bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognition in healthy older women is a predictor of 14‐year falls risk
Authors: Faux Noel G , Bird Stefanie , Michalewicz Aleks , Pasco Julie A , Sales Myrla P Reis , Russo‐Batterham Daniel , Vogrin Sara , Williams Lana j , Duque Gustavo , Szoeke Cassandra
Published: December 2021

Background

Falls are a significant cause of injuries, loss of confidence, increased morbidity, and institutionalisation in all older people, with women at 50% greater risk than men. The relationship between dementia and falls is well established and 2/3 of all dementia occurs in women. In this study we explored risk factors associated with a 14 year falls risk in a community‐based cohort of women, which included validated measures across a wide range of clinical domains including neuropsychological, mood, quality of life and biomarkers (including hormonal).

Method

The Australian Women’s Healthy Aging Project is an longitudinal observation study, assessments every year (1991 –1999), followed by assessments in 2002, 2004, 2012 and 2014. The assessments included cognitive (as of 2002), blood, and cardiovascular disease risk assessment, and questions related to falls. After data cleaning, the remaining cohort consisted of 180 participants (Table 1). Missing data were imputed using mice random forest. To identify key risk factors associated with a 14 year falls risk, random survival (time to event) forest (RSF) machine learning was used.

Result

The RSF model, using all 290+ possible predictive variables, performed well with an Out Of Bag (OOB, withheld data) prediction error (C‐index) of 32.8%. The most predictive variables in the model were identified using the variable importance measure (VIM).

The initial model was refined by taking the top 30 predictive variables and retraining the RSF. This refined model resulted in an improved OOB C‐index of 5.8% (27%). The top 20 predictive variables, Figure 1, include those associated with cardiovascular disease risk, cognitive performance, and hormone levels (e.g., family history of heart attack, digit symbol coding, and estradiol levels).

Conclusion

Ninety percent of the top 20 predictive risk variables for the 14 year fall risk in women, were from three key domains, cognition (40%), cardiovascular (25%) and hormone‐related measurements (25%). Our data suggest that for long term prevention of falls these domains may be important reducing risk of falls in the senior female population.
QyScore® MRI markers' diagnostic accuracy in the clinical spectrum of Alzheimer's disease
Authors: Cavedo Enrica , Tran Philippe , Thoprakarn Urielle , Martini Jean‐Baptiste , Samper‐Gonzàlez Jorge , Movschin Antoine , Longo dos Santos Clarisse
Published: December 2021

Background

Diagnostic criteria for Alzheimer’s disease (AD) acknowledge a key role of imaging markers such as hippocampus and amygdala volumes, for early diagnosis. Here we aim at assessing the diagnostic accuracy of QyScore® medial temporal lobe atrophy markers in distinguishing AD dementia and Mild Cognitive Impairment (MCI) individuals from healthy controls (HC) in US and EU cohorts.

Method

3DT1 images were selected from different cohorts (ADNI, MEMORA, NACC, OASIS3) and analyzed using the QyScore® automatic segmentation pipeline. Brain volumes of the hippocampus and the amygdala were normalized to the total intracranial volume. Analyses of variance were performed to compare volumetric measurements among clinical groups. Areas under the curve were calculated to identify the diagnostic accuracy of QyScore® markers in discriminating AD and MCI from HC.

Result

The sample was composed of 425 AD, 909 MCI and 993 HC with a higher prevalence of men and Apoe Ɛ4 carriers in each group. Analysis of variance showed a significant difference in hippocampal and amygdala volumes among groups. Preliminary results on the area under the curve (AUC) showed a good diagnostic accuracy in discriminating AD vs HC and MCI versus HC both for the hippocampal volumes (ADvsHC: AUC=0.86, 95%CI: 0.832‐0.877; MCIvsHC: AUC =0.75, 95%Ci: 0.726‐0.770), and the amygdala volumes (ADvsHC: AUC =0.77, 95%CI: 0.737‐0.791; MCIvsHC: AUC =0.70,95%CI 95%: 0.675‐0.720).

Conclusion

Our results highlight the good diagnostic performance of QyScore® markers, and support the relevance of implementing these markers in the diagnostic workflow of AD patients.
Metabolic syndrome impact on cognitive composites domain scores and on white matter hyperintensities in subjective cognitive decline: The FACEHBI Cohort
Authors: Ortega Gemma , Espinosa Ana , Alegret Montserrat , Monté‐Rubio Gemma , Sotolongo‐Grau Oscar , Sanabria Angela , Tartari Juan Pablo , Rodriguez‐Gomez Octavio , Marquié Marta , Vivas Assumpta , Gómez‐Chiari M , Alarcón‐Martín Emilio , Pérez‐Cordón Alba , Roberto Natalia , Hernandez Isabel , Rosende‐Roca Maitee , Vargas Liliana , Mauleon Ana , Abdelnour Carla , Antonio Ester Esteban‐De , López‐Cuevas Rogelio , Alonso‐Lana S , Moreno‐Grau Sonia , de Rojas Itziar , Orellana Adelina , Montrreal Laura , Tarraga Lluis , Ruiz Agustin , Boada Mercè , Valero Sergi
Published: December 2021

Background

To explore the impact of Metabolic Syndrome (MetS) and its components on Cognitive Composites (CCs) domain scores and on White Matter Hyperintensities (WMHs) in individuals experiencing Subjective Cognitive Decline (SCD).

Method

Two hundred participants from the FACEHBI cohort underwent structural Magnetic Resonance Imaging (MRI), 18F‐Florbetaben Positron Emission Tomography (FBB‐PET), and a comprehensive neuropsychological assessment. MetS was defined using the Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention criteria (elevated fasting glucose, elevated blood pressure, reduced HDL‐C, elevated triglycerides and elevated waist circumference). WMHs were addressed through the Fazekas scale, the Age‐related white matter changes (ARWMC) scale, and the FreeSurfer pipeline. Ten CCs domain scores were created using principal components analysis (PCA): (1) executive function fluency, (2) executive function processing speed, (3) executive function attention, (4) verbal memory, (5) visual memory, (6) face–name associative memory, (7) face–occupation associative memory, (8) language, (9) visuoperception, and (10) praxis. Age, sex, education, and Apolipoprotein E (APOE) were used as adjusting variables. Several analyses were performed to explore a sex effect.

Result

Forty‐seven individuals matched the MetS criteria. This syndrome behaves differently based on sex. Only women with MetS showed better performance in language (p = .002; OR = 2.12) than those without MetS. The only differentiating component between both groups (presence/absence MetS) was that women in the MetS subgroup presented greater abdominal obesity (Mann‐Whitney p = .001). From Mets group, antihypertensive drug treatment was significantly associated with better praxis scores (p = .012; OR = 1.84) and HDL‐C drug treatment with better language scores but worse episodic memory performance (p = .028; OR = 1.60; and p = .007; OR = .57, respectively). Drug treatment for elevated glucose was associated with low WMH load in the ARWMC scale (β= ‐.144; p = .045).

Conclusion

This study demonstrated a protective effect of MetS in cognitive performance among SCD women with greater abdominal obesity and a lack of association between MetS and WMH load, although further investigation is needed to explore the long term impact of its entity.
A panel of novel astrocytic and synaptic biomarkers in serum and CSF for the differential diagnosis of frontotemporal dementia
Authors: Bolsewig Katharina , Hok‐A‐Hin Yanaika S. , Sepe Federica Nicoletta , Boonkamp Lynn , Jacobs Dirk , Bellomo Giovanni , Paoletti Federico Paolini , Vanmechelen Eugeen , Teunissen Charlotte E. , Parnetti Lucilla , Willemse Eline A.J.
Published: December 2021

Background

Frontotemporal dementia (FTD) is the second most common form of presenile dementia. The differential diagnosis of FTD is still a challenging task due to its symptomatic overlap with other neurological diseases and the lack of diagnostic biomarkers. Here, we aimed to investigate the diagnostic potential of novel biomarkers in cerebrospinal fluid (CSF) and blood.

Method

We included 137 patients from the Centre for Memory Disturbances in Perugia with a diagnosis of FTD (n=37), Alzheimer’s disease (AD, n=47), Parkinson’s Disease (PD, n=14), Dementia with Lewy bodies (DLB, n=8), and cognitively unimpaired patients with other neurological diseases as controls (OND, n=31). All had AD biomarker measurements available. Enzyme‐linked immunosorbent assay (ELISA) or single molecule array (Simoa) were used to quantify the biomarker levels of NPTX2, NPTXR, NfL and GFAP in CSF, as well as NfL and GFAP in serum. Statistical analyses were performed using age and sex corrected analysis of covariance (ANCOVA), generalized linear mixed models (GLMM), ROC analyses, and Spearman correlation coefficients (ρ).

Result

Differences in protein levels across diagnostic groups were found for NPTX2, NPTXR, NfL (serum and CSF), and GFAP (serum and CSF, figure 1). GLMM predicted NPTX2 and total tau (t‐tau) to best distinguish FTD from OND (p<0.002), while serum GFAP and t‐tau best distinguished FTD from AD (p<0.05). A combined panel of NPTX2, serum GFAP and t‐tau differentiated FTD from the other groups with good accuracy (table 1). Serum GFAP and NPTX2 correlated negatively in FTD (ρ =‐0.40, p<0.05) and AD (ρ=‐0.31, p<0.05), but positively in DLB (ρ =0.87, p<0.01), while no significant correlation was found in OND and PD (figure 2).

Conclusion

We show the potential use of a novel biomarker panel including CSF t‐tau, CSF NPTX2 and serum GFAP, for differential diagnosis of FTD from other dementias. The included biomarkers reflect different neurological pathways, i.e. neurodegeneration, synaptic and astrocytic function, respectively. This suggests a unique interplay of these pathways in FTD and demonstrates the added value of the novel biomarkers to the established classical AD biomarkers. To assess the diagnostic potential of this novel panel, validation in a larger cohort should be performed.
Altered music processing phenotypes in patients with frontotemporal dementia
Authors: van 't Hooft Jochum J. , Fieldhouse Jay L.P. , Singleton Ellen H. , Jaschke Artur C. , Warren Jason D. , Tijms Betty M. , Pijnenburg Yolande A.L.
Published: December 2021

Background

Frontotemporal dementia (FTD) can present with changes in music appreciation. The aim of the present study was to determine the prevalence and nature of music appreciation phenotypes among FTD syndromes in a memory clinic population.

Method

Forty‐seven FTD patients (44.7% female, mean age 65.0±8.4, 31 behavioral variant FTD (bvFTD), 10 semantic dementia (SD), 6 progressive nonfluent aphasia (PNFA)) who consecutively visited our memory clinic were included in this study. Forty‐six caregivers (54.3% female, mean age 61.8±9.2) were included as a control group. Based on reported musical changes in the literature, we developed an informant‐based questionnaire by extending a previously used questionnaire (Fletcher et al., 2015). Music‐emotion recognition was assessed with a live music test in which both participants and caregivers were played 9 guitar chords, and rated if these were major, minor or dissonant (i.e. happy, sad or disharmonic). Visual emotion recognition was examined with the Ekman 60 faces test in a subgroup of patients (n= 23). Non‐parametric tests were used for group comparisons.

Result

Music appreciation phenotypes were observed in 79% of the FTD patients. Musicophilia was most often present (in 12/47 patients, 26%), followed by music anhedonia (23%), change of music taste (21%), increased singing (21%), sound‐aversion (19%), music‐aversion (13%), music agnosia (9%) and increased dancing (5%). Musicophilia was present in a third of bvFTD patients, but only in 10% of the semantic dementia and none of PNFA patients. The other reported music changes were more evenly distributed. The presence of music changes was not associated with lower performance on the music emotion recognition task (p = 0.62) or visual emotion recognition task (p = 0.87). However, compared to controls, bvFTD performed worse on the music emotion recognition task (p< .003), SD performed worse at trend level (p = .06) and no differences were found with PNFA (p = .8) patients (figure 1).

Conclusion

Music appreciation phenotypes are highly prevalent in the FTD population, consist of a variety of symptoms, differ between syndromes and do not do not correlate with emotion recognizing capacities. Furthermore, compared to controls, bvFTD performed worse on a music emotion recognition test.
A comparison between tau and amyloid‐b cerebrospinal fluid biomarkers in chronic traumatic encephalopathy and Alzheimer disease
Authors: Turk Katherine W. , Geada Alexandra W. , Alvarez Victor E. , Xia Weiming , Cherry Jonathan D. , Huber Bertrand R. , Mez Jesse , Alosco Michael L. , Meng Gaoyuan , Nicks Raymond W. , Tripodis Yorghos , Budson Andrew , Dwyer Brigid , Kowall Neil W. , Cantu Robert , Goldstein Lee E. , Katz Douglas I. , Stern Robert A. , McKee Ann C. , Stein Thor D.
Published: December 2021

Background

Cerebrospinal fluid (CSF) tau and beta‐amyloid levels in chronic traumatic encephalopathy (CTE), a disease which can be clinically indistinguishable from Alzheimer’s disease (AD), are largely unknown. We examined postmortem CSF analytes among participants with autopsy confirmed CTE and AD.

Method

A total of 192 participants from the Boston University AD Center and VA‐BU‐CLF Center had post‐mortem CSF collected at autopsy. Participants were divided into pathological groups based on consensus AD and CTE criteria, resulting in 61 participants with CTE (18 low, 43 high stage), 79 participants with AD (23 low, 56 intermediate to high pathological change), 11 participants with concurrent CTE and AD, and 41 participants lacking both CTE and AD neuropathology. The Meso Scale Discovery immunoassay system was utilized to measure amyloid‐beta (Ab1‐40, Ab1‐42), total tau (t‐tau), and phosphorylated tau (p‐tau181 and p‐tau231).

Result

The low CTE group had higher levels of p‐tau231 compared no CTE/no AD (p=0.041), and compared to the low AD group (p=0.018). The low CTE group had lower levels of Aβ1‐42 compared to no CTE/no AD (p=0.016). The high CTE group had higher levels of p‐tau231 compared to AD (p=0.025) and lower levels of Aβ1‐42 compared to the AD group (p=0.015). Importantly, p‐tau231 and Aβ1‐42 were predictors of diagnosis of CTE vs. no CTE/no AD and CTE vs. AD (Figure 1).

Conclusion

Increased CSF p‐tau231 is a promising potentially sensitive biomarkers of CTE and decreased CSF Aβ1‐42 in CTE warrants further investigation as to underlying mechanism and potential as an additional CTE biomarker.
Predicting institutionalization and mortality across the spectrum of Alzheimer’s disease
Authors: Mank Arenda , Van Maurik Ingrid S. , Bakker Els D. , Teunissen Charlotte E. , Barkhof Frederik , Scheltens Philip , Berkhof Johannes , van der Flier Wiesje M
Published: December 2021

Background

Patients and care partners express a desire for accurate prognostic information. Previous studies predicting institutionalization and mortality focused on the dementia stage. Yet, Alzheimer’s disease (AD) is characterized by a long pre‐dementia stage. We aimed to predict institutionalization and mortality in patients across the cognitive spectrum of AD.

Method

We included n=1418 non‐demented patients with Subjective Cognitive Decline (SCD) or Mild Cognitive Impairment (MCI) (age 63±7, 38%F, Mini Mental State Examination (MMSE) 27±2) and n=1179 patients with AD dementia (age 65±7, 53%F, MMSE 20±5) from the Amsterdam Dementia Cohort. The dates of institutionalization (admission to a nursing home; follow‐up 3.4±2.7 years) and mortality (follow‐up 4.5±2.7 years) were derived from Statistics Netherlands. We constructed models, stratified by dementia status, to predict institutionalization and mortality using Cox regression. We evaluated the following determinants: MMSE, Neuropsychiatric Inventory (NPI), Charlson Comorbidity Index (CCI) and APOE e4 status, MRI (medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), white matter hyperintensities (WMH)) and CSF biomarker levels (Aβ42 and p‐tau). Determinants were selected using backward selection (p<0.10). All models included age and sex. In addition, we evaluated the discriminative performance of models without MRI and CSF biomarkers. Discriminative performance of the models was assessed with Harrell’s C statistics.

Result

In non‐demented patients, n=123 (9%) patients died and n=74 (5%) patients were institutionalized. In AD dementia, n=413 (35%) patients died and n=453 (38%) patients were institutionalized. Table 1 shows the optimal prediction models for institutionalization and mortality. Discriminative performance was better in non‐demented patients than in those in the dementia stage: institutionalization (Harrell’s C 0.81 vs 0.68) and mortality (0.78 vs 0.66). Although model fit was better for the full model, discriminative performance was comparable for the model without MRI for institutionalization and without CSF for mortality in non‐demented patients (Table 1).

Conclusion

We constructed prediction models to predict institutionalization and mortality in patients across the spectrum of AD. Highest discriminative performance was found in models for non‐demented patients with SCD or MCI. CSF biomarkers contributed most to predict institutionalization and MRI biomarkers to predict mortality.
Life activity patterns and mild cognitive impairment in older adults
Authors: Wu Chao‐Yi , Gothard Sarah , Mattek Nora , Wright Kirsten M , Kaye Jeffrey A , Dodge Hiroko H , Beattie Zachary
Published: December 2021

Background

Shifting and diminished circadian and activity rhythms characterize older adults with cognitive impairment, but studies rarely consider both temporal and spatial aspects of life activity patterns. We examined hourly in‐home and out‐of‐home activity patterns using latent group trajectory models to characterize older adults with and without mild cognitive impairment (MCI).

Method

One hundred and seven older adults (19 with MCI) living alone (age=81.1±7.8, 76.6% women) from the Oregon Center for Aging & Technology (ORCATECH) were included. MCI was determined by the Clinical Dementia Rating (CDR) score = 0.5. In‐home and out‐of‐home activities were collected via passive infrared motion sensors in each room and contact sensors on the doors to the home for one month. Daily life activity patterns were estimated based on: 1) the hourly average amount of time the participant spent in each major life space (bathroom; bedroom; kitchen; living room) and out‐of‐home, and 2) the hourly average number of trips the participant made to each room and out‐of‐home.

Result

Latent trajectory models identified two distinct patterns for three features: time spent out‐of‐home (high/low outdoor), time spent in the kitchen (high/low kitchen occupancy), and trips to the bathroom (more/fewer bathroom trips) from 5 am to 1 pm. Older adults with MCI were more likely to follow a pattern of low outdoor time (β=‐2.65; p=0.03), high kitchen occupancy (β=1.68; p=0.01), and more bathroom trips (β=1.60; p=0.02) than those with intact cognition. There were no differences in the bedroom patterns or time spent in the bathroom in older adults with and without MCI from 5 am to 1 pm. Potential covariates were controlled in the models (age, gender, years of education, sleep duration, gait speed, and the number of rooms in the house).

Conclusion

Different social and mealtime activity patterns from early morning to early afternoon may signal cognitive changes and contraction of life‐space. These may be caused by environmental, as well as chronobiological changes accompanying MCI. Unobtrusive measurement of in‐home and out‐of‐home activity patterns may be useful for integrating with chronotherapies in developing strategies to mitigate potential daily mal‐entrainment for older adults at risk for MCI and dementia.
Traumatic brain injury and age at onset of cognitive decline in corticobasal degeneration, corticobasal syndrome, and progressive supranuclear palsy
Authors: Spiegel Jonathan , Sone Je Yeong , Butler Tracy , Pirraglia Elizabeth , de Leon Mony J.
Published: December 2021

Background

Traumatic brain injury (TBI) has been repeatedly shown to be a risk factor for several neurodegenerative diseases. However, no studies have yet examined TBI as a risk factor for corticobasal degeneration (CBD) or corticobasal syndrome (CBS), and few have examined progressive supranuclear palsy (PSP) in relation to TBI.

Method

This is a retrospective observational study using the National Alzheimer’s Coordinating Centers (NACC) database. TBI status was assessed based on self‐reported history. Clinicians estimate was used for determining age at onset (AAO) of cognitive decline and autopsy examination was used for neuropathological diagnosis of CBD and PSP. The most recent assessment of participants was used as of June 2018, including participant visits which occurred between 2005 and 2018. The NACC dataset includes a total of 38,249 participants. 101 (14 TBI+) participants were included with clinical (antemortem) diagnoses of PSP and 137 (16 TBI+) with CBS. 2,743 autopsy samples were also included, including 120 (14 TBI+), 58 (7 TBI+), and 11 (1 TBI+) with neuropathological (autopsy) diagnoses of PSP, CBD, or both, respectively. 181 (21 TBI+) of the participants with autopsy diagnosed PSP or CBD had antemortem cognitive decline.

Result

TBI is associated with a significant 4‐year earlier AAO of cognitive decline among participants with an antemortem diagnosis of CBS and a 6‐year earlier AAO in participants with autopsy diagnosed PSP. Additionally, TBI among participants with autopsy diagnosed CBD without concomitant Alzheimer’s disease (AD) neuropathology was associated with a 7‐year earlier AAO of cognitive decline (p=.066). History of TBI was not significantly associated with the prevalence of PSP and/or CBD pathology postmortem.

Conclusion

This is the first report linking TBI with an earlier onset of cognitive decline in CBS and in neuropathologically defined PSP.
Life satisfaction is associated with the relationship between mild cognitive impairment and the incidence of disability
Authors: Katayama Osamu , Lee Sangyoon , Bae Seongryu , Makino Keitaro , Chiba Ippei , Harada Kenji , Shinkai Yohei , Shimada Hiroyuki
Published: December 2021

Background

Life satisfaction has been shown to be lower in older adults with a higher risk for dementia. For many years, dementia has been the highest factor in the incidence of disability among older Japanese adults. The relationship between the incidence of disability and cognitive status has already been clarified, but whether life satisfaction is related to this relationship has not yet been clarified. Therefore, the purpose of this study was to clarify whether life satisfaction is related to the relationship between incidence of disability and cognitive status.

Method

Participants comprised 2798 older adults (1579 women; mean age: 73.0 years, SD = 5.9, range 65–96 years) from the National Center for Geriatrics and Gerontology–Study of Geriatric Syndromes. Baseline measurements, including cognitive status (NC, normal cognition; MCI, mild cognitive impairment; GCI, global cognitive impairment), life satisfaction, and demographic characteristics. Life satisfaction was measured using the life satisfaction scale (LSS), ranging from 13 to 52. LSS was stratified into three levels based on the score: lowest, moderate, and highest. Associations between disability incidence and cognitive status were examined for each group according to life satisfaction; monthly assessment for disability was monitored through long‐term care insurance certification for at least 2 years.

Result

During a mean follow‐up of 35.3 months (SD = 6.0), 193 participants developed a disability. The potential confounding factors adjusted hazard ratios (refer to NC) for incidence of disability in the group with the lowest life satisfaction were 1.83 (CI, 1.03 to 3.26; P = 0.040) and 1.73 (CI, 0.70 to 4.33; P = 0.238) for MCI and GCI, respectively. Similarly, in the group with moderate life satisfaction, MCI and GCI were 2.00 (CI, 1.01 to 3.94; P = 0.046) and 1.90 (CI, 0.57 to 6.28; P = 0.291), respectively. On the other hand, in the group with the highest life satisfaction, MCI and GCI were 1.41 (CI, 0.79 to 2.51; P = 0.245) and 0.96 (CI, 0.36 to 2.55; P = 0.937), respectively.

Conclusion

MCI was associated with disability incidence, and the effect was more pronounced among older adults who had lower life satisfaction.
Effect of physical environment on person‐centred dementia care in a long‐term care facility: Focus group interviews with staff
Authors: Lee Sook Young , Hung Lillian , Chaudhury Habib
Published: December 2021

Background

According to the spread of the person‐centred care approaches, the physical environment has been acknowledged as an important component of a dementia care facility. This study demonstrated that staff experiences and opinions of the physical environment in supporting their care practices for residents living with dementia in long‐term care facilities in Canada and Sweden. Focus group interviews were used with 24 staff members. Semi‐open questions were asked about the role of physical environment on care practice, job satisfaction, and interaction with residents. Data were analyzed by thematic analysis. This study yield three environmental themes: i) design atmosphere, ii) space arrangements, and iii) sensory stimuli. The findings demonstrate that well‐designed environment factors such as homelikeness, an open space plan and stimulating outdoor, positively encourage the emotion of staff as well as residents, which leads to build trust and relationship and to increase job satisfaction. This study highlights the complexities of how care was influenced by the physical environment of the care setting.
Development of D‐enantiomeric peptides as tau aggregation inhibitors directed against the hexapeptide motif PHF6* of tau
Authors: Funke Susanne Aileen , Malhis Marwa , Kaniyappan Senthilvelrajan , Aillaud Isabelle , Chandupatla Ram Reddy , Horn Anselm H.C. , Mandelkow Eckhard , Sticht Heinrich
Published: December 2021

Background

Two hexapeptide motifs within Tau, designated PHF6* (275VQIINK280) and PHF6 (306VQIVYK311), are known to drive Tau aggregation, making them attractive targets for the development of Tau aggregation inhibitors for therapeutic options.

Method

Employing mirror‐image phage display with a large peptide library, we have identified PHF6* fibril binding peptides consisting of D‐enantiomeric amino acids. D‐enantiomeric peptides are extremely protease stable and considerably less immunogenic than L‐peptides, and the suitability of D‐peptides for therapeutic purposes has already been demonstrated. The most promising D‐peptide and its ability to inhibit Tau aggregation was investigated using various biochemical and biophysical methods, and compared to the performance of PHF6‐ or other PHF6*‐binding peptides selected earlier by our and other groups.

Result

MMD3 and MMD3rev inhibited PHF6*, TauRDΔK280 and full‐length Tau fibrillization in vitro. Our data demonstrated that the peptides prevent the formation of Tau ß‐sheet‐rich fibrils by formation of large amorphous aggregates. The binding mode of MMD3 and MMD3rev to PHF6* fibrils was investigated by in silico modeling.

Conclusion

Our peptides were able to penetrate cells and might be interesting for therapeutic and diagnostic applications in AD research.
Multimorbidity and the risk of incident dementia in UK Biobank
Authors: Calvin Catherine M , Littlejohns Thomas J , Kuzma Elzbieta
Published: December 2021

Background

There is strong evidence that certain individual conditions, such as diabetes, hypertension and stroke, increase the risk of dementia. However, there is limited longitudinal research investigating the role of multimorbidity as a risk factor for developing dementia.

Method

Participants were selected from UK Biobank, a population‐based cohort of half a million women and men aged between 40‐73 years at recruitment. Between 2006‐2010, participants completed a range of assessments at baseline, which included self‐reporting pre‐existing health conditions during a nurse‐led verbal interview. This was used to determine multimorbidity, defined as having two or more, out of a possible 42, chronic physical and mental health conditions used in recent large‐scale epidemiology studies to establish multimorbidity. Incident all‐cause dementia was ascertained using cohort‐wide hospital inpatient and death records collected up to 2020.

Result

After excluding participants less than 60 years old at baseline (n=285,016), those with prevalent dementia (n=230), and those with missing covariate data (n=10,350) a total of 206,974 participants remained, of whom, 89,210 (43.1%) had multimorbidity. The five most common individual conditions in the analytic sample were hypertension (36.2%), pain (21.5%), cancer (10.7%), asthma (10.7%) and dyspepsia (10.1%). Over 2.28 million person years of follow‐up (mean = 11.0, standard deviation = 1.96), 4,813 participants developed dementia. In Cox proportional‐hazards models adjusted for age, sex, ethnicity, education, socioeconomic status and APOE‐e4, multimorbidity was associated with a 70% increased risk of developing dementia (Hazard Ratio [HR] = 1.70, 95% Confidence Interval [CI] 1.60‐1.80), compared to ≤1 conditions. The association remained consistent when restricting to incident dementia diagnosed after 3, 6 and 9 years respectively. There was evidence of a dose‐response effect, with HRs of 1.44 (95% CI 1.34‐1.55), 1.68 (95% CI 1.55‐1.82), 2.33 (95% CI 2.10‐2.59), 2.80 (95% CI 2.41‐3.24) and 3.43 (95% CI 2.84‐4.15) observed for 2, 3, 4, 5 and ≥6 conditions, respectively, compared to ≤1 conditions.

Conclusion

In a population of more than 200,000 older adults, multimorbidity was strongly associated with an increased risk of incident dementia. Further research investigating which particular combinations of conditions contribute to dementia risk is warranted.
Heparan sulfate: In vitro and in vivo proof of efficacy of this new therapeutic strategy for halting Alzheimer disease‐related tauopathy development
Authors: Maïza Auriane , Douaron Gael Le , Soria Aida Muntsant , Li Yong , Ramakrishnan Kithika , Ouidja Mohand Ouidir , Fifre Alexandre , Chantepie‐Laborde Sandrine , Jospin Estelle , Laffray Xavier , Ramos Ivan , Fernig David , Llort Lydia Gimenez , Papy‐Garcia Dulce , Team ArrestAD Consortium
Published: December 2021

Background

Deposition of amyloid plaques and neurofibrillary tangles composed of abnormally phosphorylated tau are the neuropathological hallmarks of Alzheimer's disease (AD). However, years before the accumulation of protein aggregates, the abnormal intraneuronal accumulation of heparan sulfates (HS) is observed. This phenomenon breaks a dogma, since HS are classically located on the cell surface and in the extracellular matrix, leading to a new cell autonomous concept in tauopathy, which is the conceptual core of the FET‐OPEN ArrestAD 737390 project. Previously, we provide evidence that inside the cell, HS act as molecular chaperones inducing in Tau conformational changes favoring its abnormal phosphorylation and aggregation (Sepulveda‐Diaz JE. Brain 2015, 138(Pt 5):1339‐54). Thus, molecules able to act on heparan sulfate pathway could represent a new class of compounds for the treatment of AD‐related tauopathies.

Method

PAPS is the universal sulfate donor involved in HS biosynthesis and structurally related to ATP. Thus, we first screened kinase inhibitor libraries in a sulfotransferase enzymatic assay (Byrne et al., Biochem. J. 2018; 475:2417‐2433). This strategy, in addition to a HS mimetic, were evaluated for their ability to prevent tauopathy in cells. The best molecules were then evaluated in two transgenic mice model of AD. Thereafter, proof‐of‐concept of the efficacy of compounds selected with this strategy, as well as HS mimetic (Barritault D. Glycoconj J. 2017; 34(3):325‐338) for halting AD‐related tauopathies development was assessed first in vitro and then in vivo.

Results

The screening of libraries allowed the identification of 3 hit compounds that, in addition to a HS mimetic, were evaluated for their ability to prevent tauopathy in cells. Two molecules, one HSSTs inhibitor and one heparan sulfate mimetic, were able to reduce tauopathy in cells and in 3xTg‐AD and rTg4510 mouse models of tauopathy. In the in vivo assessment in males and females 3xTg‐AD, the behavioral dose‐response of these molecules on the cognitive, neuropsychiatric‐like and motor AD‐phenotypes was determined.

Conclusion

Our results support the FET‐OPEN RIA ArrestAD cell autonomous hypothesis of tauopathy based in altered heparan sulfate biology and place HS and their biosynthetic enzymes as a potential therapeutic target for AD.
Incident stroke in patients with Alzheimer’s disease: A meta‐analysis
Authors: Pinho João , Miguel Quintas‐Neves , Imis Dogan , Reetz Kathrin , Reich Arno , Costa Ana Sofia
Published: December 2021

Background

We aimed to describe the risk of stroke in patients with Alzheimer´s disease (AD) and to compare it with matched controls without AD.

Method

We conducted a systematic review of all studies reporting incident stroke in AD patients according to the PRISMA guidelines. We included studies which: 1) reported ≥50 patients with a diagnosis of AD; 2) reported a retrospective or prospective follow‐up period; 3) specifically reported the occurrence of ischemic stroke and/or non‐traumatic ICH and/or stroke (all types) during the follow‐up period. We assessed the quality of studies using the Quality Assessment Tool for Observational Cohort and Cross‐Sectional Studies provided by the National Heart, Lung and Blood Institute. Using random effects meta‐analyses, we pooled the incidence rates and incidence rate ratios (IRR) of ischemic stroke, intracerebral hemorrhage (ICH) and stroke (all types) in AD patients.

Result

Twenty‐nine (29) articles reporting incident ischemic stroke and/or incident ICH and/or incident stroke (all types) in patients with AD and were included in the meta‐analyses. The majority of studies was judged to have a fair quality. In patients with AD the incidence rates were 13.0 per 1000 person‐years for ischemic stroke, 3.4 per 1000 person‐years for ICH and 15.4 per 1000 person years for stroke (all types). When compared to matched controls without AD, incidence rate for ICH in AD patients was significantly higher (IRR 1.67, 95%CI 1.43‐1.96), but similar for ischemic stroke. Significant study heterogeneity was found in the meta‐analyses of incidence rates of ischemic stroke and stroke (all types) and moderate for studies reporting ICH.

Conclusion

Incident stroke is not a rare event in AD population. AD is associated with an increased risk of ICH which warrants further clarification. The significant risk of bias and heterogeneity among the studies, as well as the lack of information on possible confounding variables, does warrant the need for better quality studies on the overlap of the two neurological disorders with the highest disease burden worldwide.
Network analysis for studying the dynamics of affective symptoms and treatment adherence in APOE‐ɛ4 carriers with subjective cognitive decline following a multimodal intervention: Preliminary findings from the PENSA Study
Authors: Soldevila‐Domenech Natalia , Forcano Laura , Boronat Anna , Lorenzo Thais , Piera Iris , Puig‐Pijoan Albert , Knezevic Iva , Fauria Karine , Molinuevo Jose Luis , de la Torre Rafael
Published: December 2021

Background

The co‐occurrence of subjective cognitive decline (SCD) and anxiety critically increases the risk of developing mild cognitive impairment and dementia. Understanding the influence of life style changes on affective symptoms in individuals with SCD can help implementing successful multimodal interventions that benefit both cognitive and mental health. We studied the interaction between affective symptoms and treatment adherence over time in individuals meeting SCD‐Plus criteria and being APOE‐ ɛ4 carriers that were following a multimodal intervention in the framework of the PENSA Study.

Method

We report preliminary analyses of intensive longitudinal data (ILD) weekly collected for 20 weeks in 11 participants (Figure 1). Ecological momentary assessments (EMAs) were used to evaluate anxiety, depression, mood, Mediterranean diet (MedDiet) adherence and participation in social activities. Physical activity and sleep were measured with an activity tracker. Multilevel vector autoregressive models were used to obtain the full set of interactions.

Result

The mean response rate for EMAs was 89.6% (min‐max 80‐100%). There were within‐person temporal relationships between several variables as shown in Figure 2. Physical activity had a positive forward influence on sleep (β=0.32, P=0.016). In turn, higher hours of sleep predicted higher adherence to the MedDiet (β=0.28, P=0.034) and lower anxiety levels (β=‐0.302, P=0.005). Also, higher anxiety predicted negative mood states (β=‐0.12, P=0.012) and lower number of social activities (β=‐0.27, P=0.013), being such relationship bidirectional (β=‐0.19, P=0.005). Finally, the between‐person network (Figure 3) indicated that some variables co‐varied across persons. Individuals with high average minutes of physical activity tended to be more socially active (r=0.36) and those more socially active presented lower anxiety and depression symptoms (r=‐0.24). Finally, those that slept more hours presented more positive mood states (r=0.67).

Conclusion

These preliminary findings suggest that social life, quality of sleep and physical activity could be critical to improve affective symptoms. Our findings also support the feasibility and value of ILD collection to better understand the effect of life style changes on cognitive and mental health at the individual and population levels. Finally, monitoring the mental health in ongoing clinical trials is important to understand the impact of the COVID‐19 pandemic on study outcomes.
Psychiatric misdiagnosis in behavioral variant frontotemporal dementia in Cali, Colombia
Authors: Zapata‐Restrepo Lina Maria , Possin Kate , Rivas Juan Carlos , Miranda Carlos , Miller Bruce L. , Allen Isabel Elaine
Published: December 2021

Background

Psychiatric manifestations are common in the behavioral variant of frontotemporal dementia (bvFTD) with many patients misclassified with other psychiatric diagnoses. In this study, we described the initial neuropsychiatric symptoms and the psychiatric misdiagnoses in a diverse population of patients with probable bvFTD seen at a psychiatric public hospital in Colombia.

Methods

We retrospectively reviewed the medical records of 28 patients who met diagnostic criteria for probable bvFTD based on a multidisciplinary evaluation. Neuropsychiatric symptoms were rated using the NPI. Initial psychiatric diagnoses were made using the DSM‐V. The bvFTD diagnostic criteria of the international consortium were used. Stata 16.1 and SPSS 27.0 were used for the statistical analysis.

Results

Using the NPI, we found that the most common symptoms were apathy in both genders. Delusions were present in 60.7% and hallucinations in 39.2% of the sample. 71.4% of the patients were misdiagnosed with psychiatric disease and not with dementia. In women, the most frequent psychiatric diagnoses were depression (26.3%), and bipolar disorder (26.3%), while in men it was anxiety disorders (33.3%) and psychotic disorders (22.2%).

Conclusion

Psychotic symptoms were higher in this sample than in previous studies. The presence of psychiatric symptoms and their possible overlap in patients with bvFTD make differential diagnosis difficult. The misdiagnosis could be related to factors such as a lack of knowledge about this type of dementia in the medical community. In the future, the implementation of specific biomarkers and genetic testing will help to improve the diagnosis of bvFTD.
Late‐stage dementia is associated with decreased likelihood of successful discharge to community after home health care
Authors: Knox Sara , Downer Brian , Haas Allen , Ottenbacher Kenneth J
Published: December 2021

Background

Several studies have established the efficacy of home health in meeting the health care needs of people with Alzheimer’s disease and related dementias (ADRD) and in assisting them to remain in their homes, which is a key goal for the majority of older adults. However, transitioning to the community after discharge from home health poses significant challenges to patient safety and quality of care. For individuals with ADRD, these challenges are compounded by cognitive limitations and behavioral and psychological symptoms inherent to their disease. The likelihood of a person with ADRD successfully discharging to the community may depend on the severity of their dementia. The purpose of this study was to examine the association between ADRD severity and successful discharge to community (DTC) after home health.

Method

This retrospective study derived data from 100% national CMS data files from October 1, 2016 through September 30, 2017. A cohort of 140,616 Medicare beneficiaries with ADRD who received home health was identified. Successful DTC rates with associated 95% confidence intervals (CIs) were calculated for each patient characteristic. Multilevel logistic regression was used to estimate the relative risk (RR) of successful DTC after home health, by dementia severity level, adjusted for patient and clinical characteristics.

Result

Overall, 72.5% of individuals had a successful DTC. Individuals in the first 5 stages of the dementia categorization scale had successful DTC rates greater than the cohort average (75.3%‐ 80.3%). Individuals in the 6th dementia categorization stage (69.2%) had successful DTC rates 3% less than the cohort average and individuals in the 7th dementia categorization stage had successful DTC rates almost 20% lower (55.9%) than the cohort average. Individuals in the 6th and 7th dementia severity categories had significantly lower risk of successful DTC (RR=0.67, 95% CI=0.65‐0.69 and RR= 0.42, 95% CI= 0.38‐ 0.46) than those in the lowest dementia severity category.

Conclusion

Most older adults with ADRD had a successful DTC following home health, but the likelihood for successful DTC decreased considerably with greater ADRD severity. Strategies for increasing the likelihood for successful DTC following home health among older adults with ADRD need to consider disease severity.
What happens to the worried well? Follow‐up of subjective cognitive impairment
Authors: Sutherland Maggie , Kirk Andrew , Karunanayake Chandima P , O'Connell Megan E , Morgan Debra G
Published: December 2021

Background

Perceived neurocognitive decline is becoming a more common concern, leading to an increased number of referrals to specialists for further investigation and increased stress and anxiety for patients. Subjective cognitive impairment (SCI) refers to the condition of having concerns about one’s memory but performing within the expected range on neurocognitive tests. People with SCI can also be referred to as the “worried well”. We aimed to explore how likely the “worried well” are to experience neurocognitive decline and develop a neurologic diagnosis.

Method

166 consecutive “worried well” patients who attended the Rural and Remote Memory Clinic (RRMC) in Saskatchewan, Canada between 2004 and 2019 were included. Demographic, health, social, and behavioural factors were recorded at the initial visit. Mini Mental Status Examination (MMSE) score, Center for Epidemiologic Studies Depression Scale (CESD) score, and Functional Assessment Questionnaire (FAQ) scores were measured and compared at initial assessment and at 1‐year follow‐up. MMSE scores overtime were assessed with a mean follow‐up of 2.95 years (SD 2.87). Case summaries were used to build the profile of 9 cases, which have been followed longer than one year and developed a neurologic diagnosis.

Result

There was no statistically significant difference in MMSE, CESD, or FAQ scores between clinic day and one‐year follow‐up, and no consistent pattern of MMSE score over time. Of the 166 patients with SCI on initial assessment, 5 were later diagnosed with AD at 8.5, 3.5, 5, 3, and 1.75 years; 2 were diagnosed with MCI at 1 and 2 years; 1 was diagnosed with vascular cognitive impairment at 5 years; and 1 was diagnosed with frontotemporal dementia (FTD) at 0.5 years.

Conclusion

There is no pattern of neurologic decline observed in the “worried well”. Though the likelihood of a patient with SCI developing a neurological diagnosis is reassuringly low, (9/166), it is not irrelevant. The chance of an underlying neurological problem and subsequent neurologic diagnosis, along with the benefits of early diagnosis and treatment for dementia, leads us to believe that patients with SCI should still be seen in follow‐up at least at the one‐year mark.
Association of blood cell parameters of peripheral inflammation with cognitive function
Authors: Fang Yuan , Lunetta Kathryn L. , Mez Jesse , Satizabal Claudia L. , Alosco Michael L. , Qiu Wendy , Doyle Margaret F. , Murabito Joanne M.
Published: December 2021

Background

Chronic peripheral inflammation is associated with cognitive decline and increased risk of dementia. Easily measured circulating blood cell parameters, including the neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), and mean platelet volume (MPV), reflect peripheral inflammation. We sought to investigate the cross‐sectional association between these measures and neuropsychological (NP) test performance in the Framingham Heart Study (FHS) Offspring, Third‐generation, and Omni cohorts.

Method

We identified FHS participants who attended an exam that included a complete blood cell count sample and underwent NP testing within five years of blood draw. Linear mixed effect models were used to investigate the association between the blood cell parameters (NLR, RDW, MPV) and individual NP test scores adjusting for age, sex, education, cohort, time between blood draw and NP testing, prevalent cardiovascular disease, APOE‐ε4 genotype, and C‐reactive protein, and accounting for familial correlation using a random effect. We additionally tested for interactions between age (≥ 60 years vs. < 60 years) and blood cell parameters on NP scores and associations were reported separately by age group when significant (P for interaction ≤ 0.01).

Result

Among the 3531 participants (mean age 60.3 years, range 25 to 97 years, 47% male), 80% had at least some college and 22% were APOE‐ε4 carriers. We observed significant association between higher NLR and poorer NP performance on visual reproductions – delayed recall, Trails B ‐ Trails A, and Hooper visual organization test, that assess visual memory, executive function, and visuospatial abilities respectively (Table). There was also a significant association between higher RDW and poorer performance on digit symbol test assessing executive function. We observed different effects for the two age groups for the association between RDW and a metric of executive function (i.e., Trails B ‐ Trails A), where higher RDW correlated with decreased cognitive performance in participants aged ≥ 60 years (n=1865).

Conclusion

Chronic peripheral inflammation as measured by NLR and RDW associates with lower cognitive function in FHS participants ≥ 60 years. In younger individuals, chronic peripheral inflammation may have a smaller effect on cognitive function.