Subjective cognitive decline and self-reported sleep problems: The SCIENCe project.

We aim to investigate the frequency and type of sleep problems in memory clinic patients with subjective cognitive decline (SCD) and their association with cognition, mental health, brain magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) biomarkers. Three hundred eight subjects (65 ± 8 years, 44% female) were selected from the Subjective Cognitive Impairment Cohort (SCIENCe) project. All subjects answered two sleep questionnaires, Berlin Questionnaire (sleep apnea) and Pittsburgh Sleep Quality Index (sleep quality) and underwent a standardized memory clinic work-up. One hundred ninety-eight (64%) subjects reported sleep problems, based on 107 (35%) positive screenings on sleep apnea and 162 (53%) on poor sleep quality. Subjects with sleep problems reported more severe depressive symptoms, more anxiety, and more severe SCD. Cognitive tests, MRI, and CSF biomarkers did not differ between groups. Our results suggest that improvement of sleep quality and behaviors are potential leads for treatment in many subjects with SCD to relieve the experienced cognitive complaints.

Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline.

BACKGROUND AND OBJECTIVES: Multiple biomarkers have been suggested to measure neurodegeneration (N) in the AT(N) framework, leading to inconsistencies between studies. We investigated the association of 5 N biomarkers with clinical progression and cognitive decline in individuals with subjective cognitive decline (SCD). METHODS: We included individuals with SCD from the Amsterdam Dementia Cohort and SCIENCe project, a longitudinal cohort study (follow-up 4±3 years). We used the following N biomarkers: CSF total tau (t-tau), medial temporal atrophy visual rating on MRI, hippocampal volume (HV), serum neurofilament light (NfL), and serum glial fibrillary acidic protein (GFAP). We determined correlations between biomarkers. We assessed associations between N biomarkers and clinical progression to mild cognitive impairment or dementia (Cox regression) and Mini-Mental State Examination (MMSE) over time (linear mixed models). Models included age, sex, CSF ß-amyloid (Aß) (A), and CSF p-tau (T) as covariates, in addition to the N biomarker. RESULT: We included 401 individuals (61±9 years, 42% female, MMSE 28 ± 2, vascular comorbidities 8%-19%). N biomarkers were modestly to moderately correlated (range r -0.28 - 0.58). Serum NfL and GFAP correlated most strongly (r 0.58, p < 0.01). T-tau was strongly correlated with p-tau (r 0.89, p < 0.01), although these biomarkers supposedly represent separate biomarker groups. All N biomarkers individually predicted clinical progression, but only HV, NfL, and GFAP added predictive value beyond Aß and p-tau (hazard ratio 1.52 [95% CI 1.11-2.09]; 1.51 [1.05-2.17]; 1.50 [1.04-2.15]). T-tau, HV, and GFAP individually predicted MMSE slope (range ß -0.17 to -0.11, p < 0.05), but only HV remained associated beyond Aß and p-tau (ß -0.13 [SE 0.04]; p < 0.05). DISCUSSION: In cognitively unimpaired older adults, correlations between different N biomarkers were only moderate, indicating they reflect different aspects of neurodegeneration and should not be used interchangeably. T-tau was strongly associated with p-tau (T), which makes it less desirable to use as a measure for N. HV, NfL, and GFAP predicted clinical progression beyond A and T. Our results do not allow to choose one most suitable biomarker for N, but illustrate the added prognostic value of N beyond A and T. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that HV, NfL, and GFAP predicted clinical progression beyond A and T in individuals with SCD.

Psychosocial Effects of COVID-19 Measures on (Pre-)Dementia Patients During Second Lockdown.

BACKGROUND: The COVID-19 pandemic poses enormous social challenges, especially during lockdown. People with cognitive decline and their caregivers are particularly at risk of lockdown consequences. OBJECTIVE: To investigate psychosocial effects in (pre-)dementia patients and caregivers during second lockdown and compare effects between first and second lockdown. METHODS: We included n = 511 (pre-)dementia patients and n = 826 caregivers from the Amsterdam Dementia Cohort and via Alzheimer Nederland. All respondents completed a self-designed survey on psychosocial effects of COVID-19. We examined relations between experienced support and psychosocial and behavioral symptoms using logistic regression. In a subset of patients and caregivers we compared responses between first and second lockdown using generalized estimating equation (GEE). RESULTS: The majority of patients (≥58%) and caregivers (≥60%) reported that family and friends, hobbies, and music helped them cope. Support from family and friends was strongly related to less negative feelings in patients (loneliness: OR = 0.3[0.1-0.6]) and caregivers (loneliness: OR = 0.2[0.1-0.3]; depression: OR = 0.4[0.2-0.5]; anxiety: OR = 0.4[0.3-0.6]; uncertainty: OR = 0.3[0.2-0.5]; fatigue: OR = 0.3[0.2-0.4]; stress: OR = 0.3[0.2-0.5]). In second lockdown, less psychosocial and behavioral symptoms were reported compared to first lockdown (patients; e.g., anxiety: 22% versus 13%, p = 0.007; apathy: 27% versus 8%, p < 0.001, caregivers; e.g., anxiety: 23% versus 16%, p = 0.033; patient's behavioral problems: 50% versus 35%, p < 0.001). Patients experienced more support (e.g., family and friends: 52% versus 93%, p < 0.001; neighbors: 28% versus 66%, p < 0.001). CONCLUSION: During second lockdown, patients and caregivers adapted to challenges posed by lockdown, as psychosocial and behavioral effects decreased, while patients experienced more social support compared to first lockdown. Support from family and friends is a major protective factor for negative outcomes in patients and caregivers.

BDNF-Met polymorphism and amyloid-beta in relation to cognitive decline in cognitively normal elderly: the SCIENCe project.

Brain-derived neurotrophic factor (BNDF) plays a role in synapse integrity. We investigated in 398 cognitively normal adults (60±8years, 41% female, MMSE=28±1) the joint association of the Val66Met polymorphism of the BDNF gene (Met+/-) and plasma BDNF levels and abnormal cerebrospinal fluid (CSF) amyloid-beta status (A+/-) with cognitive decline and dementia risk. Age-, sex- and education-adjusted linear mixed models showed that compared to Met-A-, Met+A+ showed steeper decline on tests of global cognition, memory, language, attention and executive functioning, while Met-A+ showed steeper decline on a smaller number of tests. There were no associations between Met+A- and cognitive decline. Cox models showed that compared to Met-A-, Met+A+ participants were at increased risk of dementia (HR=8.8, 95%CI: 2.8-27.9), as were Met-A+ participants (HR=6.5, 95%CI: 2.2-19.5). Lower plasma BDNF was associated with an increased risk of progression to dementia in the A+ participants. Our results imply that Met-carriage on top of amyloid-beta pathology might increase rate of cognitive decline to dementia.

Serum markers glial fibrillary acidic protein and neurofilament light for prognosis and monitoring in cognitively normal older people: a prospective memory clinic-based cohort study.

BACKGROUND: Serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are putative non-amyloid blood-based biomarkers indicative of ongoing inflammatory and neurodegenerative disease processes. We aimed to assess their prognostic and monitoring value for progression to dementia in individuals presenting at a memory clinic who are cognitively normal. METHODS: For this prospective cohort study, we included individuals who were cognitively normal from the Amsterdam Dementia Cohort and received screening for dementia at first visit and annual follow-up visits. Participants without a serum sample stored in the Amsterdam Dementia Biobank within 6 months of baseline visit and without a follow-up diagnosis after a minimum of 6 months were excluded. We measured serum GFAP and NfL levels at baseline for all participants and at follow-up for a subset of participants. Using Cox proportional hazard models, we investigated associations of biomarker levels (Z-transformed) with incident dementia (adjusted for age and sex), by entering the markers first separately and then simultaneously, to test independent associations. We also assessed longitudinal performance of the markers on a standardised neuropsychological test battery covering global cognition, memory, language, executive functioning, and attention (adjusted for age, sex, and education). Finally, we evaluated the association of slopes of biomarker levels with incident dementia (adjusted for age and sex). FINDINGS: Between July 13, 2001, and Aug 17, 2016, 300 individuals were included in the study. Mean baseline age was 61 years (SD 9), 125 (42%) of participants were women, and mini-mental state examination was 29 (IQR 27-29). Median follow-up time was 3·0 years (IQR 1·9-4·2), with a median of three visits per participant (range 2-12; 1010 total neuropsychological evaluations). During follow-up, 27 (9%) of 300 individuals developed dementia. Both high baseline GFAP (hazard ratio 3·6, 95% CI 2·2-5·7; p<0·0001) and high baseline NfL (1·8, 1·2-2·8; p=0·0037) were associated with increased risk of dementia. When entering both markers simultaneously in the model, only GFAP remained associated with an increased risk of dementia (3·3, 1·9-5·5; p<0·0001). When additionally entering (inverted) plasma amyloid ß42/40, both GFAP (2·6, 1·4-5·0; p=0·0026) and amyloid ß42/40 (2·1, 1·2-3·6; p=0·0091) were independently associated with incident dementia whereas NfL was not (1·4, 0·8-2·5; p=0·28). Linear mixed models showed that higher baseline GFAP levels were associated with a steeper rate of decline in the domains of memory, attention, and executive functioning (pfalse discovery rate<0·05), whereas higher NfL levels were not. Repeated serum GFAP and NfL analyses revealed that NfL levels rose more steeply over time in individuals with incident dementia compared with those without (p=0·0006), whereas GFAP levels did not (p=0·074). INTERPRETATION: Our results suggest that, while serum NfL seems to have potential as monitoring biomarker, GFAP might be a valuable prognostic biomarker, predicting incident dementia. FUNDING: Alzheimer Nederland, Gieskes Strijbis Fonds.

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

Background: 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. Methods: Between April 28th and July 13th 2020, n = 389 patients of Alzheimer center Amsterdam [n = 121 symptomatic (age = 69 ± 6, 33%F, MMSE = 23 ± 5), n = 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, n = 147 caregivers of symptomatic patients completed a similar survey with additional questions on caregiver burden. Results: Social isolation was experienced by n = 42 (35%) symptomatic and n = 67 (25%) cognitively normal patients and two third of patients [n = 129 (66%); n = 58 (75%) symptomatic, n = 71 (61%) cognitively normal] reported that care was discontinued. Worries for faster cognitive decline were existed in symptomatic patients [n = 44 (44%)] and caregivers [n = 73 (53%)], but were also reported by a subgroup of cognitively normal patients [n = 27 (14%)]. Both patients [n = 56 (46%) symptomatic, n = 102 (38%) cognitively normal] and caregivers [n = 72 (48%)] reported an increase in psychological symptoms. More than three quarter of caregivers [n = 111(76%)] reported an increase in patients' behavioral problems. A higher caregiver burden was experienced by n = 69 (56%) of caregivers and n = 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. Conclusion: 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.

An Operational Definition of 'Abnormal Cognition' to Optimize the Prediction of Progression to Dementia: What Are Optimal Cut-Off Points for Univariate and Multivariate Normative Comparisons?

BACKGROUND: In neuropsychology and neurology, there is no consensus on the definition of abnormal cognition. OBJECTIVE: To operationally define 'abnormal cognition' for optimally predicting progression to dementia in a memory clinic sample, and to test whether multivariate profile analysis of cognitive test results improves this prediction compared to standard clinical evaluation. METHODS: We used longitudinal data from 835 non-demented patients of the Amsterdam Dementia Cohort. For 10 cognitive measures at baseline, we determined which number of abnormal tests and which magnitude of score deviations best predicted progression. RESULTS: Predictive ability for progression to dementia of one, two, and three abnormal test scores out of 10 is highly similar (Cox hazard ratios: 3.7-4.1) provided cut-off values are adapted appropriately. Cut-offs have to be less stringent if the number of abnormal tests required increases: the optimal cut-off is z < -1.45 when one deviating score is required, z < -1.15 when two abnormal tests are required, and z < -0.70 when three abnormal tests are required. The profile analysis has similar predictive ability at the cut-off of p < 0.22 (hazard ratio 3.8). A likelihood ratio test showed that this analysis improves prediction of progression to dementia when added to standard clinical evaluation (p < 0.001). CONCLUSION: Abnormal cognition may be defined as one, two, or three abnormal test scores out of 10 if the magnitude of score deviations is adapted accordingly. An abnormal score profile predicts decline to dementia equally well, and improves the prediction when used complimentary to standard clinical evaluation.

ATN classification and clinical progression in subjective cognitive decline: The SCIENCe project.

OBJECTIVE: To investigate the relationship between the ATN classification system (amyloid, tau, neurodegeneration) and risk of dementia and cognitive decline in individuals with subjective cognitive decline (SCD). METHODS: We classified 693 participants with SCD (60 ± 9 years, 41% women, Mini-Mental State Examination score 28 ± 2) from the Amsterdam Dementia Cohort and Subjective Cognitive Impairment Cohort (SCIENCe) project according to the ATN model, as determined by amyloid PET or CSF ß-amyloid (A), CSF p-tau (T), and MRI-based medial temporal lobe atrophy (N). All underwent extensive neuropsychological assessment. For 342 participants, follow-up was available (3 ± 2 years). As a control population, we included 124 participants without SCD. RESULTS: Fifty-six (n = 385) participants had normal Alzheimer disease (AD) biomarkers (A-T-N-), 27% (n = 186) had non-AD pathologic change (A-T-N+, A-T+N-, A-T+N+), 18% (n = 122) fell within the Alzheimer continuum (A+T-N-, A+T-N+, A+T+N-, A+T+N+). ATN profiles were unevenly distributed, with A-T+N+, A+T-N+, and A+T+N+ containing very few participants. Cox regression showed that compared to A-T-N-, participants in A+ profiles had a higher risk of dementia with a dose-response pattern for number of biomarkers affected. Linear mixed models showed participants in A+ profiles showed a steeper decline on tests addressing memory, attention, language, and executive functions. In the control group, there was no association between ATN and cognition. CONCLUSIONS: Among individuals presenting with SCD at a memory clinic, those with a biomarker profile A-T+N+, A+T-N-, A+T+N-, and A+T+N+ were at increased risk of dementia, and showed steeper cognitive decline compared to A-T-N- individuals. These results suggest a future where biomarker results could be used for individualized risk profiling in cognitively normal individuals presenting at a memory clinic.

Plasma amyloid is associated with the rate of cognitive decline in cognitively normal elderly: the SCIENCe project.

Plasma biomarkers are promising prognostic tools in individuals with subjective cognitive decline (SCD). We aimed to investigate the relationships of baseline plasma amyloid beta (Aß)42/Aß40 and total Tau (tTau) with rate of cognitive decline, in comparison to relationships of baseline cerebrospinal fluid (CSF) Aß42, tTau, and phosphorylated tau181 (pTau181) with rate of cognitive decline. We included 241 subjects with SCD (age = 61 ± 9, 40% female, Mini-Mental State Examination = 28 ± 2) with follow-up (average: 2 ± 2 years, median visits: 3 [range: 1-11]) for re-evaluation of neuropsychological test performance (attention, memory, language, and executive functioning domains). Using age, gender and education-adjusted linear mixed models, we found that lower plasma Aß42/Aß40 was associated with steeper rate of decline on tests for attention, memory, and executive functioning, but not language. Lower CSF Aß42 was associated with steeper decline on tests covering all domains. Associations for plasma amyloid and cognitive decline mirror those of CSF amyloid. Plasma tTau was not associated with rate of cognitive decline, whereas CSF tTau and pTau181 were on multiple tests covering all domains.

The decline step-down test measuring the maximum pain-free flexion angle: A reliable and valid performance test in patients with patellofemoral pain.

OBJECTIVES: Patients with patellofemoral pain (PFP) experience pain while descending stairs. To date no reliable and valid performance-test exists to assess the maximum pain-free knee flexion angle (MPFFA) as outcome measure during a step-down task. Therefore, the intra- and inter-observer reliability and construct validity of the decline step-down test (DSDT) measuring the MPFFA in patients with PFP were evaluated. DESIGN: Reliability and construct validity. SETTING: Private practices in Nijmegen and Utrecht, the Netherlands. PARTICIPANTS: Patients with PFP. MAIN OUTCOME MEASURES: The reliability was assessed by repeated measurements of the MPFFA during the DSDT. The construct validity was assessed by correlating the measurements on the DSDT with the Anterior Knee Pain Scale Dutch Version (AKPS-DV) based on a pre-set hypothesis. RESULTS: Thirty-two participants (forty-eight knees) were eligible for inclusion. The intraclass correlation coefficient (ICC) for intra-observer reliability was ICC2,1 = 0.83 and ICC2,1 = 0.85 for inter-observer reliability. The 95% limits of agreement (LoA) showed a width of 27.56° for intra-observer reliability and a width of 24.42° for inter-observer reliability. There was an average positive correlation between the DSDT and the total score on the AKPS-DV (rs = 0.31, p = 0.030). CONCLUSION: The DSDT measuring the MPFFA is reliable and valid in patients with PFP.