Publications by authors named "Marleen van de Beek"

9 Publications

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Genetics Contributes to Concomitant Pathology and Clinical Presentation in Dementia with Lewy Bodies.

J Alzheimers Dis 2021 Jul 23. Epub 2021 Jul 23.

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

Background: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity.

Objective: We tested if genetic variants in part explain the heterogeneity in DLB.

Methods: We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer's disease (AD-PRS) and Parkinson's disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer's dementia Cohort and compared them to 2,552 control subjects. The p-tau/Aβ 1-42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration.

Results: We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ɛ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ɛ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features.

Conclusion: These finding increase our understanding of the pathological and clinical heterogeneity in DLB.
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http://dx.doi.org/10.3233/JAD-210365DOI Listing
July 2021

Diagnostic Value of the CSF α-Synuclein Real-Time Quaking-Induced Conversion Assay at the Prodromal MCI Stage of Dementia With Lewy Bodies.

Neurology 2021 Jul 1. Epub 2021 Jul 1.

IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy

Objective: To investigate whether the cerebrospinal fluid (CSF) α-synuclein (α-syn) real-time quaking-induced conversion (RT-QuIC) assay accurately identifies patients with mild cognitive impairment due to probable Lewy body disease (MCI-LB).

Methods: We applied α-syn RT-QuIC to 289 CSF samples obtained from two independent cohorts, including 81 patients with probable MCI-LB (70.7±6.6 y, 13.6% F, MMSE 26.1±2.4), 120 with probable MCI-AD (68.6±7.4 y, 45.8% F, MMSE 25.5±2.8), and 30 with unspecified MCI (65.4±9.3 y, 30.0% F, MMSE 27.0±3.0). Fifty-eight individuals with no cognitive decline or evidence of neurodegenerative disease and 121 individuals lacking brain α-syn deposits at the neuropathological examination were used as controls.

Results: RT-QuIC identified MCI-LB patients against cognitively unimpaired controls with 95% sensitivity, 97% specificity, and 96% accuracy, and showed 98% specificity in neuropathological controls. The accuracy of the test for MCI-LB was consistent between the two cohorts (97.3% vs. 93.7%). Thirteen percent of MCI-AD patients also had a positive test; of note, 44% of them developed one core or supportive clinical feature of dementia with Lewy bodies (DLB) at follow-up, suggesting an underlying LB co-pathology.

Conclusions: These findings indicate that CSF α-syn RT-QuIC is a robust biomarker for prodromal DLB. Further studies are needed to fully explore the added value of the assay to the current research criteria for MCI-LB.

Classification Of Evidence: This study provides Class III evidence that CSF α-syn RT-QuIC accurately identifies patients with MCI due to LB disease.
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http://dx.doi.org/10.1212/WNL.0000000000012438DOI Listing
July 2021

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

Neurobiol Aging 2021 Sep 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
September 2021

Psychosocial Effects of Corona Measures on Patients With Dementia, Mild Cognitive Impairment and Subjective Cognitive Decline.

Front Psychiatry 2020 26;11:585686. Epub 2020 Oct 26.

Department of Neurology, Alzheimer Center Amsterdam, Amsterdam University Medical Center, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

The recent COVID-19 pandemic is not only a major healthcare problem in itself, but also poses enormous social challenges. Though nursing homes increasingly receive attention, the majority of people with cognitive decline and dementia live at home. We aimed to explore the psychosocial effects of corona measures in memory clinic (pre-)dementia patients and their caregivers. Between April 28th and July 13th 2020, = 389 patients of Alzheimer center Amsterdam [ = 121 symptomatic (age = 69 ± 6, 33%F, MMSE = 23 ± 5), = 268 cognitively normal (age = 66 ± 8, 40% F, MMSE = 29 ± 1)] completed a survey on psychosocial effects of the corona measures. Questions related to social isolation, worries for faster cognitive decline, behavioral problems and discontinuation of care. In addition, = 147 caregivers of symptomatic patients completed a similar survey with additional questions on caregiver burden. Social isolation was experienced by = 42 (35%) symptomatic and = 67 (25%) cognitively normal patients and two third of patients [ = 129 (66%); = 58 (75%) symptomatic, = 71 (61%) cognitively normal] reported that care was discontinued. Worries for faster cognitive decline were existed in symptomatic patients [ = 44 (44%)] and caregivers [ = 73 (53%)], but were also reported by a subgroup of cognitively normal patients [ = 27 (14%)]. Both patients [ = 56 (46%) symptomatic, = 102 (38%) cognitively normal] and caregivers [ = 72 (48%)] reported an increase in psychological symptoms. More than three quarter of caregivers [ = 111(76%)] reported an increase in patients' behavioral problems. A higher caregiver burden was experienced by = 69 (56%) of caregivers and = 43 (29%) of them reported that a need for more support. Discontinuation of care (OR = 3.3 [1.3-7.9]), psychological (OR = 4.0 [1.6-9.9]) and behavioral problems (OR = 3.0 [1.0-9.0]) strongly related to experiencing a higher caregiver burden. Lastly, social isolation (OR = 3.2 [1.2-8.1]) and psychological symptoms (OR = 8.1 [2.8-23.7]) were red flags for worries for faster cognitive decline. Not only symptomatic patients, but also cognitively normal patients express worries for faster cognitive decline and psychological symptoms. Moreover, we identified patients who are at risk of adverse outcomes of the corona measures, i.e., discontinued care, social isolation, psychological and behavioral problems. This underlines the need for health care professionals to provide ways to warrant the continuation of care and support (informal) networks surrounding patients and caregivers to mitigate the higher risk of negative psychosocial effects.
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http://dx.doi.org/10.3389/fpsyt.2020.585686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649118PMC
October 2020

Diagnostic and prognostic value of EEG in prodromal dementia with Lewy bodies.

Neurology 2020 08 7;95(6):e662-e670. Epub 2020 Jul 7.

From the Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience (J.J.v.d.Z., A.A.G., I.v.S., M.v.d.B., P.S., A.W.L.), and Department of Clinical Neurophysiology (A.A.G., C.J.S.), Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands.

Objective: Early biomarkers for dementia with Lewy bodies (DLB) are lacking. To determine whether EEG differentiates the prodromal phase of DLB from other causes of mild cognitive impairment (MCI) and whether EEG is predictive for time to conversion from MCI to DLB, we compared EEGs and clinical follow-up of patients with MCI due to DLB with those of patients with MCI due to Alzheimer disease (MCI-AD).

Methods: We compared 37 patients with MCI who developed DLB during follow-up or had an abnormal I-PF-CIT SPECT scan (MCI-DLB) with 67 age-matched patients with MCI-AD. EEGs were assessed visually with a score of increasing abnormality (range 1-5). We performed fast Fourier transform to analyze the power spectrum. With survival analyses, EEG characteristics were related to time to progression to dementia.

Results: The visual EEG score was higher in MCI-DLB (score >2 in 60%) compared to MCI-AD (score >2 in 8%, < 0.001). We found frontal intermittent delta activity in 22% of MCI-DLB, not in MCI-AD. Patients with MCI-DLB had a lower peak frequency (7.5 [6.0-9.9] Hz vs 8.8 [6.8-10.2] in MCI-AD, < 0.001) and more slow-wave activity. Several individual EEG measures showed good performance to discriminate MCI-DLB from MCI-AD (areas under the curve up to 0.94). In MCI-DLB, high visual EEG score, diffuse abnormalities, and low α2 power were related to time to progression to dementia (hazard ratios 4.1, 9.9, 5.1, respectively).

Conclusions: Profound EEG abnormalities are already present in the prodromal stage of DLB and have diagnostic and prognostic value.

Classification Of Evidence: This study provides Class III evidence that EEG abnormalities are more common in MCI-DLB than MCI-AD.
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http://dx.doi.org/10.1212/WNL.0000000000009977DOI Listing
August 2020

Prodromal Dementia With Lewy Bodies: Clinical Characterization and Predictors of Progression.

Mov Disord 2020 05 11;35(5):859-867. Epub 2020 Feb 11.

Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam University Medical Centers, Amsterdam, the Netherlands.

Objective: The objective of this study was to examine clinical characteristics, cognitive decline, and predictors for time to dementia in prodromal dementia with Lewy bodies with mild cognitive impairment (MCI-LB) compared with prodromal Alzheimer's disease (MCI-AD).

Methods: We included 73 MCI-LB patients (12% female; 68 ± 6 years; Mini Mental State Examination, 27 ± 2) and 124 MCI-AD patients (48% female; 68 ± 7 years; Mini Mental State Examination, 27 ± 2) from the Amsterdam Dementia Cohort. Follow-up was available for 61 MCI-LB patients and all MCI-AD patients (3 ± 2 years). We evaluated dementia with Lewy bodies core features, neuropsychiatric symptoms, caregiver burden (Zarit caregiver burden interview), MRI, apolipoprotein genotype, and cerebrospinal fluid biomarkers (tau/Aβ ratio). Longitudinal outcome measures included cognitive slopes (memory, attention, executive functions, and language and visuospatial functions) and time to dementia.

Results: Parkinsonism was the most frequently present core feature in MCI-LB (69%). MCI-LB patients more often had neuropsychiatric symptoms and scored higher on ZARIT when compared with the MCI-AD patients. Linear mixed models showed that at baseline, MCI-LB patients performed worse on nonmemory cognitive domains, whereas memory performance was worse in MCI-AD patients. Over time, MCI-LB patients declined faster on attention, whereas MCI-AD patients declined faster on the Mini Mental State Examination and memory. Cox proportional hazards regressions showed that in the MCI-LB patients, lower attention (hazard ratio [HR] = 1.6; 95% confidence interval [CI], 1.1-2.3) and more posterior cortical atrophy (HR = 3.0; 95% CI, 1.5-5.8) predicted shorter time to dementia. In the MCI-AD patients, worse performance on memory (HR = 1.1; 95% CI, 1.0-1.2) and executive functions (HR = 1.3; 95% CI, 1.0-1.6) were independently associated with time to Alzheimer's dementia.

Conclusion: MCI-LB patients have distinct neuropsychiatric and cognitive profiles with prominent decline in attention when compared with MCI-AD patients. Our results highlight the importance of early diagnosis because symptoms already have an impact in the prodromal stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317511PMC
May 2020

The Value of Neuropsychological Assessment in the Differentiation Between Behavioral Variant Frontotemporal Dementia and Late-Onset Psychiatric Disorders.

J Clin Psychiatry 2020 02 4;81(1). Epub 2020 Feb 4.

Department of Old Age Psychiatry, GGZ inGeest, Amsterdam, The Netherlands.

Objective: To investigate which neuropsychological tests can discriminate between behavioral variant frontotemporal dementia (bvFTD) and psychiatric disorders presenting with similar late-onset frontal behavioral changes, such as apathy, disinhibition, reduced empathy, or compulsive behavior.

Methods: Patients presenting with frontal behavioral changes in middle or late adulthood received extensive baseline examinations, including neuropsychological assessment and brain imaging. After 2 years, examinations were repeated and patients were diagnosed according to DSM-IV or international bvFTD consensus criteria. The study period was April 2011-June 2015. Two groups were selected: 32 patients with bvFTD and 53 patients with a psychiatric or psychological diagnosis. Associations between neuropsychological test scores and diagnostic group were investigated with logistic regression analyses, and diagnostic accuracy was investigated with a receiver operating characteristic curve.

Results: BvFTD patients scored lower on tests for confrontational naming, gestalt completion, and verbal abstraction compared to psychiatric patients (P < .01). The confrontational naming test (Boston Naming Test) showed the strongest association with diagnostic group: a lower score indicated a higher probability for a bvFTD diagnosis (P < .001). This test could discriminate between the groups with good diagnostic accuracy (area under the curve = 0.81). Tests for attention, memory, and executive functions showed no discriminative ability between the groups.

Conclusions: Although one of the criteria of bvFTD is low performance on executive tests, these tests are not useful in differentiating bvFTD from psychiatric disorders. We recommend administering language tests, especially an extensive confrontational naming test, to aid differentiation between bvFTD and a psychiatric disorder in patients presenting with late-onset frontal behavioral changes.
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http://dx.doi.org/10.4088/JCP.19m12811DOI Listing
February 2020

Family History is Associated with Phenotype in Dementia with Lewy Bodies.

J Alzheimers Dis 2020 ;73(1):269-275

Alzheimer Center Erasmus MC, Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.

It is currently unknown whether patients with dementia with Lewy bodies (DLB) with relatives with dementia or Parkinson's disease (familial DLB patients) have a different phenotype than sporadic DLB patients. In this study, we aimed to examine disease onset, rate of cognitive decline, survival, and Alzheimer's disease (AD) biomarkers in patients with familial DLB (n = 154) and sporadic DLB (n = 137), using linear mixed model analysis and Cox regression analysis, among others. Familial patients had a shorter survival (8.0 years) and more often elevated cerebrospinal fluid AD biomarkers (47%) than sporadic patients (9.0 years; p≤0.001; 30%, p = 0.037). Our findings suggest that genetic factors are important in DLB and that the identification of new genetic factors will probably improve the prediction of prognosis.
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http://dx.doi.org/10.3233/JAD-190825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029358PMC
April 2021

Trajectories and Determinants of Quality of Life in Dementia with Lewy Bodies and Alzheimer's Disease.

J Alzheimers Dis 2019 ;70(2):389-397

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

Background: Quality of Life (QoL) is an important outcome measure in dementia, particularly in the context of interventions. Research investigating longitudinal QoL in dementia with Lewy bodies (DLB) is currently lacking.

Objective: To investigate determinants and trajectories of QoL in DLB compared to Alzheimer's disease (AD) and controls.

Methods: QoL was assessed annually in 138 individuals, using the EQ5D-utility-score (0-100) and the health-related Visual Analogue Scale (VAS, 0-100). Twenty-nine DLB patients (age 69±6), 68 AD patients (age 70±6), and 41 controls (age 70±5) were selected from the Dutch Parelsnoer Institute-Neurodegenerative diseases and Amsterdam Dementia Cohort. We examined clinical work-up over time as determinants of QoL, including cognitive tests, neuropsychiatric inventory, Geriatric Depression Scale (GDS), and disability assessment of dementia (DAD).

Results: Mixed models showed lower baseline VAS-scores in DLB compared to AD and controls (AD: β±SE = -7.6±2.8, controls: β±SE = -7.9±3.0, p < 0.05). An interaction between diagnosis and time since diagnosis indicated steeper decline on VAS-scores for AD patients compared to DLB patients (β±SE = 2.9±1.5, p < 0.1). EQ5D-utility-scores over time did not differ between groups. Higher GDS and lower DAD-scores were independently associated with lower QoL in dementia patients (GDS: VAS β±SE = -1.8±0.3, EQ5D-utility β±SE = -3.7±0.4; DAD: VAS = 0.1±0.0, EQ5D-utility β±SE = 0.1±0.1, p < 0.05). No associations between cognitive tests and QoL remained in the multivariate model.

Conclusion: QoL is lower in DLB, while in AD QoL shows steeper decline as the disease advances. Our results indicate that non-cognitive symptoms, more than cognitive symptoms, are highly relevant as they impact QoL.
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http://dx.doi.org/10.3233/JAD-190041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839497PMC
October 2020
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