and aMCI exhibited similar patterns both at baseline and follow‐up. For the left anterior insula, significant connectivity with bilateral anterior cingulate gyrus (ACC), paracingulate gyrus, putamen, frontal orbital cortex, inferior frontal gyrus, and temporal pole were identified. The right anterior insula was positively associated with bilateral insula, ACC, central opercular cortex, frontal orbital cortex, and right junction region of temporal, frontal and parietal lobe. The posterior zone of the insula (both the right and the left) exhibited significant connectivity with the bilateral Insular, ACC, central opercular cortex, precentral gyrus, postcentral gyrus, supramarginal gyrus, parietal operculum cortex, as well as the junction region of temporal, frontal and parietal lobe. For interactive main effects, the right AIC showed significantly increased FC with the left ACC, while the left PIC showed decreased FC with the right precuneous, in aMCI as compared to HC.

Conclusion

Insula rsFC changes could be potential biomarkers of aMCI and reveal some definite neuropathological mechanism due to pathologic processes in AD. We considered the rsFC increase of AIC with ACC as compensatory and decrease of the PIC with the precuneus as deterioration of follow‐up due to the course of disease.
Performances of the plasma Aβ biomarker in longitudinal data
Authors: Nakamura Akinori , Kato Takashi , Okada Yusuke , Ishii Kenji , Ishii Kazunari , Ito Kengo , Arahata Yutaka , Kaneko Naoki , Iwamoto Shinichi , Tanaka Koichi , Ikeuchi Takeshi , Yanagisawa Katsuhiko , Iwatsubo Takeshi , Toba Kenji ,   the J‐ADNI and ORANGE registry study groups
Published: December 2020

Background

We recently developed a high‐performance plasma biomarker that reliably predicts individual brain status of amyloid‐β (Aβ) burden using immunoprecipitation‐mass spectrometry (IP‐MS). This study aimed to analyze performances of the plasma Aβ biomarker in a longitudinal dataset using J‐ADNI data.

Method

There were 165 subjects, including 38 cognitively normal (CN), 61 MCI and 46 AD individuals who participated in the J‐ADNI study, and 132 of them had two times of follow‐up data within 36 months. The plasma composite biomarker was generated by combining plasma ratios of APP669‐711/Aβ1‐42 and Aβ1‐40/Aβ1‐42, which were measured by the IP‐MS assay. Using PiB‐PET as the standard of truth (Aβ+ or Aβ‐), plasma biomarker performances were analyzed using the ROC analysis. Relationships of plasma composite biomarker values and longitudinal changes in Aβ deposition (assessed by PiB‐SUVR), degree of medial temporal atrophy (assessed by VSRAD® z‐scores of structural MRI), and cognitive decline (assessed by cognitive test scores) were analyzed.

Result

The ROC analyses showed that the composite biomarker performs good both in base line data and follow up data with AUC greater than 90%. There were no significant changes in plasma composite biomarker values across longitudinal observations. The baseline composite biomarker values were significantly correlated with annual rate of Aβ deposition, especially within subjects whose baseline PiB‐SUVR was relatively small (less than 2.0). The baseline composite biomarker values were also significantly correlated with the rate of medial temporal atrophy and the rate of cognitive decline.

Conclusion

Clinical utility of the plasma Aβ biomarker was validated in J‐ADNI longitudinal data, and it provided information for future disease progression.
PERK inhibition promotes the rescue of protein translation and Nrf2‐related antioxidant response
Authors: Lanzillotta Chiara , Zuliani Ilaria , Tramutola Antonella , Abisambra Jose F. , Barone Eugenio , Perluigi Marzia , Domenico Fabio Di
Published: December 2020

Background

Many neurodegenerative disorders in which aberrant protein conformers aggregate into pathological inclusions, such as tauopathies, also present endoplasmic reticulum stress and chronic activation of the PERK branch of the unfolded protein response (UPR). The adaptive effects of the PERK pathway include reduction of translation by transient inhibition of eIF2α and antioxidant response via induction of the transcription factor Nrf2. In contrast, prolonged activation of the UPR leads to sustained reduction in protein synthesis and induction of cell death pathways. To further investigate the role of the PERK pathway in neurodegenerative disorders, we focused on Down syndrome (DS), a secondary tauopathy, in which aging confers a high risk of Alzheimer‐like dementia (AD), Aβ plaques formation and tau tangle deposition. We recently determined that the UPR is dysregulated in a murine DS model. Therefore, our project aims to investigate if restoring PERK pathway, by using a well‐established PERK inhibitor (GSK2606414), could mitigate the early UPR activation and result in reduced brain pathology.

Method

Ts2Cje (mouse model of DS) at 6 months of age were treated with GSK2606414 a well‐known PERK inhibitor. To target directly the brain, we use the intranasal route. The analysis of the proteins of interest has been carried out by confocal microscopy, Western Blot and real time PCR. Furthermore, we use SUnSET, a non‐radioactive puromycin based approach adapted in vivo, to measure protein synthesis.

Result

Our data report that the pharmacological inhibition of PERK, by GSK2606414, ameliorate chronic PERK induction observed in DS mice restoring its downstream signalling aberrantly regulated during pathology. In particular, we demonstrate, in Ts2Cje treated mice the rescue from eIF2a‐mediated disruption of protein synthesis. In addition, we show that the compound was able to promote the Nrf2‐related antioxidant response reducing protein oxidative damage. Such effect was obtained by the increase of PI3K interaction with Nrf2 and by the restrain of Bach1 binding to ARE sequences.

Conclusion

Our study provides further insights about the role of PERK in DS pathology and in the development of AD, proposing PERK inhibitors as novel therapeutic agents able to rescue trisomic‐related defects of proteostasis and antioxidant response.
Subjective cognitive decline, APOE genotype, and incident Alzheimer’s disease: The AGES‐Reykjavik Study
Authors: Geerlings Mirjam I. , Gerritsen Lotte , Vonk Jet M.J. , Gudnason Vilmundur , Launer Lenore J.
Published: December 2020

Background

Subjective cognitive decline (SCD) may be a marker of preclinical Alzheimer’s disease (AD) in some individuals and is related to biomarkers of AD. We investigated the longitudinal associations of SCD and APOE genotype with incidence of dementia and AD.

Method

Data are from 4,349 older adults (76±5 years, 59% women) without dementia who participated in the population‐based AGES‐Reykjavik Study. SCD was assessed with the question ‘Has your memory gotten worse in the past 12 months’. A 1.5T brain MRI was performed in all participants. Five mutually exclusive groups were defined: 1) normal (i.e. no SCD, no MCI, no dementia)/APOE e4 negative (n=2039); 2) normal/APOE e4 positive (n=711); 3) SCD/APOE e4 negative (n=806); 4) SCD/APOE e4 positive (n=355); 5) MCI (regardless of APOE) (n=438). MCI and dementia, including AD, were assessed according to international criteria. We used Cox regression analyses adjusted for age, sex, and education to estimate the Hazard Ratios of each group with incident dementia, including AD and non‐AD dementia.

Result

During on average 9 years of follow‐up, 843 persons developed dementia, including 397 with AD. Within the normal/APOE e4 negative group conversion rate to dementia was 13%; these rates were 20%, 20%, 30%, and 38% for groups 2 through 5, respectively. For AD, the conversion rates for groups 1 through 5 were 6%, 12%, 10%, 21%, and 23%. Cox regression analyses showed that compared to the normal/APOE e4 negative group, the normal/APOE e4 positive group had 2.48 times higher risk of AD (95% CI 1.84‐3.34), the SCD/APOE e4 negative group 1.78 times higher (1.31‐2.42), the SCD/APOE e4 positive group 5.23 times higher (3.83‐7.16), and the MCI group 4.43 times higher (3.24‐6.06) (Figure 1).

Conclusion

Subjective cognitive decline and APOE e4 positivity each increased the risk of AD development, but the combination of a subjective cognitive symptom and a biomarker posed the strongest risk for AD, comparable to that of MCI. These findings may help to identify high‐risk groups in the population to target for preventive or therapeutic interventions.
Accelerated long‐term forgetting over six months in cognitively normal APOE ɛ4 carriers
Authors: Tort‐Merino Adrià , Laine Matti , Fortea Juan , Martinez‐Lage Pablo , Sanchez‐Valle Raquel , Rami Lorena , Rodríguez‐Fornells Antoni
Published: December 2020

Background

Accelerated long‐term forgetting (ALF) refers to an abnormally rapid loss of information over days or weeks despite normal acquisition and encoding. The potential usefulness of ALF in the early detection of subtle cognitive difficulties in asymptomatic stages of familial (Weston et al., 2018) and sporadic (Zimmermann & Butler, 2018) Alzheimer’s disease (AD) has attracted particular attention. However, research on the relationships between ALF and AD biomarkers is still lacking, and forgetting curves have not been followed up over an extended period of time. We aimed to fill these gaps by administering a particularly demanding memory task, correlating task results with AD biomarkers, and registering forgetting curves over a 6‐month follow‐up.

Method

Twenty‐two cognitively healthy subjects were included: 11 APOE ɛ4 carriers (heterozygous for ɛ3 and ɛ4) were age‐, sex‐, and education‐matched with 11 APOE ɛ4 non‐carriers (homozygous for ɛ3). All subjects underwent APOE genotyping, standard neuropsychological assessment, a lumbar puncture for determining CSF Aß42, tau and ptau levels, and the demanding Ancient Farming Equipment Test (AFE‐T). The AFE‐T calls for learning 24 novel object/name pairs through two learning sessions of seven runs performed on two consecutive days (range 0‐24 points per run). Free and cued long‐term recall was examined at one week, three months and six months after the initial learning.

Result

Demographics and CSF levels are shown in Table 1. The AFE‐T showed no group differences in the learning scores, but a significant group difference (F(1,19) = 4.99; p < 0.05) emerged in the cued recall at 3 months. The APOE ɛ4 carriers showed ALF in their cued forgetting rate at 3 months (F(1,19) = 5.60; p < 0.05) and the forgetting rate between the 1‐week and 3‐month recall (F(1,19) = 8.70; p < 0.01) (Figure 1B). Correlation analyses showed a significant association between the cued forgetting rate at 3 months and the ratio CSF Aβ42/ptau (Figure 2A; r = .614; p < 0.01). Also, a significant correlation was found between the cued forgetting rate at 3 months and subjective cognitive ratings (Figure 2B; r = .636; p < 0.01).

Conclusion

Accelerated long‐term forgetting is detectable in at‐risk individuals and is linked with CSF AD biomarkers. We strongly recommend the use of demanding memory tests coupled with long‐term forgetting measures for identifying and tracking the earliest cognitive manifestations in presymptomatic Alzheimer’s disease.
White matter integrity linked to memory retrieval deficits in posterior cortical atrophy
Authors: Overman Margot Juliette , Zamboni Giovanna , Butler Christopher , Ahmed Samrah
Published: December 2020

Background

Posterior cortical atrophy (PCA) is an atypical form of Alzheimer’s disease characterised by visuospatial abilities, with episodic memory traditionally thought to be relatively preserved. However, recent work suggests that verbal memory is impaired at clinical presentation (Ahmed et al., 2016) associated with changes in functional connectivity of parietal attention networks (Veldsman et al., 2018). It is currently unclear how structural connectivity changes may contribute to memory functioning within this patient group. Here, we examine the relationship between white matter integrity and verbal episodic memory in PCA.

Method

Eighteen patients with PCA and eighteen healthy controls underwent diffusion tensor imaging (DTI) MRI scanning. Episodic memory of patients was assessed with the Free and Cued Selective Reminding Test with Immediate Recall (FCSRT‐IR). Voxel‐wise statistical analyses of fractional anisotropy and mean diffusivity measures in patient and control groups were carried out using tract‐based spatial statistics. Relationships between white matter microstructure and memory performance were examined with partial correlations controlling for age.

Result

There was no difference in encoding of verbal items between patients and healthy controls. However, PCA patients presented with significant impairments of memory retrieval on the FCSRT‐IR. In line with previous neuroimaging research, white matter degeneration in PCA was restricted to posterior regions of the cortex. Within the patient group, reduced integrity of the splenium of the corpus callosum was associated with less free recall of task items.

Conclusion

This study demonstrates that splenial atrophy may contribute to deficits in episodic memory retrieval in PCA. The findings have implications for supporting diagnostic profiling in PCA. References: Ahmed, S., Baker, I., Husain, M., Thompson, S., Kipps, C., Hornberger, M., Hodges, J.R., & Butler, C.R. (2016). Memory impairment at initial clinical presentation in posterior cortical atrophy. Journal of Alzheimer’s Disease, 52: 1245 – 1250. Veldsman, M., Zamboni, G., Butler, C., & Ahmed, S. (2018). Attention network dysfunction underlies memory impairment in posterior cortical atrophy. NeuroImage: Clinical, 22: 101773.
Cerebral autoregulation in patients with MCI and dementia due to Alzheimer's disease: Effects of blood pressure lowering on CBF
Authors: Claassen Jurgen A.H.R. , de Heus Rianne A.A. , Rikkert Marcel G.M. Olde , de Jong Daan LK , Sanders Marit
Published: December 2020

Background

Blood pressure (BP) lowering is a promising strategy to prevent dementia, including AD (SPRINT‐MIND). BP lowering should therefore be explored as a secondary prevention strategy in patients with early stages of AD (MCI due to AD and preclinical AD). However, if cerebral autoregulation is impaired in (older) patients with AD, BP lowering could cause cerebral hypoperfusion and lead to progression of disease

Method

we studied cerebral autoregulation at baseline in 40 patients with amnestic MCI and 50 patients with AD dementia, compared with 40 age matched cognitively normal controls (controls, aMCI and AD aged 70 years SD 5). Next, we studied the effects of BP lowering on CBF using a) one year exercise intervention (in aMCI) and b) BP lowering treatment with a calcium channel blocker (in AD dementia).

Result

at baseline, we found no evidence of impaired dynamic cerebral autoregulation in aMCI and AD compared to controls. BP lowering (on average ‐10 mmHg systolic BP) did not reduce global nor regional CBF in aMCI and AD. Of interest, BP lowering led to an increase in hippocampal CBF.

Conclusion

No evidence for impairment of cerebral autoregulation was found. BP lowering did not reduce CBF, in contrast, BP lowering may even improve regional and possibly global CBF. Further studies should extend these findings to a larger population and to earlier stages of AD.
Evaluation of the effectiveness of the neuro‐nutraceutical SYNAID® on a broad‐spectrum sample (subjects with dementia, cognitively preserved and with depression): Results of a 24‐month prospective clinical trial
Authors: Veneziano Massimo
Published: December 2020

Background

the increasing number of subjects with dementia in the world and the failure of drug therapies, has inspired the scientific community undertake new forms of intervention to tackle the disease such us primary prevention (reduction of risk factors, cognitive reserve). Neuro‐nutraceutical research and resulting treatments are increasingly affirming, preventing or slowing down cognitive impairment; contributing to achieve neuroplasticity. The purpose of this study was to assess the efficacy and safety of neuro‐nutraceutical SYNAID® (INPHA Duemila Srl) in patients with cognitive impairment (combination with anticholinerasic drugs) and in cognitively preserved subjects with or without anxiety and depression.

Method

Exclusion criteria: 1) psychiatric diagnosis; 2) severe sensory deficits. Inclusion criteria: 1) subjects with MCI (amnestic and vascular), 2) subjects with Alzheimer’s dementia, with vascular dementia, with mixed dementia; 3) cognitively preserved subjects with or without anxiety and depressive disorders. The enrolled patients (280) were divided into 2 groups by open‐randomised method: the treatment group (grT) with the administration of SYNAID® one tablet/day for 24 months and the control group (grC) that did not take the neuro‐nutraceutical. The groups were analysed by Student and compared at baseline, 6, 12, 18, 24 months from the beginning of treatment. The cognitive outcome was evaluated by administration of the following tests: MMSE; CDR; CDT; RAVLT; FVL. The result of psychic state evaluated through CES‐d, the result psycho‐behavioural symptoms associated with dementia via NPI. Functional outcome via IADL scale. The quality of life outcome through QoL‐SF12.

Result

grT compared to the grC showed a significant increase in scores at the MMSE, RAVLT, FVL, CDT, IADL and QoL‐SF12 tests and a significant reduction in scores at CES‐d and NPI. There were no side effects, no adverse events following the intake of neuro‐nutraceuticals. The dropouts were 20 (9 grT and 11 grC).

Conclusion

The study demonstrates that prolonged intake of SYNAID® improves memory and other neuropsychological functions in cognitively preserved subjects (neuro‐protective effect), and in patients with Alzheimer’s and/or vascular dementia and in patients with mild cognitive impairment (MCI). Furthermore, significant improvements were found in the mood outcome, in the daily functional capabilities and in the quality of life outcomes in all treated subgroups.