Publications by authors named "Dag Aarsland"

434 Publications

Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression.

Sci Rep 2021 Oct 13;11(1):20375. Epub 2021 Oct 13.

Department of Neurology, Akershus University Hospital, Lørenskog, Norway.

To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-β 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (p < 0.05) and predementia AD (p < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (p < 0.001), BACE1 (p < 0.05) and Ng/BACE1 ratio (p < 0.01). All groups had significantly lower Aβ 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as "predementia AD with depression".
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http://dx.doi.org/10.1038/s41598-021-99794-9DOI Listing
October 2021

Dementia with Lewy bodies research consortia: A global perspective from the ISTAART Lewy Body Dementias Professional Interest Area working group.

Alzheimers Dement (Amst) 2021 14;13(1):e12235. Epub 2021 Sep 14.

Centre for Age-Related Medicine (SESAM) Stavanger University Hospital Stavanger Norway.

Dementia with Lewy bodies (DLB) research has seen a significant growth in international collaboration over the last three decades. However, researchers face a challenge in identifying large and diverse samples capable of powering longitudinal studies and clinical trials. The DLB research community has begun to focus efforts on supporting the development and harmonization of consortia, while also continuing to forge networks within which data and findings can be shared. This article describes the current state of DLB research collaborations on each continent. We discuss several established DLB cohorts, many of whom have adopted a common framework, and identify emerging collaborative initiatives that hold the potential to expand DLB networks and diversify research cohorts. Our findings identify geographical areas into which the global DLB networks should seek to expand, and we propose strategies, such as the creation of data-sharing platforms and the harmonization of protocols, which may further potentiate international collaboration.
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http://dx.doi.org/10.1002/dad2.12235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438683PMC
September 2021

A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease.

Nat Genet 2021 09 7;53(9):1276-1282. Epub 2021 Sep 7.

Division of Genetic Medicine, Department of Medicine Vanderbilt University Medical Center Nashville, Nashville, TN, USA.

Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.
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http://dx.doi.org/10.1038/s41588-021-00921-zDOI Listing
September 2021

A meta-analysis of randomised controlled trials of physical activity in people with Alzheimer's disease and mild cognitive impairment with a comparison to donepezil.

Int J Geriatr Psychiatry 2021 10 25;36(10):1471-1487. Epub 2021 May 25.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, United Kingdom.

Objectives: Physical exercise may benefit people with Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, randomised controlled trials (RCTs) of exercise have shown conflicting findings and it is unclear if positive outcomes are comparable to a commonly used cholinesterase inhibitor, donepezil.

Methods: Embase, Medline, PsycINFO, PsycARTICLES, SCOPUS were searched for RCTs of physical activity compared to a control condition, and donepezil compared to placebo in people with AD and MCI. Effect sizes were calculated from pre- and post-MMSE and ADAS-Cog scores and pooled using a random effects meta-analysis.

Results: Ninteen RCTs were included in the exercise meta-analysis (AD, N = 524; MCI, N = 1269). Physical exercise improved MMSE scores in AD (Hedges' g = 0.46) and MCI groups (g = 0.63). For the MCI group, exercise appeared to have a stronger effect for those with lower MMSE scores at baseline (p = 0.022). 18 RCTs were included in the donepezil meta-analysis (AD, N = 2984, MCI, N = 1559). In people with AD, donepezil improved cognition (MMSE g = 0.23; ADAS-Cog, g = -0.17) but there was no evidence of improved cognition in MCI.

Conclusions: Physical exercise improved cognition in both AD and MCI groups. Where comparisons were possible, the effect size for physical exercise was generally comparable to donepezil. These results strengthen the evidence base for exercise as an effective intervention in AD and MCI, and future clinical trials should examine exercise type, intensity and frequency, in addition to cholinesterase inhibitors to determine the most effective interventions for AD and MCI.
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http://dx.doi.org/10.1002/gps.5581DOI Listing
October 2021

Subjective Cognitive and Communicative Complaints and Health-Related Quality of Life in Parkinson's Disease with and without Mild Cognitive Impairment.

Rev Colomb Psiquiatr (Engl Ed) 2021 Sep 3. Epub 2021 Sep 3.

Grupo de Neurociencias de Antioquia, Universidad de Antioquia, School of Medicine, Medellín, Colombia.

Introduction: Mild Cognitive Impairment (MCI) is common in Parkinson's Disease (PD). Few studies have compared the Health-Related Quality of Life (HRQoL) in patients with and without MCI due to PD (PD-MCI), and its correlation to patients' subjective cognitive and communicative difficulties has not been explored.

Objective: We aimed to compare HRQoL in PD-MCI and PD without MCI (PD-nMCI), and explore its possible relationship to subjective cognitive and communicative complaints.

Methods: We included 29 PD-nMCI and 11 PD-MCI patients. The HRQoL was assessed with the Parkinson's Disease Questionnaire-39 (PDQ-39): its Cognition dimension was used as a measure of subjective cognitive complaints, its Communication dimension for subjective communicative complaints, and the summary index (PDQ-39 SI) as an indicator of HRQoL. Non-parametric partial correlations between the Cognition and Communication dimensions, and the adjusted PDQ-39 SI were conducted.

Results: PD-MCI patients had greater subjective cognitive and communicative complaints and worse HRQoL than PD-nMCI patients. In the PD-MCI group, both subjective cognitive and communicative complaints exhibited significant direct correlations with the adjusted HRQoL scores.

Conclusions: HRQoL seems to be affected in PD-MCI, and it might be influenced by greater subjective cognitive and communicative complaints. Including patient-reported outcome measures of HRQoL, and providing cognitive and speech rehabilitation, as well as psychotherapeutic strategies to face these deficits can enhance the patient-centred approach in PD.
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http://dx.doi.org/10.1016/j.rcp.2021.07.005DOI Listing
September 2021

Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer's Disease.

J Alzheimers Dis 2021 Aug 25. Epub 2021 Aug 25.

King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.

Background: Blood plasma proteins have been associated with Alzheimer's disease (AD), but understanding which proteins are on the causal pathway remains challenging.

Objective: Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR).

Methods: Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/-PRS) and tested for association with AD status across three cohorts (n = 6,244). An AD PRS was also tested for association with protein levels in one cohort (n = 410). Proteins showing association with AD were taken forward for MR.

Results: For APOE ɛ3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p <  0.00017). No protein APOE- PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p = 0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p = 0.025, protein APOE- PRS p = 0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p <  0.05) in either direction.

Conclusion: Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.
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http://dx.doi.org/10.3233/JAD-210462DOI Listing
August 2021

Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment and Alzheimer's disease with dementia.

Int Psychogeriatr 2021 Aug 17:1-12. Epub 2021 Aug 17.

Norwegian Centre for Mental Disorders Research (NORMENT), Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

We present associations between neuropsychiatric symptoms (NPS) and brain morphology in a large sample of patients with mild cognitive impairment (MCI) and Alzheimer's disease with dementia (AD dementia).Several studies assessed NPS factor structure in MCI and AD dementia, but we know of no study that tested for associations between NPS factors and brain morphology. The use of factor scores increases parsimony and power. For transparency, we performed an additional analysis with selected Neuropsychiatric Inventory - Questionnaire (NPI-Q) items. Including regional cortical thickness, cortical and subcortical volumes, we examined associations between NPS and brain morphology across the whole brain in an unbiased fashion. We reported both statistical significance and effect sizes, using linear models adjusted for multiple comparisons by false discovery rate (FDR). Moreover, we included an interaction term for diagnosis and could thereby compare associations of NPS and brain morphology between MCI and AD dementia.We found an association between the factor elation and thicker right anterior cingulate cortex across MCI and AD dementia. Associations between the factors depression to thickness of the banks of the left superior temporal sulcus and psychosis to the left post-central volume depended on diagnosis: in MCI these associations were positive, in AD dementia negative.Our findings indicate that NPS in MCI and AD dementia are not exclusively associated with atrophy and support previous findings of associations between NPS and mainly frontotemporal brain structures.

Objectives: Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment (MCI) and Alzheimer’s disease with dementia (AD dementia), but their brain structural correlates are unknown. We tested for associations between NPS and MRI-based cortical and subcortical morphometry in patients with MCI and AD dementia.

Design: Cross-sectional.

Settings: Conducted in Norway.

Participants: Patients with MCI (n = 102) and AD dementia (n = 133) from the Memory Clinic and the Geriatric Psychiatry Unit at Oslo University Hospital.

Measurements: Neuropsychiatric Inventory – Questionnaire (NPI-Q) severity indices were reduced using principal component analysis (PCA) and tested for associations with 170 MRI features using linear models and false discovery rate (FDR) adjustment. We also tested for differences between groups. For transparency, we added analyses with selected NPI-Q items.

Results: PCA revealed four factors: elation, psychosis, depression, and motor behavior.FDR adjustment revealed a significant positive association (B = 0.20, pFDR < 0.005) between elation and thickness of the right caudal anterior cingulate cortex (ACC) across groups, and significant interactions between diagnosis and psychosis (B = −0.48, pFDR < 0.0010) on the left post-central volume and between diagnosis and depression (B = −0.40, pFDR < 0.005) on the thickness of the banks of the left superior temporal sulcus. Associations of apathy, anxiety, and nighttime behavior to the left temporal lobe were replicated.

Conclusions: The positive association between elation and ACC thickness suggests that mechanisms other than atrophy underly elation. Interactions between diagnosis and NPS on MRI features suggest different mechanisms of NPS in our MCI and AD dementia samples. The results contribute to a better understanding of NPS brain mechanisms in MCI and AD dementia.
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http://dx.doi.org/10.1017/S1041610221000934DOI Listing
August 2021

Validity and Cultural Generalisability of a 5-Minute AI-Based, Computerised Cognitive Assessment in Mild Cognitive Impairment and Alzheimer's Dementia.

Front Psychiatry 2021 22;12:706695. Epub 2021 Jul 22.

Cognetivity Ltd, London, United Kingdom.

Early detection and monitoring of mild cognitive impairment (MCI) and Alzheimer's Disease (AD) patients are key to tackling dementia and providing benefits to patients, caregivers, healthcare providers and society. We developed the Integrated Cognitive Assessment (ICA); a 5-min, language independent computerised cognitive test that employs an Artificial Intelligence (AI) model to improve its accuracy in detecting cognitive impairment. In this study, we aimed to evaluate the generalisability of the ICA in detecting cognitive impairment in MCI and mild AD patients. We studied the ICA in 230 participants. 95 healthy volunteers, 80 MCI, and 55 mild AD participants completed the ICA, Montreal Cognitive Assessment (MoCA) and Addenbrooke's Cognitive Examination (ACE) cognitive tests. The ICA demonstrated convergent validity with MoCA (Pearson r=0.58, p<0.0001) and ACE (r=0.62, p<0.0001). The ICA AI model was able to detect cognitive impairment with an AUC of 81% for MCI patients, and 88% for mild AD patients. The AI model demonstrated improved performance with increased training data and showed generalisability in performance from one population to another. The ICA correlation of 0.17 ( = 0.01) with education years is considerably smaller than that of MoCA ( = 0.34, < 0.0001) and ACE ( = 0.41, < 0.0001) which displayed significant correlations. In a separate study the ICA demonstrated no significant practise effect over the duration of the study. The ICA can support clinicians by aiding accurate diagnosis of MCI and AD and is appropriate for large-scale screening of cognitive impairment. The ICA is unbiased by differences in language, culture, and education.
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http://dx.doi.org/10.3389/fpsyt.2021.706695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339427PMC
July 2021

What does feeling younger or older than one's chronological age mean to men and women? Qualitative and quantitative findings from the PROTECT study.

Psychol Health 2021 Aug 5:1-24. Epub 2021 Aug 5.

College of Medicine and Health, University of Exeter, Exeter, United Kingdom.

Objective: We explored which factors are associated with subjective age (SA), i.e. feeling younger, the same as, or older than one's chronological age, and whether these factors differ between men and women and between two age sub-groups.

Design: Cross-sectional study using qualitative and quantitative data for 1457 individuals (mean age= 67.2 years).

Main Outcome Measures: Participants reported how old they feel they are and provided comments in relation to their SA judgments.

Results: By using content analysis participants' comments were assigned to 13 categories, grouped into three higher-order categories ( and ). SA may result from the interaction between factors that increase or decrease age-related thoughts and mental processes that individuals use to interpret age-related changes. Chi-squared tests show that individuals reporting an older SA are more likely to experience significant negative changes and to engage in negative age-related thoughts than individuals reporting an age-congruent SA or a younger SA. Women experience a more negative SA and more age-salient events than men.

Conclusion: Individuals reporting an older SA may benefit from interventions promoting adaptation to negative age-related changes. There is the need to eradicate negative societal views of older women.
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http://dx.doi.org/10.1080/08870446.2021.1960989DOI Listing
August 2021

Muscle volume and intramuscular fat of the tongue evaluated with MRI predict malnutrition in people living with dementia: a five-year follow-up study.

J Gerontol A Biol Sci Med Sci 2021 Aug 2. Epub 2021 Aug 2.

Department of Medicine-Western Health, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia.

Malnutrition is highly prevalent in older persons with dementia. Therefore, strong predictors of malnutrition in this population are crucial to initiating early interventions. This study evaluates the association between the probability of having malnutrition with the muscle volume and intramuscular fat (iMAT) of the masseter and the tongue in magnetic resonance images (MRI) of community-dwelling older persons diagnosed with mild dementia followed for five years. This is a longitudinal study conducted in the western part of Norway. Muscle volume and iMAT of the tongue and masseter were computed from structural head MRIs obtained from 65 participants of The Dementia Study of Western Norway (DemVest) using Slice-O-Matic software for segmentation. Malnutrition was assessed using the glim index. Linear mix models were conducted. Having malnutrition at baseline was associated with lower muscle volume (OR 0.60 SE 0.20 p=0.010) and higher iMAT (OR 3.31 SE 0.46 p=0.010) in the tongue. At five years follow-up, those with lower muscle volume (OR 0.55, SE 0.20 p=0.002) and higher iMAT (OR 2.52, SE 0.40 p=0.022) in the tongue had a higher probability of presenting malnutrition. The masseter iMAT and volume were not associated with malnutrition in any of the adjusted models.In people diagnosed with mild dementia, tongue muscle volume and iMAT were associated with baseline malnutrition and the probability of developing malnutrition in a 5-year trajectory. In the masseter, there were no significant associations after adjustments.
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http://dx.doi.org/10.1093/gerona/glab224DOI Listing
August 2021

A 3D deep learning model to predict the diagnosis of dementia with Lewy bodies, Alzheimer's disease, and mild cognitive impairment using brain 18F-FDG PET.

Eur J Nucl Med Mol Imaging 2021 Jul 30. Epub 2021 Jul 30.

Department of Clinical Physiology, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.

Purpose: The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimer's disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model's performance to that of multiple expert nuclear medicine physicians' readers.

Materials And Methods: Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer's disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model's performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention.

Results: The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6-100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7-100) in AD, 71.4% (51.6-91.2) in MCI-AD, and 94.7% (90-99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders.

Conclusion: Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus.
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http://dx.doi.org/10.1007/s00259-021-05483-0DOI Listing
July 2021

Association Between Amygdala Volume and Trajectories of Neuropsychiatric Symptoms in Alzheimer's Disease and Dementia With Lewy Bodies.

Front Neurol 2021 7;12:679984. Epub 2021 Jul 7.

Centre for Age-Related Medicine (SESAM), Stavanger University Hospital, Stavanger, Norway.

The amygdala is implicated in psychiatric illness. Even as the amygdala undergoes significant atrophy in mild dementia, amygdala volume is underexplored as a risk factor for neuropsychiatric symptoms (NPS). To analyze the association between baseline amygdala volume and the longitudinal trajectories of NPS and cognitive decline in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) over 5 years. Eighty-nine patients with mild dementia were included (AD = 55; DLB = 34). Amygdala volume was segmented from structural magnetic resonance images (sMRI) using a semi-automatic method (Freesurfer 6.0) and normalized by intracranial volumes. The intracranial volume-normalized amygdala was used as a predictor of the Neuropsychiatric Inventory (NPI) total score, ordinal NPI item scores (0 = absence of symptoms, 1-3 = mild symptoms, ≥4 = clinically relevant symptoms), and Mini-Mental State Examination (MMSE) as measured annually over 5 years using gamma, ordinal, and linear mixed-effects models, respectively. The models were adjusted for demographic variables, diagnosis, center of sMRI acquisition, and cognitive performance. Multiple testing-corrected -values (-values) are reported. Larger intracranial volume-normalized amygdala was associated with less agitation/aggression (odds ratio (OR) = 0.62 [0.43, 0.90], = 0.011, = 0.038) and less MMSE decline per year (fixed effect = 0.70, [0.29, 1.03], = 0.001, = 0.010) but more depression (OR = 1.49 [1.09, 2.04], = 0.013, = 0.040). Greater amygdala volume in mild dementia is associated with lower odds of developing agitation/aggression, but higher odds of developing depression symptoms during the 5-year study period.
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http://dx.doi.org/10.3389/fneur.2021.679984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292611PMC
July 2021

Author Correction: Parkinson disease-associated cognitive impairment.

Nat Rev Dis Primers 2021 Jul 13;7(1):53. Epub 2021 Jul 13.

Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

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http://dx.doi.org/10.1038/s41572-021-00292-zDOI Listing
July 2021

Treatment Efficacy and Acceptabilityof Pharmacotherapies for Dementia with Lewy Bodies: A Systematic Review and Network Meta-Analysis.

Arch Gerontol Geriatr 2021 Sep-Oct;96:104474. Epub 2021 Jul 2.

Institute of Psychiatry, King's College London, UK; Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; College of Medicine, China Medical University, Taichung, Taiwan; An-Nan Hospital, China Medical University, Tainan, Taiwan. Electronic address:

Introduction: We investigated the efficacy and acceptability of pharmacotherapy for dementia with Lewy bodies (DLB) while simultaneously considering the neuropsychiatric symptoms (NPS), cognitive function, motor symptoms, and acceptability.

Methods: Electronic databases were searched from inception through June 5, 2019, for randomized controlled trials (RCTs) and open-label trials (OLTs) in patients with DLB. We performed a pairwise conventional meta-analysis (PWMA) and network meta-analysis (NMA) within a frequentist framework. The main outcomes were mean change scores in NPS, general cognition, motor symptoms and acceptability. The effect sizes and odds ratios with 95% confidence intervals (CIs) were calculated. This study was registered with PROSPERO (CRD42018096996).

Results: In total, we included 29 studies (9 RCTs and 20 OLTs). In the NMA with 9 RCTs, both high- (mean difference [MD] 2.00, 95% CIs, 0.69 to 3.31) and low-dose (1.86, 0.58 to 3.15) donepezil were associated with a greater cognitive improvement than placebo. High-dose zonisamide was associated with greater motor symptom improvement ( -4.10, -7.03 to -1.17]). No medications reached statistical significance regarding improving neuropsychiatric symptoms or developing intolerable adverse effects as compared to placebo. In the second NMA, with 29 studies as an exploratory analysis, aripiprazole and yokukansan may be effective for neuropsychiatric symptoms, while levodopa may be associated with cognitive impairment.

Conclusions: We report the most comprehensive evidence for the selection of pharmacotherapy for treating different clusters of DLB-related symptoms. Due to the limited availability of RCTs on DLB, more well-conducted RCTs are needed for MMA to warrant clinical efficacy in the future.
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http://dx.doi.org/10.1016/j.archger.2021.104474DOI Listing
September 2021

Relieving Caregiver Burden Through Evidence-Based Treatment for Dementia-Related Psychosis.

J Clin Psychiatry 2021 07 6;82(4). Epub 2021 Jul 6.

National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation and Institute of Psychiatry, Psychology & Neuroscience at King's College London, United Kingdom.

Dementia-related psychosis (DRP), which includes delusions and hallucinations, contributes to patient and caregiver burden of dementia. Delusions and hallucinations occur in all forms of dementia and at all stages. Certain tactics should be used when talking with patients and their care partners, and some evidence can be shared that may relieve some of the distress of DRP. When treating symptoms of DRP, clinicians should follow guidelines recommendations, such as using medication only if the patient or others are in severe distress or danger and starting with low doses. Long-term treatment is not recommended. Novel antipsychotics or alternative agents may offer superior efficacy and safety compared with standard atypical antipsychotics, but more evidence-based treatment options are needed.
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http://dx.doi.org/10.4088/JCP.AD19038AH5CDOI Listing
July 2021

Polypharmacy is associated with functional decline in Alzheimer's disease and Lewy body dementia.

Arch Gerontol Geriatr 2021 Sep-Oct;96:104459. Epub 2021 Jun 24.

Centre for Age-Related Medicine (SESAM), Stavanger University Hospital, Stavanger, Norway; Department of Old Age Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.

Background: In dementia, a number of factors may influence functional decline in addition to cognition. In this study, we aimed to study the potential association of the number of prescribed medications with functional decline trajectories over a five-year follow-up in people diagnosed with mild Alzheimer's disease (AD) or Lewy Body dementia (LBD).

Methods: This is a longitudinal analysis of a Norwegian cohort study entitled "The Dementia Study of Western Norway". We included 196 patients newly diagnosed with AD (n=111) and LBD (n=85), followed annually for 5 years. We conducted linear mixed-effects models to analyse the association of the number of medications with functional decline measured by the Rapid Disability Rating Scale - 2.

Results: The mean prescribed medications at baseline was 4.18∓2.60, for AD 3.92∓2.51 and LBD 4.52∓2.70. The number of medications increased during the follow-up; at year five the mean for AD was 7.28∓4.42 and for LBD 8.11∓5.16. Using more medications was associated with faster functional decline in AD (Est 0.04, SE 0.01, p-value 0.003) and LBD (Est 0.08, SE 0.03, p-value 0.008) after adjusting for age, sex, comorbidity, neuropsychiatric symptoms, and cognition. For each medication added during the follow-up, functional trajectories worsened by 1% for AD and 2% for LBD. The number of medications was not associated with cognitive decline.

Conclusion: We found that higher number of medications was related to a faster functional decline, both in AD and LBD. With disease progression, there was an increase in the number of medications. Prescription in dementia should be carefully assessed, possibly improving the functional prognosis.
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http://dx.doi.org/10.1016/j.archger.2021.104459DOI Listing
September 2021

Parkinson disease-associated cognitive impairment.

Nat Rev Dis Primers 2021 07 1;7(1):47. Epub 2021 Jul 1.

Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting >1% of the population ≥65 years of age and with a prevalence set to double by 2030. In addition to the defining motor symptoms of PD, multiple non-motor symptoms occur; among them, cognitive impairment is common and can potentially occur at any disease stage. Cognitive decline is usually slow and insidious, but rapid in some cases. Recently, the focus has been on the early cognitive changes, where executive and visuospatial impairments are typical and can be accompanied by memory impairment, increasing the risk for early progression to dementia. Other risk factors for early progression to dementia include visual hallucinations, older age and biomarker changes such as cortical atrophy, as well as Alzheimer-type changes on functional imaging and in cerebrospinal fluid, and slowing and frequency variation on EEG. However, the mechanisms underlying cognitive decline in PD remain largely unclear. Cortical involvement of Lewy body and Alzheimer-type pathologies are key features, but multiple mechanisms are likely involved. Cholinesterase inhibition is the only high-level evidence-based treatment available, but other pharmacological and non-pharmacological strategies are being tested. Challenges include the identification of disease-modifying therapies as well as finding biomarkers to better predict cognitive decline and identify patients at high risk for early and rapid cognitive impairment.
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http://dx.doi.org/10.1038/s41572-021-00280-3DOI Listing
July 2021

An international, randomized, placebo-controlled, phase 2b clinical trial of intepirdine for dementia with Lewy bodies (HEADWAY-DLB).

Alzheimers Dement (N Y) 2021 20;7(1):e12171. Epub 2021 Jun 20.

Department of Neurology University of Nevada (NLV) and Cleveland Clinic Lou Ruvo Center for Brain Health Las Vegas Nevada USA.

Introduction: A phase 2b clinical trial, HEADWAY-DLB, was performed to assess treatment with intepirdine, a serotonin receptor antagonist, in patients with dementia with Lewy bodies (DLB).

Methods: HEADWAY-DLB was a multinational, double-blind, randomized, placebo-controlled study. Two hundred sixty-nine DLB patients were randomized to receive placebo, 70 mg/day intepirdine, or 35 mg/day intepirdine over 24 weeks. The primary endpoint was change from baseline to week 24 on the Unified Parkinson's Disease Rating Scale-Part III (UPDRS-III).

Results: Both intepirdine groups did not demonstrate significant benefits over placebo at 24 weeks on the UPDRS-III (35 mg/day:  = .1580, 70 mg/day:  = .6069). All other endpoints were not significant. Intepirdine was well tolerated, with a slightly higher incidence of gastrointestinal adverse events observed in the intepirdine groups versus placebo.

Discussion: Intepirdine treatment did not lead to improvements over placebo in patients with DLB. As one of the largest DLB studies to date, HEADWAY-DLB demonstrates that international trials for DLB are feasible within a reasonable timeframe.
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http://dx.doi.org/10.1002/trc2.12171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215076PMC
June 2021

Plasma Neurofilament Light Chain Predicts Cognitive Progression in Prodromal and Clinical Dementia with Lewy Bodies.

J Alzheimers Dis 2021 ;82(3):913-919

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex, and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB.
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http://dx.doi.org/10.3233/JAD-210342DOI Listing
September 2021

Cerebrovascular disease, neurodegeneration, and clinical phenotype in dementia with Lewy bodies.

Neurobiol Aging 2021 09 14;105:252-261. Epub 2021 May 14.

Department of Radiology, Mayo Clinic, Rochester, MN, USA. Electronic address:

We investigated whether cerebrovascular disease contributes to neurodegeneration and clinical phenotype in dementia with Lewy bodies (DLB). Regional cortical thickness and subcortical gray matter volumes were estimated from structural magnetic resonance imaging (MRI) in 165 DLB patients. Cortical and subcortical infarcts were recorded and white matter hyperintensities (WMHs) were assessed. Subcortical only infarcts were more frequent (13.3%) than cortical only infarcts (3.1%) or both subcortical and cortical infarcts (2.4%). Infarcts, irrespective of type, were associated with WMHs. A higher WMH volume was associated with thinner orbitofrontal, retrosplenial, and posterior cingulate cortices, smaller thalamus and pallidum, and larger caudate volume. A higher WMH volume was associated with the presence of visual hallucinations and lower global cognitive performance, and tended to be associated with the absence of probable rapid eye movement sleep behavior disorder. Presence of infarcts was associated with the absence of parkinsonism. We conclude that cerebrovascular disease is associated with gray matter neurodegeneration in patients with probable DLB, which may have implications for the multifactorial treatment of probable DLB.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338792PMC
September 2021

A genome-wide association study of plasma phosphorylated tau181.

Neurobiol Aging 2021 10 4;106:304.e1-304.e3. Epub 2021 May 4.

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. Electronic address:

Plasma phosphorylated tau at threonine-181 (P-tau181) demonstrates promise as an accessible blood-based biomarker specific to Alzheimer's Disease (AD), with levels recently demonstrating high predictive accuracy for AD-relevant pathology. The genetic underpinnings of P-tau181 levels, however, remain elusive. This study presents the first genome-wide association study of plasma P-tau181 in a total sample of 1153 participants from 2 independent cohorts. No loci, other than those within the APOE genomic region (lead variant = rs429358, beta = 0.32, p =8.44 × 10) demonstrated association with P-tau181 at genome-wide significance (p < 5 × 10), though rs60872856 on chromosome 2 came close (beta = -0.28, p = 3.23 × 10, nearest gene=CYTIP). As the APOE ε4 allele is already a well-established genetic variant associated with AD, this study found no evidence of novel genetic associations relevant to plasma P-tau181, though presents rs60872856 on chromosome 2 as a candidate locus to be further evaluated in future larger size GWAS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.04.018DOI Listing
October 2021

Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.

Mol Psychiatry 2021 Jun 10. Epub 2021 Jun 10.

Neuroscience Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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http://dx.doi.org/10.1038/s41380-021-01152-8DOI Listing
June 2021

A multicentre validation study of the diagnostic value of plasma neurofilament light.

Nat Commun 2021 06 7;12(1):3400. Epub 2021 Jun 7.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
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http://dx.doi.org/10.1038/s41467-021-23620-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185001PMC
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration in .

Brain Commun 2021 22;3(2):fcab049. Epub 2021 Mar 22.

Department of Basic & Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London SE5 9RX, UK.

Alpha-synuclein (α-syn) mislocalization and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying α-syn accumulation and toxicity in a model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human α-syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, cysteine string protein, synapsin, and syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These α-syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of dementia with Lewy bodies. Together, these findings demonstrate that presynaptic accumulation of α-syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that α-syn-mediated synaptopathy is an initiating cause of age-related neurodegeneration.
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http://dx.doi.org/10.1093/braincomms/fcab049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111063PMC
March 2021

Regression-based norms for the FAS phonemic fluency test for ages 40-84 based on a Norwegian sample.

Appl Neuropsychol Adult 2021 May 8:1-10. Epub 2021 May 8.

Department of Psychology, Faculty of Health Sciences, The Arctic University of Norway, Tromsø, Norway.

The FAS phonemic fluency test is a commonly used neuropsychological test of executive function and processing speed. Although Norwegian discrete norms have been developed for the FAS test, American regression-based norms are frequently used by clinicians in Norway.However, language and cultural differences impact performance on the FAS test, and using foreign norms may not be appropriate. Moreover, while discrete norming relies on stratified subgroups of demographics, regression-based norming uses the entire sample to estimate the influence of demographics on performance and may thus improve normative estimates. Here we develop regression-based norms for the FAS phonemic fluency test based on  = 204 healthy Norwegian controls between the ages 40-84 from the Norwegian Dementia Disease Initiation cohort (DDI). We compare the proposed regression norms to published Norwegian discrete norms and American regression-based norms in an independent sample of  = 182 cognitively healthy adults reporting subjective cognitive decline (SCD). We found that years of education was the only significant predictor of FAS performance in our normative sample, accounting for 14.9% of the variance. Both the proposed regression-based norms and previously published discrete norms adequately adjusted for demographics in the independent sample. In contrast, the American norms underestimated the effect of education and overestimated the effect of age. While both the proposed Norwegian regression norms and the previously published discrete norms are suitable for use in Norway, the proposed regression norms may be less vulnerable to sub-stratification sample characteristics posed by discrete norming procedures, and thereby improve normative estimation.
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http://dx.doi.org/10.1080/23279095.2021.1918128DOI Listing
May 2021

Remote monitoring technologies in Alzheimer's disease: design of the RADAR-AD study.

Alzheimers Res Ther 2021 04 23;13(1):89. Epub 2021 Apr 23.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, the Netherlands.

Background: Functional decline in Alzheimer's disease (AD) is typically measured using single-time point subjective rating scales, which rely on direct observation or (caregiver) recall. Remote monitoring technologies (RMTs), such as smartphone applications, wearables, and home-based sensors, can change these periodic subjective assessments to more frequent, or even continuous, objective monitoring. The aim of the RADAR-AD study is to assess the accuracy and validity of RMTs in measuring functional decline in a real-world environment across preclinical-to-moderate stages of AD compared to standard clinical rating scales.

Methods: This study includes three tiers. For the main study, we will include participants (n = 220) with preclinical AD, prodromal AD, mild-to-moderate AD, and healthy controls, classified by MMSE and CDR score, from clinical sites equally distributed over 13 European countries. Participants will undergo extensive neuropsychological testing and physical examination. The RMT assessments, performed over an 8-week period, include walk tests, financial management tasks, an augmented reality game, two activity trackers, and two smartphone applications installed on the participants' phone. In the first sub-study, fixed sensors will be installed in the homes of a representative sub-sample of 40 participants. In the second sub-study, 10 participants will stay in a smart home for 1 week. The primary outcome of this study is the difference in functional domain profiles assessed using RMTs between the four study groups. The four participant groups will be compared for each RMT outcome measure separately. Each RMT outcome will be compared to a standard clinical test which measures the same functional or cognitive domain. Finally, multivariate prediction models will be developed. Data collection and privacy are important aspects of the project, which will be managed using the RADAR-base data platform running on specifically designed biomedical research computing infrastructure.

Results: First results are expected to be disseminated in 2022.

Conclusion: Our study is well placed to evaluate the clinical utility of RMT assessments. Leveraging modern-day technology may deliver new and improved methods for accurately monitoring functional decline in all stages of AD. It is greatly anticipated that these methods could lead to objective and real-life functional endpoints with increased sensitivity to pharmacological agent signal detection.
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http://dx.doi.org/10.1186/s13195-021-00825-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063580PMC
April 2021

Serum tyrosine is associated with better cognition in Lewy body dementia.

Brain Res 2021 08 16;1765:147481. Epub 2021 Apr 16.

Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.

Amino acids' neuroactivity, and roles in excitotoxity and oxidative stress are linked to dementia. We aimed to investigate whether circulating amino acid concentrations were associated with cognitive decline in patients with mild Alzheimer's disease (AD) and Lewy body dementia (LBD). Baseline serum amino acid concentrations were measured in 89 patients with AD and 65 with LBD (13 with Parkinson's disease dementia and 52 with dementia with Lewy bodies). The Mini-Mental State Examination (MMSE) was administered at baseline and annually for five years. Associations between baseline amino acid concentrations and longitudinal MMSE score were assessed using a linear-mixed effects model stratified by diagnosis with adjustment for multiple comparisons. The results of the study indicated that serum tyrosine was positively associated with MMSE performance during the five-year follow-up period in patients with LBD (q-value = 0.012), but not AD. In conclusion, higher baseline serum concentrations of tyrosine, the precursor amino acid in dopamine and norepinephrine synthesis, was associated with better cognitive performance in patients with LBD, but not AD, throughout the 5-year follow-up period.
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http://dx.doi.org/10.1016/j.brainres.2021.147481DOI Listing
August 2021

Constipation is Associated with Development of Cognitive Impairment in de novo Parkinson's Disease: A Longitudinal Analysis of Two International Cohorts.

J Parkinsons Dis 2021;11(3):1209-1219

Institute of Psychiatry, Psychology & Neuroscience, Department of Neurosciences, King's College London, London, United Kingdom.

Background: Constipation is regarded as one of the prodromal features of Parkinson's disease (PD) and there is emerging evidence linking gastrointestinal dysfunction and cognitive impairment (CI) in PD.

Objective: We explored whether constipation is associated with development of CI in two independent cohorts of de novo PD patients (n = 196 from the Non-motor International Longitudinal Study [NILS] and n = 423 from the Parkinson's Progression Markers Initiative [PPMI] study).

Methods: Constipation was clinically defined using the Non-Motor Symptoms Scale (NMSS) item-21 [NILS] and Scales for Outcomes in PD-Autonomic (SCOPA-AUT) item-5 [PPMI]. We assessed baseline group differences (PD with or without constipation) in CI, global non-motor symptoms burden, motor dysfunction, and striatal dopaminergic denervation. Kaplan-Meier method estimated group differences in cumulative proportion of patients with incident CI over three years. In PPMI, we subsequently performed univariate and multivariate Cox survival analyses to evaluate whether constipation predicts incident mild cognitive impairment or dementia over a 6-year period, including constipation and other known predictors of CI as covariates.

Results: Patients with constipation had greater motor and global non-motor burden in both cohorts at baseline (p < 0.05). Kaplan-Meier plots showed faster conversion to CI in patients with constipation in both cohorts (p < 0.05). In PPMI, 37 subjects developed dementia during a mean follow-up of 4.9 years, and constipation was an independent predictor of dementia onset (hazard ratio = 2.311; p = 0.02).

Conclusion: Constipation in de novo PD patients is associated with development of cognitive decline and may serve as a clinical biomarker for identification of patients at risk for cognitive impairment.
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http://dx.doi.org/10.3233/JPD-212570DOI Listing
January 2021
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