bluuebunny/crossref_metadata_2025 huggingface dataset:
An observational study in real world daily clinical practice to evaluate the effect of the medical food Souvenaid on instrumental activities of daily living in people with mild Alzheimer’s disease
Authors: Ziere Gijsbertus , Vanneste Vincent G. , Kalisvaart Kees , de Wilde Janneke , Boelaarts Leo , Sikkes Sietske A.M.
Published: December 2020

Background

Alzheimer’s disease (AD) coincides with a progressive decline in instrumental activities of daily living (iADL), such as cooking and everyday technology. Souvenaid is a medical food designed to enhance synapse formation and function; it contains the specific nutrient combination Fortasyn Connect. Randomized controlled trials showed beneficial effects on memory in mild AD patients and on the cognitive‐functional outcome CDR‐SB and hippocampal atrophy in prodromal AD. In this observational study we evaluated the effects of Souvenaid on iADL of people with mild AD in real‐world, daily clinical practice.

Method

Participants were recruited from specialized memory clinics and received the medical food once a day. iADL were assessed at baseline, 6 months follow‐up, and optionally at 12 months follow‐up, using the Amsterdam iADL questionnaire (A‐IADL). Changes in A‐IADL scores were compared with a reference population (n=57), using a one‐sample t‐test. Exploratory sub‐group analyses will also be presented.

Result

116 participants were enrolled in the study. Self‐reported adherence to Souvenaid was high. The 6‐month change from baseline in A‐IADL was significantly less than the dementia reference population (‐1.56 [SD 6.71] vs. ‐3.68 respectively, p=0.009). The effect was maintained in participants completing the 12‐month period with a mean change from baseline of ‐3.12 (SD 8.04) compared with the reference value of ‐7.35 (p=0.011). People using AD medication showed a mean 6‐month change from baseline of ‐1.29 [SD 5.38]. People not using AD medication showed a mean change of ‐1.65 [SD 7.14]. Participants completing the 12‐month period showed a mean change of ‐5.62 [SD 6.19] when using AD medication and ‐2.06 [SD 8.63] when not using AD medication. In individuals with baseline MMSE > median, 6‐month change from baseline was ‐1.34 [SD 5.76] and ‐1.99 [SD 7.86] in individuals when baseline MMSE < median, whereas the 12‐month changes from baseline were ‐4.24 [SD 7.32] and – 1.91 [SD 8.89], respectively.

Conclusion

People with mild AD receiving Souvenaid showed less decline in iADL over 6 and 12 months compared with a reference population. This observational study suggests that this specific medical food might have an impact on iADL in mild AD in a real‐world clinical setting.
The prevalence, associated factors, and the burden on health state utilities for dementia in Chile
Authors: Zitko Pedro , Slachevsky Andrea , Jimenez Daniel
Published: December 2020

Background

New procedures based on attributional methods have not been used to estimate the burden of Dementia in term of loss of Health‐State Utilities (HSU) or Quality‐Adjusted Life Years (QALY) at the populational level. Chile, in recent decades, has presented an accelerated aging process and has few studies on dementia.

Method

We analysed data from the Chilean National Health Survey carried out between 2016‐2017 (n=5,004). Participants older than 59 years were screened for dementia, defined by a score higher than 5 in the Pfeffer and lower than 13/19 points in a modified MMSE‐version, previously validated in Chile. HSU were measured using the health‐related quality of life instrument EQ5D plus national values for utilities for each health state. The number and fraction of total HSU lost due to dementia were calculated using attributable fraction methods. We repeated the procedure on each one of five domains of EQ5D. Factors associated with dementia were explored using a logistic regression model. Other comorbidities (depression, chronic musculoskeletal pain, hypertension, diabetes) were included in the models.

Result

We estimated a prevalence of 4.4% [2.9‐5.9] for dementia in people older than 59 years. Dementia, compared with other comorbidities, showed the highest loss of HSU, accounting 38.3 [26.0‐50.6] additional points of loss of HSU over the score from those without dementia (where 0 means healthy, and 100 is equivalent to death). Prevalent cases of dementia were associated with a loss of 41,046 QALYs [29,727 – 52,158], which was equivalent to a 5.0% [3.0‐7.6] of total burden among elderlies, and 1.5% [0.9‐2.4] in the population older than 14 years. ‘Self‐care’ was the domain were dementia accounted higher burden followed by ‘usual activities’ (see figure). Age was associated with dementia, while male sex, lower education, widower compared with married, and some comorbidities showed high OR but without reaching statistical significance.

Conclusion

Dementia at the population level showed a high impact in terms of QALY lost, as well as at the individual level in terms of loss of HUS, overpassing to other diseases. Key domains of quality of life affected higher for Dementia were self‐care and usual activities. FONDAP Program Grant 15150012.
Sniffin' Sticks Screening 12 Test can assist in the clinical distinction between psychiatric disorders and neurological/neurodegenerative disorders
Authors: Pachi Ioanna , Evans Andrew H , Loi Samantha M , Eratne Dhamidhu , Malpas Charles B , Walterfang Mark , Farrand Sarah , Kelso Wendy , Velakoulis Dennis
Published: December 2020

Background

Distinguishing primary psychiatric disorders (PPD) from neurological/neurodegenerative disorders (NND) is a common diagnostic dilemma in clinical practice. Numerous studies have focused on whether cognitive, neuroimaging or blood/ cerebrospinal fluid (CSF) are of assistance in this clinical scenario. Olfactory impairment has not however been systematically examined as a clinical tool for this purpose. The aim of this study was to identify whether performance in olfactory identification can distinguish NND and PPD.

Method

This was a cross‐sectional retrospective study of inpatients assessed in Neuropsychiatry, Royal Melbourne Hospital (RMH) over the period 2015‐2019. Neuropsychiatry is a tertiary / quaternary service which provides diagnostic work up for patients with cognitive, psychiatric and neurological symptoms. Data extracted from the admission records included: demographics, tobacco use, medical comorbidities, cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), and odour identification assessed using the Sniffin’ Sticks Screening 12 Test (SS12). The final discharge diagnosis for all patients was informed by established diagnostic criteria.

Result

121 patients were identified who had valid Sniffin Stick testing over this period. 88 patients (72.7%) were diagnosed with NND (mean age‐ 60, including Alzheimer’s dementia, frontotemporal dementia, Lewy body parkinsonian‐related dementias [Parkinson’s disease, Multiple Systematic Atrophy, Dementia with Lewy bodies] and other neurological causes of dementia), 33 patients (27.3%) were diagnosed with PPD (mean age=57 years, including mood and psychotic disorders). Patients who scored ≤8 in SS12 were more likely to have NND than PPD, even after adjustment for age, gender and tobacco use [(p=0.005, unadjusted OR=3.51, 95% CI=1.463,8.410), (p=0.009, adjusted OR=3.848, 95% CI=1.395,10.617)]. Receiver Operating Curve (ROC) analyses demonstrated that a score of ≤8 differentiated NND from PSY with sensitivity of 56.8% and specificity of 72.7% (ROC area under the curve of 0.672, p=0.004).

Conclusion

Patients presenting with diagnostically complex neurocognitive / neuropsychiatric difficulties who score 8 or less on Sniffin’ Sticks are more likely to have a neurodegenerative illness. A cut‐off score of 8 is potentially a “red‐flag” for clinicians faced with the diagnostic question of PPD versus NND.
The possible role of Optical Coherence Tomography (OCT) and OCT‐Angiography (OCTA) as new non‐invasive biomarkers of prodromal Alzheimer’s disease
Authors: Biscetti Leonardo , Luchetti Elisa , Menduno Paola Santina , Lupidi Marco , Eusebi Paolo , Chipi Elena , Lisetti Viviana , Cataldi Samuela , Cagini Carlo , Parnetti Lucilla
Published: December 2020

Background

Several papers support the existence of a possible link between reduced retinal thickness and Alzheimer’s disease (AD) [1]. Other explorative studies based on retinal oximetry and Doppler flowmetry suggest an alteration of retinal perfusion in AD [2, 3]. Nowadays, retina layers and retinal perfusion can be studied by means of non invasive techniques, ie, Optical Coherence Tomography (OCT) and OCT‐Angiography (OCT‐A). So far, data on OCT‐A in AD patients are scarce, conflicting [4‐5] and refer mostly to the dementia phase. Here, we have compared the retinal thickness and the perfusion index, measured by means of OCT and OCT‐A, in patients with mild cognitive impairment showing a CSF profile compatible with AD (MCI‐AD), and age‐matched cognitively healthy controls.

Method

We enrolled 37 subjects, 24 MCI‐AD patients, and 13 sex and age‐matched cognitively healthy subjects as control group. The mean age was 69.8 in MCI‐AD and 73.6 in controls. The MCI‐AD patients underwent neurological evaluation, neuropsychological assessment and lumbar puncture: in all these patients, the CSF profile, based on t‐tau, p‐tau, Aβ42 and Aβ42/40, was compatible with AD. OCT and OCT‐A have been used for evaluating retinal nerve fiber layer, ganglion cell layer and other retinal thicknesses and retinal and choroidal capillary plexuses. ANCOVA was used for comparing OCT measurements after adjustment for age, diabetes and hypertension.

Result

A significant reduction of superficial capillary plexus (10.10±0.81 vs. 10.79±0.67, p=0.012), deep capillary plexus (72.80±3.31 vs. 75.78±3.71, p=0.012) and intermediate capillary plexus (75.57±2.85 vs. 78.03±2.84, p=0.015) was found in MCI‐AD patients compared to controls. Conversely, the fractal dimension (FD) was increased in MCI‐AD with respect to control (1.51±0.02 vs. 1.50±0.01, p=0.044); CSF Abeta42/Tau ratio correlated negatively with FD (r=‐0.51, p=0.010).

Conclusion

A reduction of retinal perfusion as opposed to an increased fractal dimension in MCI‐AD patients vs controls has been found. The latter finding could be due to a compensative mechanism. These data could support the role of OCT‐A as possible biomarker of prodromal AD. Further larger prospective studies are needed in order to confirm this hypothesis.
Urokinase plasminogen activator (uPA) as a novel biomarker for cerebral amyloid angiopathy
Authors: Vervuurt Marc , de Kort Anna M. , Schreuder Floris HBM , Klijn Catharina J.M. , Kuiperij H. Bea , Verbeek Marcel M.
Published: December 2020

Background

Current diagnostic criteria for cerebral amyloid angiopathy (CAA) are predominantly based on radiological identification of evidence of CAA (micro‐ or macrobleeds). These criteria present only end‐stage manifestations of the disease, however. The development of transgenic rat models for CAA, carrying the E693Q/D694N mutations in APP (rTg‐DI rats), has the potential of discovery of novel biomarkers for CAA. Shotgun proteomics analysis of rTg‐DI tissue, compared to wild‐type rats has yielded elevated levels of urokinase plasminogen activator (uPA) in CAA. uPA is a serine protease active in the conversion of plasminogen to plasmin, a fibrinolytic factor. We investigated the potential of uPA in a pilot biomarker discovery study for the diagnosis of CAA by analyzing uPA concentrations in cerebrospinal fluid (CSF) of patients with CAA compared to control patients.

Method

CSF was obtained from patients with possible or probable CAA (according to the current diagnostic imaging tool, the Boston Criteria) (n=28), and control subjects (n=42). uPA levels in CSF were determined using a uPA Quantikine ELISA (R&D Systems, Minneapolis, USA). Total protein levels were assayed using a Pierce® BCA Protein Assay (Thermo Fisher, Waltham, USA). Associations of uPA with known concentrations of other neurological markers, including aβ peptides and tau proteins were also analysed.

Result

The concentration of uPA was significantly increased in the CSF of CAA patients compared to controls (303 ± 23.2 vs. 227 ± 12.5 pg/mL; p=0.001). CSF uPA levels (very) weakly correlated with age at lumbar puncture (rSP=0.33, p=0.005) and total protein content (rSP=0.24, p=0.042). uPA levels in controls were correlated in a weak‐to‐moderate extent with Aβ‐38, 40, 42, and total‐ and phosphorylated tau protein (rSP=0.46, 0.63, 0.47, 0.53 and 0.41 respectively, p<0.02), whereas this correlation was practically absent in the CAA group.

Conclusion

Comparison of CSF levels of uPA shows a significant elevation in CAA patients compared against controls. CAA patients show lower levels of correlation of uPA with circulating aβ peptides and tau protein variants as compared to controls. This reinforces the potential of uPA as an effective biomarker in the diagnosis of CAA patients and incentivizes further research into this biomarker.
Is kidney disease associated with both Alzheimer’s disease and vascular dementia?
Authors: Basit Saima , Damholt Mette Brimnes , Wohlfahrt Jan , Boyd Heather A
Published: December 2020

Background

Previous studies have found associations between renal dysfunction and cognitive impairment. Associations between kidney disease and dementia are less well‐established and the available evidence for associations with dementia subtypes is conflicting.

Method

Our study cohort included 4,320,824 individuals ≥40 years of age and living in Denmark at some point during 1996‐2017. Of these, 123,269 persons developed dementia during 60,043,110 person‐years of follow‐up (median follow‐up time, 14.8 years). We compared the risks of dementia in persons with and without a history of kidney disease using Cox regression with age as underlying time scale. All analyses were adjusted for sex, birth year, cardiovascular disease, autoimmune diseases, diabetes and hypertension.

Result

Compared with persons without kidney disease, persons with any kidney disease had a higher risk of dementia overall (hazard ratio [HR] 1.22, 95% confidence interval [CI] 1.19‐1.25) and of early‐onset (<65 years) dementia in particular (HR 1.66, 95% CI 1.50‐1.85). Stronger associations were observed for acute kidney disease (dementia overall: HR 1.45, 95% CI 1.38‐1.52; early‐onset dementia: HR 2.12, 95% CI 1.70‐2.63; late‐onset dementia: HR 1.44, 95% CI 1.36‐1.52) than for chronic kidney disease (dementia overall: HR 1.15, 95% CI 1.10‐1.20; early‐onset dementia: HR 1.49, 95% CI 1.24‐1.78; late‐onset dementia(≥65 years): HR 1.15, 95% CI 1.11‐1.19). Persons with kidney disease had increased risks of vascular dementia (HR 1.43, 95% CI 1.33‐1.54) and other/unspecified dementia (HR 1.30, 95% CI 1.26‐1.34); in contrast, kidney disease was not associated with the risk of Alzheimer’s disease (HR 0.98, 95% CI 0.94‐1.03). The magnitude of the association with vascular dementia overall was similar for acute kidney disease (HR 1.57, 95% CI 1.33‐1.86) and chronic kidney disease (HR 1.44, 95% CI 1.28‐1.63). However, acute kidney disease was very strongly associated with the risk of early‐onset vascular dementia (HR 3.09, 95% CI 1.65‐5.81).

Conclusion

Kidney disease, especially acute kidney disease, was associated with increased risks of dementia, early‐onset dementia in particular. Kidney disease was associated with increased risks of vascular dementia but not of Alzheimer’s disease.
Characterisation of Alzheimer’s disease patients with agitation and their antipsychotic use: A study using the UK Clinical Practice Research Datalink
Authors: Baker Ross A , Lind Stefan , Qizilbash Nawab , Johnson Michelle , Collings Shuk‐Li , Bøg Martin , Tran Cam Thanh , Jørgensen Kristian Tore
Published: December 2020

Background

There are few data on patients with agitation in Alzheimer’s disease (AD) and their use of antipsychotics (APs). This study characterised patients with agitation in AD (AAD) in terms of falls, and disease duration and examined their AP use compared to AD patients with other neuropsychiatric symptoms (NPS) and no NPS.

Methods

Data from the UK Clinical Practice Research Datalink were analysed in two ways. Cross‐sectionally to characterise patients with AAD, other NPS and no NPS on 01/07/2016, using chi‐square and ANOVA for differences in proportions and means between groups, respectively. Retrospectively between 01/01/2015 and 31/12/2017 to compare AP use between AD patients with agitation, other NPS and no NPS using a Cox proportional hazards model adjusted for covariates.

Results

At 01/07/2016, there were 10,573 AD patients with a mean age of 83 years. Patients with AAD (n=605) had longer mean duration of disease (4.3 years) versus patients with other NPS (n=5102, 2.8 years) and no NPS (n=4772, 2.5 years) (p<0.001); more falls (53%) versus patients with other NPS (47%) and no NPS (33%) (p<0.001); were more likely to be prescribed atypical APs within last 60 days (24%) versus patients with other NPS (7%) and no NPS (4%) (p<0.001); and were more likely to have ever been prescribed benzodiazepine (64%) versus patients with other NPS (52%) and no NPS (24%) (p<0.001). During the 3‐year follow‐up, there were 24,464 AD patients with median follow‐up of 1.1 years. The proportion of patients with an AP prescription during follow‐up was: 38% (AAD, n=2432), 20% (other NPS, n=13,076) and 12% (no NPS, n=11,816). Compared to patients with no NPS, the adjusted hazard ratio for AP use was 3.45 (95% CI 2.86‐4.17) for patients with AAD and 1.31 (95% CI 1.19‐1.44) for patients with other NPS.

Conclusion

Patients with AAD are a particularly difficult to manage group. More patients with AAD had experienced falls and had a longer duration of AD than patients with other or no NPS. At the same time AP use was more than 3‐fold higher in patients with AAD than in patients without NPS.
Pronounced regional spectral, connectivity and network changes reflect visual deficits in posterior cortical atrophy: An EEG study on PCA
Authors: Briels Casper T. , Eertink J.J. , Stam Cornelis J. , van Der Flier Wiesje , Scheltens Philip , Gouw Alida A.
Published: December 2020

Background

Electroencephalography (EEG) has shown differences in spectral, functional connectivity and network measures between typical Alzheimer’s disease (AD) and controls. Subjects with posterior cortical atrophy (PCA) show more severe visuospatial and perceptual deficits compared to typical AD. The aim of this study was to investigate whether functional alterations measured by EEG can help understand the mechanisms that explain the clinical heterogeneity.

Methods

21‐channel EEG recordings of 29 PCA subjects, with positive biomarkers for amyloid pathology, were compared with 29 typical AD subjects and 29 controls with subjective cognitive decline matched for age, gender and disease duration (respectively 41%/38%/45% male, age:63±5/63±5/63±5yr, median MMSE:19/18/28). Relative band power, alpha band functional connectivity (defined by volume conduction corrected amplitude envelope correlation) and network characteristics of the minimum spanning tree(MST) were assessed at global and electrode levels. Differences between diagnostic groups were analysed with pairwise permutation testing. Correlations between electrode level peak frequency with visual (dotcounting and fragmented letters) and memory (Rey Auditory Verbal Learning Test) tasks were assessed within the PCA group.

Results

PCA and AD subjects had a lower global relative alpha and beta and higher theta power compared to controls (p<0.05). PCA subjects had higher global relative delta and lower alpha power compared to AD subjects (p<0.05), driven by a decrease in the dominant posterior frequency (Figure 1). Global functional connectivity was decreased in both PCA and AD compared to controls (both p<0.001). The MST showed an increased network diameter, a decreased posterior and an increased frontal degree in PCA compared to controls (Figure 2). In PCA, decreased right posterior peak frequency correlated with worse performance on visual tasks (Dotcounting: r=0.50, p=0.012; fragmented letters: r=0.51, p=0.008) but not with the memory task (Figure 3).

Conclusion

The clinical differences between PCA and typical AD subjects corresponded with a more severe slowing of oscillatory activity in the posterior regions in PCA subjects. The network of PCA subjects showed a less efficient topology and a shift in hubness from posterior to frontal channels. This indicates that in PCA, regional synaptic dysfunction might interplay with previously reported atrophy and tau accumulation in the networks responsible for visual processing.
Pilot study: Stress‐induced noradrenergic activity as potential indicator for practice effects — Association between acute stress, noradrenaline response and practice effects
Authors: Pagen Linda H.G. , Smeets Tom , Müller‐Ehrenberg Lisa , Yassa Michael A. , Verhey Frans R.J. , Jacobs Heidi I.L.
Published: December 2020

Background

Stress has both enhancing and impairing influences on memory performance. Interestingly, aging has been associated with changes in the stress system as well as a decline in memory performance. Reductions in memory practice effects have gained interest as a risk factor for future cognitive decline, yet research on how stress influences practice effects in older individuals is scarce. Considering the age‐related changes in the stress systems, it is conceivable that exposure to stressors may facilitate the identification of individuals with an absence or attenuation of practice effects.

Method

A total of thirty healthy individuals aged 40‐70 years old were subjected to a pattern separation memory task with and without an acute cognitive stressor before encoding. Several salivary alpha amylase (SAA) samples were obtained at different time points as a proxy of noradrenaline activity. Using the change scores on the memory task, we divided participants in learners (exhibiting practice effects) and non‐learners (Figure 1A). Spearman correlation coefficients were calculated to examine the relation between practice effects and SAA levels. Subsequently, an age by SAA interaction on practice scores was explored with a linear model for SAA levels at all time points.

Result

In the entire group, higher baseline SAA levels correlated to worse practice effects (r
s= ‐0.46, p=0.02) while controlling for age. The non‐learners showed significantly higher SAA scores at all time points compared to learners (table 1). The learners demonstrated a significant interaction between age and SAA levels after encoding (b=0.02, t=4.35,p=0.0019) on pattern separation difference scores controlled for SAA baseline levels (Figure 1B). No such interaction was observed for non‐learners (b=0.0009, t=0.56, p=0.6; Figure 1C).

Conclusion

These results show that elevated baseline noradrenaline activation is associated with the absence of practice effects. Additionally, in learners practice effects were observed in middle‐aged individuals with relatively lower levels of noradrenergic activity. These findings suggest that noradrenergic system activation may be a promising indicator of imminent cognitive decline. Future research is needed to understand variability in noradrenaline activation and practice effects over the adult age span.
Life expectancy with and without dementia after diagnosis of mild cognitive impairment: A population‐based study
Authors: Mooldijk Sanne S , Yaqub Amber , Wolters Frank J , Licher Silvan , Koudstaal Peter J , Ikram M Kamran , Ikram M Arfan
Published: December 2020

Background

Reliable prognosis of mild cognitive impairment (MCI) in terms of life expectancy (LE) with and without dementia is important to inform patients and their relatives, as well as health policy makers, but data from unselected older populations are scarce.

Method

Between 2002 and 2015, all participants aged 60‐105 years of the population‐based Rotterdam Study were assessed for the presence of MCI and were followed subsequently for the onset of dementia or death. MCI was defined as subjective cognitive complaints with objective cognitive impairment in the absence of dementia. We constructed multistate life‐tables for the transitions from MCI to dementia, MCI or dementia to death, and determined age‐specific LE with and without dementia by gender, APOE‐ε4 carrier status, and educational attainment.

Result

Of 648 individuals with MCI (median age at entry 71.7 years (interquartile range 65.0‐78.1); 53.9% women), during 4423.4 person‐years of follow‐up, 136 developed dementia and 293 died. Overall LE in women ranged from 23.4y [90% confidence interval (CI) 21.6‐25.5] at age 60 to 4.4y [3.1‐6.2] at age 90, and in men from 19.3y [17.5‐21.7] at age 60 to 3.3y [2.2‐5.2] at age 90. Women were at higher risk of conversion to dementia (HR 1.20; 95% CI 0.85‐1.71), and consequently lived more years with dementia than men (from age 60: 3.7y [2.7‐5.2] vs. 2.0y [1.4‐3.0]; from age 90: 1.9y [1.0‐3.6] vs. 1.0y [0.5‐2.5]). APOE‐ε4 carriers were at higher risk of conversion to dementia as well as death, such that their expected life years with dementia were similar to non‐carriers (2.9y [2.0‐4.4] for carriers vs. 2.8y [2.0‐4.1] for non‐carriers). Higher education conferred a benefit in overall life expectancy compared to further and lower education, but these additional years were lived predominantly with dementia (at age 60: 4.9y [3.7‐6.6] vs. 2.9y [2.2‐4.1] and 2.0y [1.5‐2.9]).

Conclusion

Women with MCI live longer than men, both with and without dementia. To provide accurate information to patients and policy makers, acknowledged prognostic factors like APOE‐ε4 carrier status and educational attainment should be interpreted against the backdrop of remaining life expectancy.
Association of periodontitis and cognitive impairment: A systematic review and meta‐analysis
Authors: Asher Sam , Stephen Ruth , Suominen Anna Liisa , Mäntylä Päivi , Solomon Alina
Published: December 2020

Background

Emerging evidence suggests link between poor periodontal status and cognitive impairment. This review systematically assessed longitudinal evidence on the association of periodontitis and tooth loss with cognition.

Methods

Comprehensive literature search for studies examining effect of periodontitis on cognition was conducted on two electronic databases, Medline and Scopus. Longitudinal studies having periodontitis or its surrogate measure (tooth loss) as exposure and cognition as outcome were included. Meta‐analysis was conducted on RevMAN‐5 software. Primary random effects model analyzing the effect of periodontitis (all measures) on cognition was generated. Secondary analyses included models based on periodontal specific measures 1 and tooth loss. Quality assessment of included studies was conducted.

Results

Out of 97 studies, 16 were included in the systematic review. Meta‐analysis included 9 studies. In preliminary results, primary model showed significant association between periodontitis and cognitive impairment (OR=1.22, 95%CI:1.01–1.49, p=0.04). In secondary analyses, neither periodontitis (based on specific measures) nor tooth loss was associated with cognitive impairment. However, further stratification of tooth loss found significant association between partial tooth loss and cognitive impairment (OR=1.53, 95%CI:1.03–2.29, p=0.04). The overall quality of evidence was low.

Conclusion

Periodontitis appears to contribute to overall risk of cognitive impairment. This association may be driven by specific aspects of periodontitis such as severity, chronicity and corresponding tooth count. However, firm conclusions cannot be drawn due to overall low quality of evidence and lack of coherent methodology among studies (e.g. variability across periodontal and cognitive assessments). Well‐designed longitudinal studies with larger sample size and including comprehensive and standardized assessment of both periodontal and cognitive status are warranted.
Phenotypic heterogeneity of the rare R377W PSEN1 mutation: Late‐onset presentation with mixed Alzheimer’s and frontotemporal dementia features
Authors: Scarioni Marta , Arighi Andrea , Fenoglio Chiara , Serpente Maria , Rotondo Emanuela , Pietroboni Anna , Fumagalli Giorgio G. , Carandini Tiziana , Scarpini Elio , Galimberti Daniela
Published: December 2020

Background

Autosomal dominant mutations in the PSEN1 gene have been associated with the earliest Alzheimer’s disease onset and a typical amnestic syndrome of the hippocampal type, although behavioural and psychiatric presentations have also been reported. The R377W PSEN1 mutation has only been found in two patients until now. Here, we want to describe an unusual presentation of the rare R377W PSEN1 mutation in an Italian patient with a late age of onset, and to provide for the first time antemortem pathological evidence for this mutation.

Method

A 71‐years old female patient with progressive cognitive decline in the past three years underwent neurological evaluation, neuropsychological testing, lumbar puncture, conventional brain imaging, amyloid‐PET and extensive genetic screening with a next generation sequencing technique.

Result

The diagnostic work‐up revealed mixed frontotemporal dementia and typical Alzheimer’s disease features on neuropsychological tests, MRI and FDG‐PET. Amyloid‐PET detected amyloid deposition in the frontal areas as well as in the parietal lobes and the precunei. The genetic screening unraveled the presence of the rare R377W mutation in the PSEN1 gene.

Conclusion

Extensive genetic screening is advisable also for late onset presentations of Alzheimer’s disease, especially in the presence of a positive family history.
Identifying individuals with mild cognitive impairment who are at higher genetic risk of further substantial cognitive decline due to Alzheimer's disease
Authors: Pither Richard , Daunt Paula , Davidson Greg , Gibson Alex , Hill Anthony , Oshota Olusegun
Published: December 2020

Background

The development of tools to identify disease risk is critical to enable selection of suitable individuals for inclusion in clinical trials and cohort studies. The utility of Polygenic Risk Scores (PRS) is gaining increased attention for generating genetic risk profiles and subsequent estimation of future disease risk in Alzheimer’s Disease. We have previously reported on the performance of our PRS to differentiate AD cases from healthy controls in the ADNI cohort using individual's most recent diagnosis. In this work we have analysed whether the PRS is able to predict substantial cognitive decline towards an AD phenotype of individuals with MCI at the point of entering the study. The aim being to demonstrate the utility of PRS approaches in longitudinal studies and future clinical practice.

Method

This longitudinal study explored the performance of the Cytox genoSCORE™ PRS algorithm as measured using ROC, AUC analysis when predicting a change in ADAS‐Cog13 score of 5,10 and 15 points at 2, 3 and 4‐year assessment timepoints. Subjects are included in the analysis based on availability of ADAS‐Cog13 data at those timepoints and availability of genetic data in the ADNI database. Change in cognition as measured by ADAS‐Cog13 was used instead of change of diagnosis given the broad spectrum of baseline cognitive performance in those individuals with MCI.

Result

Individuals with low PRS clearly have a lower likelihood of experiencing substantial cognitive decline (>10 points on the ADAS‐Cog13 scale over 4 years) than those individuals with higher PRS. In a population of 285 individuals with an MCI diagnosis at baseline genoSCORE™ has an accuracy as measured by area under the curve of 74% in predicting those individuals who declined substantially over 4 years, with very high negative predictive values.

Conclusion

Identifying individuals of higher risk for substantial cognitive decline towards AD will allow clinical trialists to enrich their studies with more appropriate patients. In addition, use of such risk evaluation techniques in clinical practice will enable clinicians to make more informed decisions on how to manage their patients. Cytox is able to provide a robust end‐to‐end process to provide this comprehensive genetic risk assessment.
Does optimal cardiovascular health protect against cognitive decline in aging?
Authors: Speh Andreja , Wang Rui , Winblad Bengt , Kramberger Milica G , Bäckman Lars , Fratiglioni Laura , Qiu Chengxuan , Laukka Erika J
Published: December 2020

Background

The presence of cardiovascular risk factors leads to negative consequences in old age. To promote the intervention of such risk factors, the American Heart Association defined a metric of ideal cardiovascular health, also referred to as Life’s Simple 7 (LS7). The adherence to the LS7 recommendations has previously been linked to a lower risk of dementia and cognitive decline. The objective of this study was to investigate the association between individual and composite cardiovascular health metrics and rate of cognitive decline in an older population‐based sample.

Method

Participants aged ≥60 years from the Swedish National Study on Aging and Care‐Kungsholmen underwent repeated neuropsychological testing across 12 years. Domain specific scores were calculated for episodic memory, semantic memory, verbal fluency, and processing speed. The LS7 score, assessed at baseline, was composed of four behavioral (smoking, body mass index, diet, and physical activity) and three biological (serum total cholesterol, plasma glucose, and blood pressure) metrics. All metrics were categorized into three levels (poor = 0, intermediate = 1, and optimal = 2), where the LS7 total score was the sum of seven metrics (range 0‐14). On the basis of tertiles, it was categorized into poor (scores 0‐6), intermediate (7‐9) and optimal (10‐14). Data were analyzed with linear mixed‐effects models.

Result

Among 1828 participants with data on LS7 (mean age 70.4; 60.8% women), nobody achieved optimal levels for all 7 metrics. The average total score was 7.7 (SD = 1.9) and participants were classified as having poor (26.3%), intermediate (55.6%), or optimal (18.2%) cardiovascular health. People belonging to the intermediate or optimal group of cardiovascular health showed higher levels of cognitive performance. Although a more ideal level on specific metrics (e.g. blood pressure) was significantly associated with slower rates of cognitive decline, we observed no significant associations of the composite cardiovascular health metric with rate of cognitive change.

Conclusion

In this cohort study, a composite score of cardiovascular health (LS7) did not predict rate of cognitive decline. Ideal cardiovascular health in specific metrics, however, was associated with slower decline rates. Further analyses of subgroups and interaction effects are ongoing.
Differences in functional connectivity in mild cognitive impairment for amyloid‐positive versus SNAP
Authors: Magalhaes Thamires Naela Cardoso , Casseb Raphael Fernandes , de Campos Brunno , Teixeira Camila Vieira de Ligo , Forlenza Orestes Vicente , Talib Leda Leme , Cendes Fernando , Balthazar Marcio Luiz Figueredo
Published: December 2020

Background

The default mode network (DMN) is a neurofunctional network particularly relevant to Alzheimer's disease (AD) since its structures are vulnerable to the deposition of amyloid (Aβ) and neurofibrillary tangles [1]. Observing the more up‐to‐date classifications, we classified our patients according to AT(N) (alterations in amyloid (A), tau (T) and neurodegeneration (N)) classification: normal AD biomarkers (AD‐) (A‐T‐N‐); suspected non‐Alzheimer pathophysiology (SNAP) (A‐T+N‐, A‐T‐N+, or A‐T+N+) and AD pathophysiologic continuum (AD+) (any A+ combination) [2]. We investigated whether the activity and functional connectivity (FC) can differentiate MCI subgroups according to AD biomarkers classification.

Method

We recruited 58 mild cognitive impairment (MCI) patients who underwent: lumbar puncture to analyze Aβ1‐42, p‐Tau and t‐Tau levels; Magnetic Resonance Imaging in a 3T Philips Achieva scanner; and a broad neuropsychological evaluation. Was considered pathophysiological evidence of AD (AD continuum) low Aβ1‐42 concentrations < 416 pg/m and was considered Tau alteration: p‐Tau > 36.7 pg/mL and t‐Tau > 76.7 pg/mL [3]. To identify the DMN we used the UF2C software and seed‐based analysis using a mask of the posterior cingulate cortex to extract the reference time‐series. We obtained FC values for 8 DMN regions for each patient. We performed a general linear model to compare the groups with FC values of DMN regions.

Result

There was a statistically significant difference between groups SNAP and AD continuum and FC of left hippocampus (p = .017). AD continuum group shows more connectivity than SNAP group.

Conclusion

CSF protein profiles seem to be related to alterations in resting state activity. In this study we were able to differentiate clinically similar patients through neuroimaging biomarkers. With further refinement, resting‐state connectivity hold promise as non‐invasive neuroimaging markers. References: [1] Matura S, et al., doi: 10.1017/neu.2019.49; [2] Jack CR, et al., doi: 10.1016/j.jalz.2018.02.018; [3] Forlenza OV, et al., doi: 10.1016/j.dadm.2015.09.003.
Difference between Okinawan and Dutch elderly in working memory‐related brain activation
Authors: Ćurčić‐Blake Branislava , Willcox Craig D , Futenma Yuko , Ueda Yukihiko , Aleman André
Published: December 2020

Background

Okinawan elderly have been reported to suffer from less age‐related diseases (including dementia) in comparison to elderly people elsewhere. However, there is a lack of research studying functional brain characteristics of succesful aging as found in Okinawan elderly. The current study is designed to take the first step in this regard. Specifically, we want to investigate brain activation during executive functioning in Okinawan elderly as compared to Western‐European elderly (in this case, Dutch elderly). We predicted that Okinawan elderly would need less prefrontal brain activation during a working memory task.

Method

We included the first data from 50 participants of the Okinawa‐Groningen study in which brain activation patterns are studied cross‐culturally in eldery subjects. The study is ongoing and aims to include N=40 at both sites. Here we present the first results based on a comparison of 34 Okinawan to 16 Dutch participants. Working memory‐related brain activation was measured using fNIRS during a visual N‐back task. 1‐back task consisted of 3 blocks (120s) including figures of objects and animals. fNIRS measurement was performed with 16 optodes (NIRx Scout, Germany) placed between Fp1 and F5 on the left and Fp2 and F6 on the right side. fNIRS data were analyzed using NIRSLab (NIRx, Germany). As groups differed slightly in level of education (higher in the Dutch sample) we included cognitive performance on a related task, verbal fluency (category and letter fluency) as covariate, to control for cognitive ability.

Result

GLM analysis revealed significantly higher activation in the bilateral Inferior Frontal Gyrus (IFG) of Dutch participants. After correcting for performance on verbal fluency ANCOVA revealed significantly stronger IFG activation in the Dutch subjects, F(3, 47)=9.83 (0.003). Though in the same direction, this difference was non‐significant for the left IFG (p=0.062).

Conclusion

Our results reveal lower of activation of dorsolateral prefrontal cortex during working memory processing in elderly subjects from Okinawa as compared to elderly Dutch subjects. Cognitive reserve has been shown to be related to less activation during a task involving executive functioning (Oh et al. 2018). We suggest that Okinawan elderly may need less executive processing resources to perform the task.
Baseline features of the AMYPAD Diagnostic and Patient Management Study (DPMS) participants
Authors: Altomare Daniele , Collij Lyduine , Garibotto Valentina , Poitrine Léa , Moro Christian , Alves Isadora Lopes , van Maurik Ingrid S. , Berkhof Johannes , Scheltens Philip , Delrieu Julien , Molinuevo Jose Luis , Nordberg Agneta K , Jessen Frank , Walker Zuzana , Démonet Jean‐François , Gismondi Rossella , Farrar Gill , Barkhof Frederik , Stephens Andrew W , Frisoni Giovanni B ,   AMYPAD Consortium
Published: December 2020

Background

AMYPAD‐DPMS is the largest European, multicenter, prospective and randomized study assessing clinical utility and cost‐effectiveness of amyloid‐PET in a controlled but realistic clinical setting. In the present abstract we report preliminary results on the baseline features of the first study participants.

Method

A total of 900 participants (300 with subjective cognitive decline plus [SCD+], 300 with mild cognitive impairment [MCI], and 300 with dementia) will be enrolled and randomized into 3 study arms: ARM‐1, amyloid‐PET performed early in the diagnostic workup; ARM‐2, amyloid‐PET performed late in the diagnostic work‐up; and ARM‐3, amyloid‐PET performed if and when the physician chooses to.

Result

As of January 23rd 2020, 617 participants (154 SCD+, 303 MCI, and 160 dementia) have been enrolled from 8 centers. Baseline features are reported in Table 1. SCD+ participants are younger than MCI (p=0.006) and dementia (p<0.001) participants. SCD+ are more highly educated than MCI and dementia (p<0.001), and MCI are more highly educated that dementia (p=0.008). As expected, worse global cognition is observed in dementia (p<0.001) compared to MCI and SCD+, and in MCI compared to SCD+ (p<0.001). Among those who already underwent amyloid‐PET, 34% (30/88) of SCD+, 58% (90/155) of MCI, and 74% (60/81) of dementia patients were amyloid‐positive based on visual PET scan assessment.

Conclusion

The socio‐demographic and cognitive features of the first 68% of AMYPAD‐DPMS participants are as expected for a memory clinic population, confirming the inclusion/exclusion criteria resulted in a representative sample. These results support the generalizability of the final study results. The end of participants’ enrolment is expected by mid‐2020.
How dominant hand dexterity could help in characterizing different grades of cognitive decline: A motor and cognitive dual‐task study
Authors: Mancioppi Gianmaria , Fiorini Laura , Rovini Erika , Zeghari Radia , Gros Auriane , Manera Valeria , Mouton Aurelie , Philippe Robert , Cavallo Filippo
Published: December 2020

Background

The combined provision of an arising number of dementia cases, and the substantial absence of effective treatments, led the scientific community toward the identification of early phases of this condition. Such an effort aims at the recognition of therapeutic windows and the characterization of the disease’s different grades. In the last years, Motor and Cognitive Dual‐Tasks (MCDT) have been widely used to address the early diagnosis of several neurocognitive disorders, among which dementia.

Method

In this work, we presented a brand‐new sensor‐based MCDT approach, regarding the upper limb activity: the index‐tapping MCDT (FTAP). We tested this protocol on 30 subjects, among which: 10 Healthy Older Adults (HOA), 10 Subjective Cognitive Decline (SCD), and 10 Minor Neurocognitive Disorders (m‐NCD).

Result

The preliminary results suggest that the FTAP protocols seem to enlarge the possibility to differentiate among different grades of cognitive decline. The FTAP within‐group analysis revealed a low rate of task saturation if such a task is compared to the gold standard protocols. Furthermore, several motor parameter differs among the aforementioned clinical label (opening and closing velocity, tapping frequency, number of tapping, etcetera), suggesting the possibility to better discriminate among clinical condition.

Conclusion

This paper presents a brand‐new application of MCDT, enlarging the literature about the motor‐cognitive interface. Moreover, FTAP protocols, differently from gait analysis, can also be easily applied in neuroimaging studies.
Differential gene expression in genetic and early‐onset Alzheimer’s disease in two biological samples: Brain tissue and lymphoblastoid cell lines
Authors: Ramos‐Campoy Oscar , Lladó Albert , Bosch Beatriz , Aldecoa Iban , Gonzalo Ricardo , Muñoz Cristina , Ximelis Teresa , Fernandez‐Villullas Guadalupe , Balasa Mircea , Sanchez‐Pla Alex , Sanchez‐Valle Raquel , Antonell Anna
Published: December 2020

Background

Several previous studies have analyzed the genetic expression in late‐onset Alzheimer’s disease (AD). In this study, we aim to analyze the differential gene expression between sporadic early‐onset AD (sEOAD) and autosomal dominant AD due to the presence of PSEN1 mutations (PSEN1) in two type of samples, brain tissue and lymphoblastoid cell lines (LCL).

Method

Frozen prefrontal cortex (5 CTRL, 4 sEOAD and 4 PSEN1) was obtained from the Neurological Tissue Bank and LCL (5 CTRL, 5 sEOAD and 5 PSEN1) from the Alzheimer’s Disease Unit, both from the Hospital Clinic of Barcelona, IDIBAPS. Gene expression was measured with microarray Clariom D (Affymetrix). Differentially expressed genes (DEG) were obtained selecting the 35% most variable genes (n = 8473) by adjusting a linear model with empirical Bayes moderation of the variance. Significance threshold was set at p.value < 0.05 and fold change in absolute value >0.5. The analysis of biological significance was based on gene set enrichment analysis on Reactome Pathway Knowledge database.

Result

781/355 (brain/LCL) genes were differentially expressed in the sEOAD vs CTRL comparison, 503/275 in the PSEN1 vs CTRL, and 244/115 in the PSEN1 vs EOAD. No DEG were found with a significance threshold of an adjusted p.value <0.05. Any of the DEG survived after multiple comparisons correction. The top 10 enriched pathways for each comparison, using the most significative p.value and a normalized enrichment score (NES) absolute value >1.8, were considered. Pathways involved in synapsis were found in 2 comparisons: sEOAD vs CTRL (brain) and PSEN1 vs CTRL (LCL). Pathways related to metabolism (mainly Krebs cycle) were identified in all comparisons between patients and controls in both tissues. Signal transduction pathways were found in all comparisons. Immune system was observed in all comparisons between PSEN1 and sEOAD, as well as sEOAD vs CTRL in brain.

Conclusion

Genes involved in the immune system and signal transduction pathways were differentially expressed in sporadic and autosomal dominant AD caused by PSEN1 mutations. The number of DEG was higher in brain tissue than in LCL comparisons. Validation of these findings by quantitative‐PCR would be necessary to discard false positive results.