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Philip Scheltens

Publications and source records attributed to Philip Scheltens.

At least 19 recordsLinked to original sources
PubMed2025

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer's disease.

BACKGROUND: Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear. METHODS: To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls. RESULTS: In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects. CONCLUSION: Our results justify a debate on whether HPV carriers should be considered for clinical counseling.

Humans↗
PubMed2025

Synaptic protein CSF levels relate to memory scores in individuals without dementia.

BACKGROUND: We investigated how cerebrospinal fluid levels of synaptic proteins associate with memory function in normal cognition (CN) and mild cognitive impairment (MCI), and investigated the effect of amyloid positivity on these associations. METHODS: We included 242 CN (105(43%) abnormal amyloid), and 278 MCI individuals (183(66%) abnormal amyloid) from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). For 181 (EMIF-AD MBD) and 36 (ADNI) proteins with a synaptic annotation in SynGO, associations with word learning recall were analysed with linear models. RESULTS: Subsets of synaptic proteins showed lower levels with worse recall in preclinical AD (EMIF-AD MBD: 7, ADNI: 5 proteins, none overlapping), prodromal AD (EMIF-AD MBD only, 27 proteins) and non-AD MCI (EMIF-AD MBD: 1, ADNI: 7 proteins). The majority of these associations were specific to these clinical groups. CONCLUSIONS: Synaptic disturbance-related memory impairment occurred very early in AD, indicating it may be relevant to develop therapies targeting the synapse early in the disease.

Humans↗
PubMed2007

CSF and MRI markers independently contribute to the diagnosis of Alzheimer's disease.

BACKGROUND: Decreased amyloid beta (1-42) (Abeta42) and increased (phosphorylated) tau in cerebrospinal fluid (CSF) are considered to be a reflection of plaques, tangles, and neuronal degeneration in Alzheimer's disease (AD). Atrophy of the medial temporal lobe (MTA) on magnetic resonance imaging (MRI) reflects neuronal loss in this area. OBJECTIVE: To compare diagnostic accuracy of CSF biomarkers and MTA in AD versus controls. METHODS: Abeta42, tau and tau phosphorylated at threonine 181 (Ptau-181) were measured in CSF from 61 AD patients and 32 controls by sandwich enzyme-linked immunosorbent assay. A CSF biomarker profile for AD was constructed. MTA was rated visually on MRI. RESULTS: When AD patients and controls were evaluated separately, no correlations were present between the CSF markers and MTA score. Both MTA and CSF biomarker profile were independently associated with the diagnosis AD (MTA: OR (95% CI)=28 (3-239); CSF biomarker profile: OR (95% CI)=57 (13-262)). Among individuals younger than 65 years old and without MTA 60% suffered AD, and the finding of an abnormal CSF biomarker profile was limited to AD patients only. CONCLUSIONS: MTA and CSF biomarkers seem to be of incremental value for the diagnosis AD. CSF analysis is most sensitive in the absence of MTA, and especially among early-onset AD patients.

Aged↗
PubMed2007

Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia.

BACKGROUND: Individuals diagnosed as having mild cognitive impairment (MCI) have a high likelihood of progressing to dementia within 3 to 5 years, but not all individuals with MCI progress to dementia. Prognostic uncertainty suggests the need for additional measures to assist the clinician. OBJECTIVE: To assess the added value of qualitative measures of medial temporal atrophy (MTA) to estimate the relative risk of progressing from MCI to dementia. DESIGN: A 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study initially designed to evaluate the efficacy of donepezil hydrochloride or vitamin E vs placebo to delay progression of MCI to dementia. SETTING: Memory assessment centers. PATIENTS: A total of 190 individuals with MCI. MAIN OUTCOME MEASURES: Ratings of MTA performed using magnetic resonance images obtained at baseline. Log-rank tests and Cox proportional hazards ratios examining the significance of MTA estimates in predicting progression of MCI to dementia. RESULTS: A mean MTA score greater than 2.0 was associated with a greater than 2-fold increased likelihood of progression to dementia during the observation period (hazards ratio, 2.30; 95% confidence interval, 1.09-4.92; P = .03) after controlling for age, education, sex, and baseline Mini-Mental State Examination score. CONCLUSIONS: Adjusted estimates of MTA were associated with significantly increased risk of developing dementia within 3 years, suggesting that obtaining a magnetic resonance image during the evaluation of MCI may offer additional independent information about the risk of progression to dementia. Given the relatively high prevalence of MCI in the general population, use of this method as part of routine clinical evaluation may help identify individuals who might benefit from increased surveillance and future treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000173.

Aged↗
PubMed2006

Brain lesions on MRI in elderly patients with type 2 diabetes mellitus.

BACKGROUND AND PURPOSE: Diabetes mellitus (DM) type 2 has been associated with poor cognitive performance and dementia, particularly in elderly patients. The exact mechanisms underlying the cognitive dysfunction in DM remain unclear. Imaging studies of the brain could be helpful to give more insight into possible structural brain lesions underlying these cognitive dysfunctions. Therefore, we performed a study in independently living patients with DM type 2 in order to investigate the association between DM and brain imaging abnormalities. METHODS: The study population consisted of 45 patients with DM type 2 without hypertension (mean age 73.4 +/- 5.1 years, mean duration 16.5 +/- 11.5 years), 45 patients with DM type 2 and hypertension (mean age 73.5 +/- 6.1 years, mean duration 11.9 +/- 9.2 years) and 44 control subjects (mean age 73.1 +/- 5.4 years). All patients and control subjects underwent an MRI of the brain. White matter lesions (WML), cerebral atrophy and medial temporal lobe atrophy were rated by a standardized visual rating scale. Lacunar infarcts were defined as focal hypo-intensities on fluid-attenuated inversion recovery sequences with a hyperintense rim around it. RESULTS: WML occurred more frequently in diabetic patients with hypertension as well as without hypertension. Significantly more deep WML were found in DM patients with and without hypertension when compared to control subjects, whereas no difference was found in the occurrence of periventricular hyperintensities. In all 3 groups, lacunar infarcts occurred sporadically. A trend towards higher atrophy scores was seen in patients with DM compared to control subjects. CONCLUSIONS: The data of this cross-sectional study suggest that type 2 DM is an independent risk factor for deep WML in the independently living elderly patients.

Aged↗
PubMed2006

Cognitive impairment in heart failure: a systematic review of the literature.

BACKGROUND: Heart failure (HF) and cognitive impairment are common medical conditions that are becoming increasingly prevalent in the aging Western population. They are associated with frequent hospitalisation and increased mortality, particularly when they occur simultaneously. Evidence from a number of studies suggests that HF is independently associated with impairment in various cognitive domains. AIMS: This systematic literature review evaluates the relation between cognitive deterioration and heart failure. METHODS: We searched electronic databases from 1966 to May 2006 for studies that investigated cognitive function in HF patients. Twenty-two controlled studies that met the inclusion criteria were selected for analysis. Study characteristics and data on global cognitive performance, memory scores, psychomotor speed and depression scores were extracted and analysed using the Cochrane Review Manager software. RESULTS: Pooled analysis shows diminished neuropsychological performance in HF patients, as compared to control subjects. In a pooled sample of 2937 heart-failure patients and 14,848 control subjects, the odds ratio for cognitive impairment was 1.62 (95% confidence interval:1.48-1.79, p<0.0001) among subjects with HF. CONCLUSION: This review confirms the relationship between HF and cognitive impairment, but it also stresses the need for additional systematic neuropsychological data and adequate neuro-imaging from representative populations of HF patients.

Case-Control Studies↗
PubMed2006

Apolipoprotein E genotype influences presence and severity of delusions and aggressive behavior in Alzheimer disease.

AIM: We investigated differences in the prevalence and severity of 10 neuropsychiatric and behavioral symptoms according to apolipoprotein E (APOE) genotype and dementia severity in Alzheimer disease (AD). METHODS: Neuropsychiatric and behavioral symptoms of 110 AD patients were assessed using the Neuropsychatric Inventory. Dementia severity was assessed using the Mini Mental State Examination (MMSE). RESULTS: There were 27 APOE-epsilon4-negative patients, 65 heterozygous patients and 18 homozygous patients. There was a significant association between the number of APOE epsilon4 alleles and prevalence and severity of neuropsychiatric and behavioral symptoms that was mainly attributable to delusions and agitation/aggression, which were more common and severer among homozygous APOE epsilon4 carriers. In addition, the presence of hallucinations, anxiety, apathy and aberrant motor behavior increased with deteriorating MMSE score, independently of APOE epsilon4 status. CONCLUSIONS: The present study showed that the APOE epsilon4 genotype modifies neuropsychiatric and behavioral phenotype in AD. In particular, it was shown that delusions and agitation/aggression were more common and severer among homozygous APOE epsilon4 carriers than among heterozygous or APOE-epsilon4-negative patients.

Aged↗
PubMed2006

Corpus callosum atrophy is associated with mental slowing and executive deficits in subjects with age-related white matter hyperintensities: the LADIS Study.

BACKGROUND: Previous research has indicated that corpus callosum atrophy is associated with global cognitive decline in neurodegenerative diseases, but few studies have investigated specific cognitive functions. OBJECTIVE: To investigate the role of regional corpus callosum atrophy in mental speed, attention and executive functions in subjects with age-related white matter hyperintensities (WMH). METHODS: In the Leukoaraiosis and Disability Study, 567 subjects with age-related WMH were examined with a detailed neuropsychological assessment and quantitative magnetic resonance imaging. The relationships of the total corpus callosum area and its subregions with cognitive performance were analysed using multiple linear regression, controlling for volume of WMH and other confounding factors. RESULTS: Atrophy of the total corpus callosum area was associated with poor performance in tests assessing speed of mental processing--namely, trail making A and Stroop test parts I and II. Anterior, but not posterior, corpus callosum atrophy was associated with deficits of attention and executive functions as reflected by the symbol digit modalities and digit cancellation tests, as well as by the subtraction scores in the trail making and Stroop tests. Furthermore, semantic verbal fluency was related to the total corpus callosum area and the isthmus subregion. CONCLUSIONS: Corpus callosum atrophy seems to contribute to cognitive decline independently of age, education, coexisting WMH and stroke. Anterior corpus callosum atrophy is related to the frontal-lobe-mediated executive functions and attention, whereas overall corpus callosum atrophy is associated with the slowing of processing speed.

Aged↗
PubMed2006

Effects of high-frequency cranial electrostimulation on the rest-activity rhythm and salivary cortisol in Alzheimer's disease: a pilot study.

OBJECTIVE: In a previous study, low-frequency (0.5 Hz) cranial electrostimulation (CES) neither improved the rest-activity rhythm nor reduced the level of salivary cortisol in patients with probable Alzheimer's disease (AD). To investigate whether the frequency of CES was responsible for these negative findings, we set out to examine the effects of high-frequency CES on the rest-activity rhythm and salivary cortisol of patients with probable AD. We hypothesized that a decreased level of cortisol would parallel a positive effect of high-frequency CES on nocturnal restlessness in AD patients. METHODS: Twenty AD patients were randomly assigned to an experimental group (n = 10) and a control group (n = 10). The experimental group was treated with high-frequency CES, the control group received sham stimulation, for 30 min a day, during 6 weeks. The rest-activity rhythm was assessed by actigraphy. Level of cortisol was measured by means of salivette tubes. RESULTS: The rest-activity rhythm and the level of salivary cortisol did not react positively to high-frequency CES. In contrast, both groups showed an increase in the level of cortisol after the 6-week treatment period. CONCLUSIONS: High-frequency CES appeared to be ineffective in AD patients.

Aged↗
PubMed2006

White matter lesions are associated with progression of medial temporal lobe atrophy in Alzheimer disease.

BACKGROUND AND PURPOSE: Medial temporal lobe atrophy (MTA) is a hallmark of Alzheimer disease (AD). Its progression is often seen during the course of AD, but its frequency and risk factors remain unclear. METHODS: We investigated MTA in 35 patients with AD from whom sequential magnetic resonance imaging scans were available. White matter lesions (WML; for the periventricular [PV] and subcortical [SC] regions separately) and MTA were rated semiquantitatively. RESULTS: In approximately two thirds of all patients, progression of MTA was found. The mean MTA progression was 0.8 (standard deviation: 0.5) and 0.3 (standard deviation: 0.4) for patients with or without PVWML at baseline (P=0.01). Patients who showed progression of PVWML over the course of their disease had a significantly higher mean progression of MTA than those without PVWML progression (0.9 [SD: 0.4]) and 0.4 [SD: 0.5]; P=0.01). Patients with PVWML at baseline had a 40-fold increased risk for progression of MTA compared with those without baseline PVWML (odds ratio=40.0, 95% CI=1.3 to 1.2x10(3), P=0.03). Patients with progression of PVWML during the course of the disease had an increased risk for MTA progression (odds ratio=3.7 per unit increase of progression of PVWML, 95% CI=1.1 to 12.9, P=0.04). There was higher risk for progression of MTA for those with progression of PVWML than those without (odds ratio=10.9, 95% CI=1.0 to 122.5, P=0.05). This was not found for SCWML. CONCLUSIONS: Our findings suggest that the presence and the progression of WML are associated with progression of MTA in AD. WML may be a predictor of the course of the disease and a potential treatment target in AD.

Aged↗
PubMed2006

Endogenous cortisol level interacts with noradrenergic activation in the human amygdala.

Animal studies show that high cortisol levels exert their effect on stressful task performance via modulation of the amygdala. Availability of noradrenaline in this brain region appears to be a critical prerequisite for this effect. This relationship between noradrenaline and cortisol is explained by an animal model where the amygdala constitutes a crucial region for this interaction. In humans this model has not been extensively tested so far. In a previously reported study human subjects (aged 20.93+/-2.38) were scanned using fMRI when watching sets of emotional and neutral pictures after taking the beta-adrenergic antagonist propranolol or placebo. Stimulus sets consisted of 92 pictures, divided in four emotional categories that ranged from neutral scenes of domestic objects (CAT1) to extremely negative scenes of mutilation or accidents (CAT4). Confrontation with arousing emotional pictures, accompanied by increased noradrenaline levels, evoked increased amygdala activation under placebo but not under betablocker condition. This new and additional analysis of this data set was carried out to determine the effect of differential endogenous cortisol levels on amygdala activation. Cortisol levels during scanning were determined using salivary samples and subjects were post hoc divided in a High (n=14) and Low cortisol group (n=14). When subjects were watching emotional stimuli, presumably associated with enhanced noradrenaline (NA) levels, amygdala activation was contrasted between the two cortisol groups. We hypothesized that emotional stimuli would elicit more amygdala activation in the High than in the Low cortisol group. Here we demonstrate indeed a significant interaction effect of the endogenous cortisol level with increasing activation in the amygdala under placebo but not under betablocker condition, thereby extending the rodent based model of a synergistic effect of the two stress hormones to the human.

Adolescent↗
PubMed2006

Pain intensity and pain affect in relation to white matter changes.

Since aging is a risk factor for both dementia and the occurrence of painful conditions, with the number of aged people increasing in the next decades, an increase in the number of elderly people suffering from both conditions can be anticipated. Reliable pain assessment in this population is restricted by reduced communicative and cognitive capacity, with serious consequences for effective pain treatment. White matter changes are frequently observed in the various subtypes of dementia as well as in normal aging, and may play a crucial role in pain processing. In healthy elderly people, reliable pain assessment can be accomplished, which enables examining the relationship between pain experience and white matter changes. A normal structure and function of the white matter is extremely important for dorsolateral prefrontal cortex (DLPFC) functioning, which has recently been linked to pain inhibition. The present study focused on the relation between white matter changes and both pain intensity and pain affect in elderly people without dementia. The Coloured Analogue Scale (CAS) and the Number of Words Chosen-Affective (NWC-A) were applied to measure pain intensity and pain affect, respectively. The presence of white matter changes was significantly related to a higher score on the NWC-A but not the CAS score. These results suggest that pain experience may change as a result of aging and that white matter changes might be indicative for these alterations.

Affect↗
PubMed2006

Mild cognitive impairment.

Mild cognitive impairment is a syndrome defined as cognitive decline greater than expected for an individual's age and education level but that does not interfere notably with activities of daily life. Prevalence in population-based epidemiological studies ranges from 3% to 19% in adults older than 65 years. Some people with mild cognitive impairment seem to remain stable or return to normal over time, but more than half progress to dementia within 5 years. Mild cognitive impairment can thus be regarded as a risk state for dementia, and its identification could lead to secondary prevention by controlling risk factors such as systolic hypertension. The amnestic subtype of mild cognitive impairment has a high risk of progression to Alzheimer's disease, and it could constitute a prodromal stage of this disorder. Other definitions and subtypes of mild cognitive impairment need to be studied as potential prodromes of Alzheimer's disease and other types of dementia.

Aged↗
PubMed2006

Age, hypertension, and lacunar stroke are the major determinants of the severity of age-related white matter changes. The LADIS (Leukoaraiosis and Disability in the Elderly) Study.

BACKGROUND: Age-related white matter changes (ARWMC), seen on neuroimaging with high frequency in older people, are thought to be consequent to the effect of vascular risk factors and vascular diseases including hypertension and stroke. Among the proofs conventionally required for a factor to be considered a risk factor for a definite pathology, there is the demonstration of a trend in risk exposure related to disease severity. We sought whether such a trend existed in the association of vascular risk factors or comorbidities with the severity of ARWMC aiming particularly at further elucidating the relative roles of hypertension and stroke in this regard. METHODS: The LADIS (Leukoaraiosis and Disability) Study is evaluating the role of ARWMC as an independent determinant of the transition to disability in the elderly. Six hundred and thirty-nine nondisabled subjects (mean age 74.1+/-5.0, M/F: 288/351) with ARWMC of different severity grades on MRI (mild, moderate, or severe according to the Fazekas scale) were assessed at baseline for demographics, vascular risk factors, and comorbidities, and are being followed up for 3 years. RESULTS: Age, frequency of hypertension and history of stroke increased along with increasing ARWMC severity independently of other factors. For hypertension, however, this occurred only in subjects without a stroke history, while for stroke history, it mainly depended on lacunar stroke. The amount of cigarettes smoked and the interaction between hypercholesterolemia and smoking predicted only the most severe ARWMC grade. CONCLUSIONS: The LADIS Study confirms that age, hypertension and lacunar strokes are the major determinants of ARWMC. Smoking and hypercholesterolemia provide additional risk.

Age Factors↗
PubMed2006

Impact of white matter hyperintensities scoring method on correlations with clinical data: the LADIS study.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) are associated with decline in cognition, gait, mood, and urinary continence. Associations may depend on the method used for measuring WMH. We investigated the ability of different WMH scoring methods to detect differences in WMH load between groups with and without symptoms. METHODS: We used data of 618 independently living elderly with WMH collected in the Leukoaraiosis And DISability (LADIS) study. Subjects with and without symptoms of depression, gait disturbances, urinary incontinence, and memory decline were compared with respect to WMH load measured qualitatively using 3 widely used visual rating scales (Fazekas, Scheltens, and Age-Related White Matter Changes scales) and quantitatively with a semiautomated volumetric technique and an automatic lesion count. Statistical significance between groups was assessed with the chi2 and Mann-Whitney tests. In addition, the punctate and confluent lesion type with comparable WMH volume were compared with respect to the clinical data using Student t test and chi2 test. Direct comparison of visual ratings with volumetry was done using curve fitting. RESULTS: Visual and volumetric assessment detected differences in WMH between groups with respect to gait disturbances and age. WMH volume measurement was more sensitive than visual scores with respect to memory symptoms. Number of lesions nor lesion type correlated with any of the clinical data. For all rating scales, a clear but nonlinear relationship was established with WMH volume. CONCLUSIONS: Visual rating scales display ceiling effects and poor discrimination of absolute lesion volumes. Consequently, they may be less sensitive in differentiating clinical groups.

Aged↗
PubMed2006

Differential regional atrophy of the cingulate gyrus in Alzheimer disease: a volumetric MRI study.

Magnetic resonance imaging-based volumetric measurements provide a useful technique for quantifying in vivo regional cerebral atrophy in Alzheimer disease (AD). Histopathological studies have shown the cingulate cortex, a cytoarchitectonically heterogeneous region, to be severely affected in AD. In this study, we developed and validated a manual segmentation protocol, based on macroscopic characteristics such as gyri and sulci patterns, in order to assess volumetric changes in 4 cingulate regions of interest. Cingulate cortical volumes of 10 familial AD patients were compared with 10 age- and sex-matched controls. Inter- and intrarater reliability coefficients were high for all cingulate regions (91.9-99.4%). All 4 cingulate regions were significantly smaller (P < 0.05) in AD cases compared with controls: rostral anterior cingulate gyrus (22.5% smaller), caudal anterior cingulate gyrus (20.7% smaller), posterior cingulate gyrus (44.1% smaller), and retrosplenial cortex (21.5% smaller). The atrophy in the posterior cingulate region was significantly greater than that in other cingulate regions (P < 0.001), suggesting a higher vulnerability for this region in familial AD. Considering the functional and connectional differences of these 4 cingulate regions, detection and monitoring of their atrophy may provide insights into the natural history of AD and may help in the search for diagnostic markers for early AD.

Alzheimer Disease↗