Disentangling pain and fatigue in chronic fatigue syndrome: a resting state connectivity study before and after cognitive behavioral therapy.

BACKGROUND: Fatigue is a central feature of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), but many ME/CFS patients also report comorbid pain symptoms. It remains unclear whether these symptoms are related to similar or dissociable brain networks. This study used resting-state fMRI to disentangle networks associated with fatigue and pain symptoms in ME/CFS patients, and to link changes in those networks to clinical improvements following cognitive behavioral therapy (CBT). METHODS: Relationships between pain and fatigue symptoms and cortico-cortical connectivity were assessed within ME/CFS patients at baseline (N = 72) and after CBT (N = 33) and waiting list (WL, N = 18) and compared to healthy controls (HC, N = 29). The analyses focused on four networks previously associated with pain and/or fatigue, i.e. the fronto-parietal network (FPN), premotor network (PMN), somatomotor network (SMN), and default mode network (DMN). RESULTS: At baseline, variation in pain and fatigue symptoms related to partially dissociable brain networks. Fatigue was associated with higher SMN-PMN connectivity and lower SMN-DMN connectivity. Pain was associated with lower PMN-DMN connectivity. CBT improved SMN-DMN connectivity, compared to WL. Larger clinical improvements were associated with larger increases in frontal SMN-DMN connectivity. No CBT effects were observed for PMN-DMN or SMN-PMN connectivity. CONCLUSIONS: These results provide insight into the dissociable neural mechanisms underlying fatigue and pain symptoms in ME/CFS and how they are affected by CBT in successfully treated patients. Further investigation of how and in whom behavioral and biomedical treatments affect these networks is warranted to improve and individualize existing or new treatments for ME/CFS.

"Cinderella was attacked by the big bad wolf, but the police saved her": intrusions and confabulations on story recall in Korsakoff's syndrome and alcohol-related cognitive impairments.

BACKGROUND: The relation between confabulations and intrusions in patients with Korsakoff's syndrome (KS) and patients with alcohol-related cognitive impairments (ARCI) remains under debate. This study examines (1) differences in the production of confabulations and intrusions between patients with KS and ARCI, (2) whether an altered fairy tale induces more intrusions, and (3) whether different types of intrusions were significantly related to confabulations. METHODS: Twenty-three patients with KS and twenty-two patients with ARCI recalled three different types of stories: a novel story, a fairy tale, and a modified fairy tale. Different types of intrusions were correlated with confabulation measures. RESULTS: Patients with KS produced more intrusions in the modified fairy tale condition than patients with ARCI, but these were unrelated to confabulations. Only unrelated intrusions were related to provoked confabulations. CONCLUSIONS: The results of this study indicate that researchers and clinicians must be aware that in general, intrusions on memory tests should not be interpreted as confabulations. Especially spontaneous confabulations appear to be something completely different from intrusions on any type of story recall. When measuring confabulations it is crucial to use validated instruments.

Classification Of MeMory InTerventions: Rationale and developmental process of the COMMIT tool.

ABSTRACTOver the last decades, numerous memory interventions have been developed to mitigate memory decline in normal ageing. However, there is a large variability in the success of memory interventions, and it remains poorly understood which memory intervention programs are most effective and for whom. This is partially explained by the heterogeneity of memory intervention protocols across studies as well as often poor reporting of the study design. To facilitate a reporting framework that enables researchers to systemize the content and design of memory intervention paradigms, we developed the Classification Of MeMory InTerventions (COMMIT) tool using a 3-stage developmental process. Briefly, COMMIT was based on qualitative content analysis of already existing memory intervention studies published between April 1983 and July 2020, and iteratively validated by both internal and external expert panels. COMMIT provides an easily-applicable interactive tool that enables systematic description of memory intervention studies, together with instructions on how to use this classification tool. Our main goal is to provide a tool that enables the reporting and classification of memory interventions in a transparent, comprehensible, and complete manner, to ensure a better comparability between memory interventions, and, to ultimately contribute to the question which memory intervention shows the greatest benefits.

[Pain and neurocognitive disorders: current state of the art and remaining challenges]. / Pijn en neurocognitieve stoornissen: stand van zaken en de weg nog te gaan.

The detection and treatment of pain is hampered by cognitive disorders. In this review we discuss the epidemiology of pain in cognitive disorders, and elaborate further on the current state of the art on pain in these populations. We will specifically highlight current gaps and recommendations for the future for the following knowledge domains: 1) Biology and neuropathology,  2) Assessment and evaluation, 3) Treatment and management , and 4) Contextual factors such as the organization and education.  We identify the following knowledge gaps: 1) (Biology): Do pain experience and pain expressions change in different types of cognitive disorders, and how? 2) (Assessment): How to recognize, evaluate and assess pain, in case the self-report of pain is no longer reliable? 3) (Treatment): Which treatment possibilities are effective? How can we organize this in an interdisciplinary way? And how to monitor this? How can we ensure proper implementation of pain assessment and treatment in clinical practice? Specifically with regard to non-pharmacological treatment, how can we communicate observations from different disciplines, family members and clinicians to improve the detection of pain as well as treatment monitoring/evaluation? 4) (Contextual): How can we increase knowledge and skills on pain in cognitive impairment within educational training?

Cognitive reserve relates to executive functioning in the old-old.

Cognitive reserve (CR) is known to reduce or even protect against the negative effects of aging on cognitive functioning. Nonetheless, little is known about how CR influences the relationship between different cognitive abilities and age in the old-old. The goal of the present study was, therefore, to test the hypothesis whether, in the old-old, CR still modifies the relationship between age and cognitive functioning. Eighty-three adults (aged 71-94) without mild cognitive impairment or dementia residing in residential care facilities completed a detailed neuropsychological test battery. CR was estimated using a combination of educational attainment and an estimation of verbal intelligence. Moderation analyses revealed a significant effect for fluency and a trend for flexibility, showing that the negative relationship between age and cognitive performance is reduced as the level of CR increases. These results demonstrate that CR still influences the relationship between age and executive functions in adults of advanced age.

Validity of the Mini-Mental State Examination-2 in Diagnosing Mild Cognitive Impairment and Dementia in Patients Visiting an Outpatient Clinic in the Netherlands.

This study examined the utility of the recently published MMSE-2:SV in detecting cognitive impairment. We used receiver operating characteristics to test the discriminative power of the MMSE-2:SV for distinguishing between older adults without mild cognitive impairment (MCI) or dementia (n=67) and patients with MCI (n=76) or dementia (n=79). The results show that the MMSE-2:SV had excellent discriminative ability in distinguishing older controls from patients with dementia, with cut-off scores of 26 and 27 (max=30) yielding appropriate sensitivity (0.810 and 0.924, respectively) and specificity (0.940 and 0.806). Discriminative power was close to good in distinguishing between older controls and patients with MCI. Here, however, no optimal cut-off point could be determined. Even though this study shows good sensitivity and adequate specificity for the MMSE-2:SV in discriminating individuals without MCI or dementia from those with dementia, its validity is limited for identifying patients with MCI.

Memory Strategy Training in Older Adults with Subjective Memory Complaints: A Randomized Controlled Trial.

OBJECTIVES: Subjective memory complaints (SMC) in older adults are associated with a decline in everyday functioning and an increased risk for future cognitive decline. This study examines the effect of a memory strategy training compared to a control memory training on memory functioning in daily life. METHODS: This was a randomized controlled trial with baseline, post-treatment, and 6-month follow-up assessments conducted in 60 older adults (50-87 years) with SMC. Participants were randomly assigned to either seven sessions of memory strategy training or seven sessions of control memory training. Both interventions were given in small groups and included psycho-education. Primary outcome measure was memory functioning in daily life. Objective measures of memory performance and self-reported measures of strategy use were included as secondary outcome measures. RESULTS: Participants in each intervention group reported an improvement in personal memory goals (p<.0005), up to 6 months after training. An interaction effect showed that participants following memory strategy training reported a larger improvement in personal memory goals (p=.002). Both intervention groups improved on two memory tests (p<.001 and p<.01). In the memory strategy training group, an increase in strategy use in daily life was the strongest predictor (p<.05) of improvement in subjective memory functioning. CONCLUSIONS: Older adults with subjective memory complaints benefit from memory strategy training, especially in their memory functioning in daily life. (JINS, 2018, 24, 1110-1120).

Pain in Patients with Different Dementia Subtypes, Mild Cognitive Impairment, and Subjective Cognitive Impairment.

Objective: To assess the pain prevalence, pain intensity, and pain medication use in older patients with a diagnosed subtype of dementia, mild cognitive impairment (MCI), or subjective cognitive impairment (SCI). Design: Cross-sectional. Setting: Outpatient memory clinics. Subjects: In total, 759 patients with Alzheimer's disease (AD), vascular dementia, mixed AD and vascular pathology (MD), frontotemporal dementia, dementia with Lewy Bodies, MCI, or SCI. Methods: Self-reported presence and intensity of pain, prescribed medication, and related descriptive variables were given for each group. To compare groups on prevalence of pain, logistic regression analyses were adjusted for age, gender, and mood. Differences in pain intensity were tested using a Kruskall-Wallis test, and differences in analgesic use with chi-square analyses. Results: Pain prevalence ranged from 34% in MD to 50% in SCI. AD (odds ratio [OR] = 0.56, 95% confidence interval [CI] = 0.34-0.93) and MD (OR = 0.45, CI = 0.20-0.98) patients were less likely to report pain than SCI patients. The self-reported pain intensity did not differ between groups. In total, 62.5% of patients did not use any analgesic medication despite being in pain, which did not differ significantly between groups. Conclusion: Outpatient memory clinic patients with mild to moderate AD and MD are less likely to report pain than patients with SCI. No difference in self-reported pain intensity was present. The high percentage of patients with and without dementia who do not use analgesics when in pain raises the question of whether pain treatment is adequate in older patients.

Pain and executive functions: a unique relationship between Stroop task and experimentally induced pain.

There is a growing body of evidence that a higher level of cognitive inhibition is associated with lower experimental pain sensitivity. However, a systematic examination of the association between executive functions, which include not only inhibition but also updating and shifting, and experimental pain sensitivity is lacking. This study aimed to overcome this limitation by exploring the relationship between a range of executive functions and different measures of experimentally induced cold pain in healthy participants. In a group of 54 healthy participants (age 21-24 years), executive functions (EF) were investigated in a systematic manner following a well-established framework developed by Miyake and collaborators. The investigation included multiple tests of inhibition (Stroop, Stop-signal, and Left-right), updating (Keep-track, Letter-memory, and Spatial n-back), and set-shifting (Plus-minus, Number-letter, and Local-global). The cold pressor test was used to obtain measures of pain threshold (the first sensation of pain), sensitivity to pain (the moment when substantial pain was reported), and pain tolerance (the moment when pain became unbearable). Results showed no relationship between pain measures and measures of updating and shifting. All pain measures were related to Stroop interference inhibition score, but not to other two inhibition tasks. Further analyses confirmed the unique relationship between Stroop-type of inhibition and response to pain. We argue that there is a fundamental relationship between cognitive inhibition and pain experience, which relies on one's ability to suppress automatic processes.

The influence of cognitive reserve and age on the use of memory strategies.

BACKGROUND: Whether older adults use effective memory strategies to compensate for their memory decline partly depends on their executive functioning (EF). However, many studies have overlooked the role of cognitive reserve (CR). This study examines the effects of age, EF, and CR on memory strategy use. METHODS: A total of 83 participants (aged 18-85 years) were included. Strategy use was assessed using three measures: (1) self-reported strategy use in daily life, (2) self-reported and observed strategy use in a simulated daily life situation, and (3) self-reported strategy use during a word-pair task. RESULTS: Results showed that CR was the strongest predictor of strategy use, both in daily life and during memory tasks. Although effects of age and EF were found, most of these effects disappeared when CR was added to the model. Furthermore, a higher CR was related to the use of more complex strategies and to more effective strategies in relation to task performance. CONCLUSIONS: Higher levels of CR seem to enable individuals to use effective strategies. These results highlight the importance of the role of CR in compensating for the aging-related memory decline.

Memory strategy use in older adults with subjective memory complaints.

BACKGROUND: Subjective memory complaints (SMC) are common among older adults, but it is unclear to what extent adults with SMC spontaneously use memory strategies to compensate for their memory problems. As SMC may be a risk factor for memory decline later, it is important to extend our knowledge about spontaneous compensatory mechanisms in older adults with SMC. METHOD: Self-reported strategy use and observed strategy use were assessed in 38 adults with and 38 without SMC. RESULTS: Adults with SMC used more strategies in daily life than those without. In the SMC group, memory complaints were positively correlated with strategy use. Only in adults without SMC, a significant correlation was found between observed strategy use and task performance. CONCLUSION: Strategy use in older adults with SMC may be compensatory in nature, but did not increase their objective memory performance. Therefore, older adults with SMC might benefit from interventions aimed at optimizing strategy use.

[The association between paid or voluntary employment and neuropsychological test performance at an older age]. / Langer doorwerken: wellicht zo slecht nog niet? Een pilotstudie naar de relatie tussen werkzaam zijn en cognitief functioneren op latere leeftijd.

Studies have convincingly shown that both physical and mental activity are positively associated with cognitive task performance in aging. Little is known, however, about whether still being employed or doing volunteer work, which obviously engages physical and/or mental activity, is similarly associated with cognitive ability at an older age. The current study explored this relationship in 28 volunteers aged sixty years and older. Participants completed a neuropsychological test battery, and data regarding the number of working hours (paid and voluntary) per week were collected. A total of 28 participants were included, 13 of whom worked three or more hours per week. As a group, these active participants achieved better episodic memory, sustained attention and psychomotor speed results. This study shows that older people who are still working demonstrate better neuropsychological task performance. An important question for future research concerns the causality of this relationship.

The Combined Effect of Neuropsychological and Neuropathological Deficits on Instrumental Activities of Daily Living in Older Adults: a Systematic Review.

To date, studies have consistently demonstrated associations between either neuropsychological deficits or neuroanatomical changes and instrumental activities of daily living (IADL) in aging. Only a limited number of studies have evaluated morphological brain changes and neuropsychological test performance concurrently in relation to IADL in this population. As a result, it remains largely unknown whether these factors independently predict functional outcome. The current systematic review intended to address this lack of information by reviewing the literature on older adults, incorporating studies that examined e.g., normal aging, but also stroke or dementia patients. A comprehensive search of databases (Pubmed, Embase, Medline, Web of Science, PsycINFO) and reference lists was performed, focusing on papers in the English language that examined the combined effect of neuropsychological and neuroanatomical factors on IADL in samples of adults with an average age above 50. In total, 58 potential articles were identified; 20 were included in the review. The results show that especially neuropsychological variables (primarily memory and executive functions) independently predict IADL. Although some unique predictive value of brain morphological changes, such as hippocampal atrophy, was found, support for the importance of white matter changes was limited. However, the results of the studies reviewed are diverse, and appear to be at least partially determined by the variables included. For example, studies were less likely to find an independent effect of cognition if they solely employed a cognitive screening instrument. This indicates that a structured examination of neuroanatomical and neuropsychological correlates of IADL in different patient populations is warranted.

Chronic pain in "probable" vascular dementia: preliminary findings.

BACKGROUND: In a previous study, the levels of pain reported by patients with "possible" vascular dementia (VaD) were higher than those reported by older individuals without dementia. OBJECTIVE: To examine experienced pain in patients with "probable" VaD, confirmed by brain imaging. STUDY DESIGN: Observational, cross sectional. SETTING: Nursing home. METHODS: The participants were 20 nursing home residents (14 females, 6 males) who met the NINDS-AIREN criteria for "probable" VaD and 22 nursing home residents with a normal mental status (18 females, 4 males). The patients were in a mild to moderate stage of dementia. All of the participants were suffering from arthritis/arthrosis or osteoporosis. Global cognitive functioning was measured by the Mini-Mental State Examination. Pain was assessed by the Coloured Analogue Scale (CAS: original and modified version) and the Faces Pain Scale. The Geriatric Depression Scale and the Symptom Checklist-90 were used to assess mood. RESULTS: The main finding was that, after controlling for mood, the pain levels indicated by patients with "probable" VaD (M = 102.32; standard deviation [SD] = 53.42) were significantly higher than those indicated by the control group (M = 59.17; SD = 38.75), only according to the CAS modified version (F[1,29]) = 5.62, P = 0.01, η2 = 0.16). CONCLUSION: As VaD patients may experience greater pain than controls, it is essential for prescribers to be aware of the presence of this neuropathology if these patients are to receive adequate treatment.

Simple and complex rule induction performance in young and older adults: contribution of episodic memory and working memory.

This study tested the hypothesis that part of the age-related decline in performance on executive function tasks is due to a decline in episodic memory. For this, we developed a rule induction task in which we manipulated the involvement of episodic memory and executive control processes; age effects and neuropsychological predictors of task performance were investigated. Twenty-six younger (mean age, 24.0; range, 19-35 years) and 27 community-dwelling older adults (mean age, 67.5; range, 50-91 years) participated. The neuropsychological predictors consisted of the performance on tests of episodic memory, working memory, switching, inhibition and flexibility. Performance of the older adults was worse for the learning and memorization of simple rules, as well as for the more demanding executive control condition requiring the manipulation of informational content. Episodic memory was the only predictor of performance on the simple learning and memorization task condition whereas an increase in rule induction complexity additionally engaged working memory processes. Together, these findings indicate that part of the age-related decline on rule induction tests may be the result of a decline in episodic memory. Further studies are needed that examine the role of episodic memory in other executive function tasks in aging.

When pain memories are lost: a pilot study of semantic knowledge of pain in dementia.

OBJECTIVE: It has been documented that pain in people with dementia is often under-reported and poorly detected. The reasons for this are not clearly defined. This project aimed to explore semantic concepts of pain in people with dementia and whether this is associated with clinical pain report. DESIGN: Cohort study with nested cross-sectional analysis. SETTING: Acute general hospital medical wards for older people. SUBJECTS: People with dementia (N = 26) and control participants (N = 13). METHODS: Two subtests of semantic memory for pain: (1) Identifying painful situations from a standardized range of pictures; (2) Describing the concept of pain. Participants also indicated whether they were in pain or not, were observed for pain (PAINAD scale) and completed the Wong-Baker FACES scale to indicate pain severity. RESULTS: Compared with the control group, people with dementia were less able to identify painful situations and used fewer categories to define their concept of pain. In turn, the performance on these two measures was related to the reported presence and, albeit less strongly, to the reported severity of pain, indicating that a reduction in semantic memory for pain is associated with a decline in reported pain. CONCLUSIONS: This study is the first to show that semantic memory for pain is diminished in dementia patients. When using clinical pain tools, clinicians should consider these effects which may bias clinical pain ratings when they evaluate and manage pain in these patients. This might improve the recognition and management of pain in people with dementia.

The Advanced BRain Imaging on ageing and Memory (ABRIM) data collection: Study design, data processing, and rationale.

To understand the neurocognitive mechanisms that underlie heterogeneity in cognitive ageing, recent scientific efforts have led to a growing public availability of imaging cohort data. The Advanced BRain Imaging on ageing and Memory (ABRIM) project aims to add to these existing datasets by taking an adult lifespan approach to provide a cross-sectional, normative database with a particular focus on connectivity, myelinization and iron content of the brain in concurrence with cognitive functioning, mechanisms of reserve, and sleep-wake rhythms. ABRIM freely shares MRI and behavioural data from 295 participants between 18-80 years, stratified by age decade and sex (median age 52, IQR 36-66, 53.20% females). The ABRIM MRI collection consists of both the raw and pre-processed structural and functional MRI data to facilitate data usage among both expert and non-expert users. The ABRIM behavioural collection includes measures of cognitive functioning (i.e., global cognition, processing speed, executive functions, and memory), proxy measures of cognitive reserve (e.g., educational attainment, verbal intelligence, and occupational complexity), and various self-reported questionnaires (e.g., on depressive symptoms, pain, and the use of memory strategies in daily life and during a memory task). In a sub-sample (n = 120), we recorded sleep-wake rhythms using an actigraphy device (Actiwatch 2, Philips Respironics) for a period of 7 consecutive days. Here, we provide an in-depth description of our study protocol, pre-processing pipelines, and data availability. ABRIM provides a cross-sectional database on healthy participants throughout the adult lifespan, including numerous parameters relevant to improve our understanding of cognitive ageing. Therefore, ABRIM enables researchers to model the advanced imaging parameters and cognitive topologies as a function of age, identify the normal range of values of such parameters, and to further investigate the diverse mechanisms of reserve and resilience.

The presence of attentional and interpretation biases in patients with severe MS-related fatigue.

OBJECTIVE: Severe fatigue is a prevalent and disabling symptom in multiple sclerosis (MS). This study tested if a fatigue- and physical activity-related attentional bias (AB) and a somatic interpretation bias (IB) are present in severely fatigued patients with MS. Biases were compared to healthy controls and patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). METHOD: Severely fatigued patients with MS or ME/CFS and healthy controls completed a Visual Probe Task (VPT) assessing fatigue- and physical activity-related AB and an IB task that assesses the tendency to interpret ambiguous information in either a somatically threatening way or in a more neutral manner. The VPT was completed by 38 MS patients, 44 ME/CFS patients, and 46 healthy controls; the IB task was completed by 156, 40 and 46 participants respectively. RESULTS: ANOVA showed no statistically significant group differences in a fatigue-related AB or physical activity-related AB (omnibus test of interaction between topic × condition: F2,125 = 1.87; p = .159). Both patient groups showed a tendency to interpret ambiguous information in a somatically threatening way compared to healthy controls (F1,2 = 27.61, p < .001). This IB was significantly stronger in MS patients compared to ME/CFS patients. IB was significantly correlated with cognitive responses to symptoms in MS patients. CONCLUSION: MS patients tend to interpret ambiguous information in a somatically threatening way. This may feed into unhelpful ways of dealing with symptoms, possibly contributing to the perpetuation of severe fatigue in MS.

A multidomain lifestyle intervention to maintain optimal cognitive functioning in Dutch older adults-study design and baseline characteristics of the FINGER-NL randomized controlled trial.

BACKGROUND: Evidence on the effectiveness of multidomain lifestyle interventions to prevent cognitive decline in older people without dementia is mixed. Embedded in the World-Wide FINGERS initiative, FINGER-NL aims to investigate the effectiveness of a 2-year multidomain lifestyle intervention on cognitive functioning in older Dutch at risk individuals. METHODS: Multi-center, randomized, controlled, multidomain lifestyle intervention trial with a duration of 24 months. 1210 adults between 60-79 years old with presence of ≥ 2 modifiable risk factors and ≥ 1 non-modifiable risk factor for cognitive decline were recruited between January 2022 and May 2023 via the Dutch Brain Research Registry and across five study sites in the Netherlands. Participants were randomized to either a high-intensity or a low-intensity intervention group. The multidomain intervention comprises a combination of 7 lifestyle components (physical activity, cognitive training, cardiovascular risk factor management, nutritional counseling, sleep counseling, stress management, and social activities) and 1 nutritional product (Souvenaid®) that could help maintain cognitive functioning. The high-intensity intervention group receives a personalized, supervised and hybrid intervention consisting of group meetings (on-site and online) and individual sessions guided by a trained lifestyle coach, and access to a digital intervention platform that provides custom-made training materials and selected lifestyle apps. The low-intensity intervention group receives bi-monthly online lifestyle-related health advice via the digital intervention platform. Primary outcome is 2-year change on a cognitive composite score covering processing speed, executive function, and memory. RESULTS: Within 17 months, participant recruitment has been successfully completed (N = 1210; mean age: 67.7 years (SD: 4.6); 64% female). Modifiable risk factors commonly present at baseline were physical inactivity (89%), low mental/cognitive activity (50%), low social engagement (39%), hypertension (39%) and high alcohol consumption (39%). The mean body mass index of participants was 28.3 (SD: 4.2) and the total serum cholesterol was 5.4 mmol/L (SD: 1.2). CONCLUSIONS: Baseline lifestyle and clinical measurements showed successful recruitment of participants with sufficient potential for prevention. Results of FINGER-NL will provide further insight into the efficacy of a multidomain lifestyle intervention to prevent cognitive decline in older adults. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT05256199)/2022-01-11.

Medial temporal lobe atrophy relates to executive dysfunction in Alzheimer's disease.

BACKGROUND: White matter hyperintensities (WMH) have frequently been associated with lower executive function performance. Little is known, however, about the effects of hippocampal atrophy on executive control in Alzheimer's disease (AD). The present study focused on the association of hippocampal atrophy with executive function in AD patients and examined whether a threshold effect is present, indicating that a certain amount of brain damage must be present before cognitive function becomes impaired. Finally, we examined the combined effect of hippocampal atrophy and WMH on cognitive task performance. METHODS: We retrospectively collected neuropsychological and neuroimaging data of 94 AD patients. These patients completed tasks of general cognitive function, executive function, memory, and processing speed. With magnetic resonance imaging (MRI), hippocampal atrophy was rated as medial temporal lobe atrophy (MTA) and cerebrovascular disease was rated as WMH using validated visual rating scales. RESULTS: Medial temporal lobe atrophy (MTA) was associated with lower executive function, general cognitive function, and episodic memory performance. A threshold effect was present, indicating that severe to very severe, but not moderate, MTA was associated with lower executive function. WMH were significantly associated with a single executive test only, whereas the interaction between WMH and MTA was not significantly related to any of the cognitive tasks. CONCLUSIONS: Our findings suggest that AD neuropathology in itself may be responsible for executive dysfunction. Potential explanations for these findings are discussed, focusing on the role of the hippocampus in executive function tests and reduced frontal-posterior connectivity in this patient sample.