Clinical applicability of quantitative atrophy measures on MRI in patients suspected of Alzheimer's disease.

OBJECTIVES: Neurodegeneration in suspected Alzheimer's disease can be determined using visual rating or quantitative volumetric assessments. We examined the feasibility of volumetric measurements of gray matter (GMV) and hippocampal volume (HCV) and compared their diagnostic performance with visual rating scales in academic and non-academic memory clinics. MATERIALS AND METHODS: We included 231 patients attending local memory clinics (LMC) in the Netherlands and 501 of the academic Amsterdam Dementia Cohort (ADC). MRI scans were acquired using local protocols, including a T1-weighted sequence. Quantification of GMV and HCV was performed using FSL and FreeSurfer. Medial temporal atrophy and global atrophy were assessed with visual rating scales. ROC curves were derived to determine which measure discriminated best between cognitively normal (CN), mild cognitive impairment (MCI), and Alzheimer's dementia (AD). RESULTS: Patients attending LMC (age 70.9 ± 8.9 years; 47% females; 19% CN; 34% MCI; 47% AD) were older, had more cerebrovascular pathology, and had lower GMV and HCV compared to those of the ADC (age 64.9 ± 8.2 years; 42% females; 35% CN, 43% MCI, 22% AD). While visual ratings were feasible in > 95% of scans in both cohorts, quantification was achieved in 94-98% of ADC, but only 68-85% of LMC scans, depending on the software. Visual ratings and volumetric outcomes performed similarly in discriminating CN vs AD in both cohorts. CONCLUSION: In clinical settings, quantification of GM and hippocampal atrophy currently fails in up to one-third of scans, probably due to lack of standardized acquisition protocols. Diagnostic accuracy is similar for volumetric measures and visual rating scales, making the latter suited for clinical practice. In a real-life clinical setting, volumetric assessment of MRI scans in dementia patients may require acquisition protocol optimization and does not outperform visual rating scales. KEY POINTS: • In a real-life clinical setting, the diagnostic performance of visual rating scales is similar to that of automatic volumetric quantification and may be sufficient to distinguish Alzheimer's disease groups. • Volumetric assessment of gray matter and hippocampal volumes from MRI scans of patients attending non-academic memory clinics fails in up to 32% of cases. • Clinical MR acquisition protocols should be optimized to improve the output of quantitative software for segmentation of Alzheimer's disease-specific outcomes.

Diagnostic Impact of CSF Biomarkers in a Local Hospital Memory Clinic Revisited.

BACKGROUND/AIMS: Research guidelines on predicting and diagnosing Alzheimer's disease (AD) acknowledge cerebrospinal fluid (CSF) levels as pivotal biomarkers. We studied the usefulness of CSF biomarkers in the diagnostic workup of patients in a geriatric outpatient memory clinic of a community-based hospital, attempted to determine a cutoff age for the use of CSF biomarkers in this group of patients, and compared the total τ/Aß ratio as an alternative CSF diagnostic rule with the usual rules for interpreting CSF levels. METHODS: This was a prospective study of consecutively referred patients. Inclusion criteria were described on the basis of previous study results in the same setting. The CSF tool was applied either to differentiate between AD and no AD or to increase certainty having made the diagnosis of AD. Clinicians were asked to judge whether the CSF results were helpful to them or not. RESULTS: The reasons to use the CSF tool in the diagnostic workup were in 78/106 patients to decide between the diagnosis "AD" and "no AD" and in 28/106 patients to increase the certainty regarding the diagnosis. In 75% of cases the CSF levels were considered diagnostically helpful to the clinicians. Results in the present setting suggest 65 years as the cutoff age to use CSF as a diagnostic tool. The sensitivity and specificity of the total τ/Aß ratio using the clinical diagnosis as the gold standard were at least as good as the usual categorization rule. CONCLUSIONS: Our study results corroborate earlier findings that the CSF tool is of added value to the diagnostic workup in daily clinical practice outside tertiary referral centers. CSF levels can best be used in patients under 66 years of age. Given the limited use of this tool in settings outside research facilities, we recommend that the usefulness of CSF biomarkers is studied in a multicenter study. When in the future CSF levels can be reliably measured in plasma, this may become even more relevant.

Communicating uncertainties when disclosing diagnostic test results for (Alzheimer's) dementia in the memory clinic: The ABIDE project.

BACKGROUND: The development of novel diagnostics enables increasingly earlier diagnosis of Alzheimer's disease (AD). Timely diagnosis may benefit patients by reducing their uncertainty regarding the cause of symptoms, yet does not always provide patients with the desired certainty. OBJECTIVE: To examine, using both quantitative and qualitative methods, uncertainty communicated by memory clinic clinicians in post-diagnostic testing consultations with patients and their caregivers. METHODS: First, we identified all uncertainty expressions of 22 clinicians in audiotaped post-diagnostic testing consultations with 78 patients. Second, we statistically explored relationships between patient/clinician characteristics and uncertainty expressions. Third, the transcribed uncertainty expressions were qualitatively analysed, determining the topic to which they pertained, their source and initiator/elicitor (clinicians/patients/caregivers). RESULTS: Within 57/78 (73%) consultations, clinicians expressed in total 115 uncertainties, of which 37% elicited by the patient or caregiver. No apparent relationships were found between patient/clinician characteristics and whether or not, and how often clinicians expressed uncertainty. Uncertainty expressions pertained to ten different topics, most frequently patient's diagnosis and symptom progression. Expressed uncertainty was mostly related to the unpredictability of the future and limits to available knowledge. DISCUSSION AND CONCLUSIONS: The majority of clinicians openly discussed the limits of scientific knowledge and diagnostic testing with patients and caregivers in the dementia context. Noticeably, clinicians did not discuss uncertainty in about one quarter of consultations. More evidence is needed on the beneficial and/or harmful effects on patients of discussing uncertainty with them. This knowledge can be used to support clinicians to optimally convey uncertainty and facilitate patients' uncertainty management.

Haloperidol versus placebo for delirium prevention in acutely hospitalised older at risk patients: a multi-centre double-blind randomised controlled clinical trial.

Background: because the few randomised placebo-controlled trials investigating the potential role for prophylactic haloperidol in delirium prevention have focused on specific surgical populations, we investigated its efficacy and safety in acutely hospitalised older patients. Methods: this multi-centre, double-blind, stratified, block randomised, placebo-controlled trial was conducted at six Dutch hospitals. Patients age ≥70 years, acutely admitted through the emergency department for general medicine or surgical specialties and at risk for delirium were randomised (n = 245) to haloperidol or placebo 1 mg orally twice-daily (maximum of 14 doses) on top of standard nonpharmacological prevention strategies. The primary outcome was delirium incidence. Other endpoints included delirium severity and duration, drug safety and clinical outcomes. Results: intention-to-treat analysis included 242 participants (calculated sample size n = 390, statistical power of current sample 59%) allocated to haloperidol (n = 118) or placebo (n = 124). In the haloperidol and placebo group, delirium incidence was 19.5 versus 14.5% (OR 1.43, 95% CI 0.72 to 2.78); median (IQR) delirium duration 4 (2, 5) versus 3 (1, 6) days (P = 0.366); maximum DRS-R-98 score 16 (9.8, 19.5) versus 10 (5.5, 22.5) (P = 0.549; 53.7% missing data); hospital LOS 7 (4, 10.3) versus 7 (5, 11.8) days (P = 0.343); 3-month mortality 9.9 versus 12.5% (OR 0.77, 95% CI 0.34 to 1.75), respectively. No treatment-limiting side effects were noted. Conclusions: prophylactic low-dose oral haloperidol did not reduce delirium incidence in acutely hospitalised older patients. Therefore, prophylactic use of haloperidol in this population is not recommended.

Using magnetic resonance imaging in diagnosing dementia: a Dutch outpatient memory clinics survey.

BACKGROUND: In the Netherlands, dementia syndromes are diagnosed in specialized memory outpatient clinics (MC). Many radiologists are not trained to assess magnetic resonance imaging (MRI) scans with respect to possible radiological changes that may indicate neurodegenerative disease. METHODS: This is a cross-sectional descriptive study. A survey was sent to all Dutch MC and included questions as to how MRI scans are assessed by radiologists and how these assessments are used in the diagnostic process. RESULTS: In most MC, radiologists report on typical Alzheimer pathology and large vessel disease. Small vessel disease and other anatomical changes signifying neurodegenerative disease frequently are not assessed. In the majority of MC, the radiological assessment is not standardized, and physicians assess MRI for themselves to use this information to discuss the consensus diagnosis subsequently. CONCLUSION: MRI assessment by radiologists in Dutch MC probably underestimates the presence of cerebrovascular and neurodegenerative disease. The validity of standardized assessment protocols in routine clinical practice deserves further study, as the implementation of standardization outside research settings could improve diagnostic accuracy.

Efficacy and safety of haloperidol prophylaxis for delirium prevention in older medical and surgical at-risk patients acutely admitted to hospital through the emergency department: study protocol of a multicenter, randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: Delirium is associated with substantial morbidity and mortality rates in elderly hospitalised patients, and a growing problem due to increase in life expectancy. Implementation of standardised non-pharmacological delirium prevention strategies is challenging and adherence remains low. Pharmacological delirium prevention with haloperidol, currently the drug of choice for delirium, seems promising. However, the generalisability of randomised controlled trial results is questionable since studies have only been performed in selected postoperative hip-surgery and intensive care unit patient populations. We therefore present the design of the multicenter, randomised, double-blind, placebo-controlled clinical trial on early pharmacological intervention to prevent delirium: haloperidol prophylaxis in older emergency department patients (The HARPOON study). METHODS/DESIGN: In six Dutch hospitals, at-risk patients aged 70 years or older acutely admitted through the emergency department for general medicine and surgical specialties are randomised (n = 390) for treatment with prophylactic haloperidol 1 mg or placebo twice daily for a maximum of seven consecutive days. Primary outcome measure is the incidence of in-hospital delirium within seven days of start of the study intervention, diagnosed with the Confusion Assessment Method, and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for delirium. Secondary outcome measures include delirium severity and duration assessed with the Delirium Rating Scale Revised 98; number of delirium-free days; adverse events; hospital length-of-stay; all-cause mortality; new institutionalisation; (Instrumental) Activities of Daily Living assessed with the Katz Index of ADL, and Lawton IADL scale; cognitive function assessed with the Six-item Cognitive Impairment Test, and the Dutch short form Informant Questionnaire on Cognitive Decline in the Elderly. Patients will be contacted by telephone three and six months post-discharge to collect data on cognitive- and physical function, home residency, all-cause hospital admissions, and all-cause mortality. DISCUSSION: The HARPOON study will provide relevant information on the efficacy and safety of prophylactic haloperidol treatment for in-hospital delirium and its effects on relevant clinical outcomes in elderly at-risk medical and surgical patients. TRIAL REGISTRATION: EudraCT Number: 201100476215; ClinicalTrials.gov Identifier: NCT01530308; Dutch Clinical Trial Registry: NTR3207.

Motivations of patients and their care partners for visiting a memory clinic. A qualitative study.

OBJECTIVE: We investigated motivations of patients and care partners for their memory clinic visit, and whether these are expressed in consultations. METHODS: We included data from 115 patients (age 71 ± 11, 49% Female) and their care partners (N = 93), who completed questionnaires after their first consultation with a clinician. Audio-recordings of these consultations were available from 105 patients. Motivations for visiting the clinic were content-coded as reported by patients in the questionnaire, and expressed by patients and care partners in consultations. RESULTS: Most patients reported seeking a cause for symptoms (61%) or to confirm/exclude a (dementia) diagnosis (16%), yet 19% reported another motivation: (more) information, care access, or treatment/advice. In the first consultation, about half of patients (52%) and care partners (62%) did not express their motivation(s). When both expressed a motivation, these differed in about half of dyads. A quarter of patients (23%) expressed a different/complementary motivation in the consultation, then reported in the questionnaire. CONCLUSION: Motivations for visiting a memory clinic can be specific and multifaceted, yet are often not addressed during consultations. PRACTICE IMPLICATIONS: We should encourage clinicians, patients, and care partners to talk about motivations for visiting the memory clinic, as a starting point to personalize (diagnostic) care.

Episodic recognition memory based on incidental learning of visual associations is largely preserved compared to recall in amnestic mild cognitive impairment and mild Alzheimer's disease.

We investigated preserved episodic recognition memory based on incidental learning of visual associations in Alzheimer's disease (AD). In a cross-sectional design, we analyzed episodic memory score profiles of patients with amnestic mild cognitive impairment (a-MCI) (n = 42) or mild AD (n = 19) who had hippocampal atrophy, and healthy elderly controls (n = 43). The Visual Association Test-Extended served as a measure of episodic memory. Multiple-choice cued recognition was compared with paired associate recall and free recall within groups. Results showed that patients recognized learned material much better compared to when they had to recall material, resulting in large effect sizes (Cohen's d) ranging from 1.3 to 3.5. We conclude that episodic recognition memory based on incidental learning of visual associations is largely preserved when compared to recall in a-MCI and mild AD. This suggests that the episodic memory impairment in AD may be characterized as a retrieval impairment rather than a consolidation impairment, indicating that preserved recognition compared to recall may be compatible with AD being the correct diagnosis. Measuring the episodic memory impairment in AD may benefit from using tests that capture different aspects of memory processes such as incidental learning of visual associations.

Diagnostic impact of CSF biomarkers in a local hospital memory clinic.

BACKGROUND: CSF biomarkers amyloid-beta 1-42 (Abeta42), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) are useful diagnostic markers for Alzheimer's disease (AD). We examined the impact of these biomarkers in the diagnostic process in a non-academic memory clinic. METHODS: One hundred and nine patients with available CSF were included from the local hospital memory clinic. Initially, patients were clinically diagnosed, and the clinician indicated their confidence in the diagnosis. Next the CSF results were presented, and the clinician re-evaluated his initial diagnosis. The main outcomes were changes in initial diagnosis and diagnostic confidence. RESULTS: Forty-seven patients were initially diagnosed with AD, 26 were diagnosed with another type of dementia, 18 were diagnosed with mild cognitive impairment, and 18 received a non-dementia diagnosis. All biomarkers distinguished between AD and non-dementia (p < 0.01); tau and ptau-181 also distinguished AD from other types of dementia (p < 0.001). After CSF biomarker levels were revealed, 11 diagnoses changed. In 31% of the diagnoses, the clinician gained confidence, while in 10% confidence decreased. CONCLUSION: We found that knowledge of CSF biomarker profiles changed the diagnosis in 10% of the cases, and confidence in the diagnosis increased for one third of the patients.

What patients want to know, and what we actually tell them: The ABIDE project.

BACKGROUND: We studied to what degree and at whose initiative 25 informational topics, formerly identified as important, are discussed in diagnostic consultations. METHODS: Audio recordings of clinician-patient consultations of 71 patients and 32 clinicians, collected in eight Dutch memory clinics, were independently content-coded by two coders. The coding scheme encompassed 25 informational topics. RESULTS: Approximately half (Mdn = 12) of the 25 topics were discussed per patient during the diagnostic process, with a higher frequency among individuals receiving a dementia diagnosis (Mdn = 14) compared to others (Mdn = 11). Individual topics ranged from being discussed with 2/71 (3%) to 70/71 (99%) of patients. Patients and/or care partners rarely initiated topic discussion (10%). When they did, they often enquired about one of the least frequently addressed topics. CONCLUSION: Most patients received information on approximately half of the important informational topics. Providing the topic list to patients and care partners beforehand could allow consultation preparation and stimulate participation.

Clinicians' communication with patients receiving a MCI diagnosis: The ABIDE project.

BACKGROUND: We aimed to explore clinicians' communication, including the discussion of diagnosis, cause, prognosis and care planning, in routine post-diagnostic testing consultations with patients with Mild Cognitive Impairment (MCI). METHODS: Thematic content analysis was used to analyze audiotaped consultations in which 10 clinicians (eight neurologists and two geriatricians) from 7 memory clinics, disclosed diagnostic information to 13 MCI patients and their care partners. We assessed clinician-patient communication regarding diagnostic label, cause, prognosis and care planning to identify core findings. RESULTS: Core findings were: clinicians 1) differed in how they informed about the MCI label; 2) tentatively addressed cause of symptoms; 3) (implicitly) steered against further biomarker testing; 4) rarely informed about the patient's risk of developing dementia; 5) often informed about the expected course of symptoms emphasizing potential symptom stabilization and/or improvement, and; 6) did not engage in a conversation on long-term (care) planning. DISCUSSION: Clinicians' information provision about the underlying cause, prognosis and implications for long-term (care) planning in MCI could be more specific. Since most patients and care partners have a strong need to understand the patient's symptoms, and for information on the prognosis and implications for the future, clinicians' current approach may not match with those needs.

Testing Episodic Memory in Elderly Subjects: Not as Simple as It Looks.

BACKGROUND/AIMS: The available episodic memory tests are not specifically constructed to examine older subjects. Their use in outpatient memory clinics may result in aborted test administration. We used a strict adherence to the test protocol in cognitively healthy, amnestic mild cognitive impairment (aMCI), and Alzheimer's disease dementia subjects to assess the possibility of preventing this. METHODS: This is a cross-sectional study in memory outpatient subjects with a mean age of 74.5 years. Primary study outcomes were: number of missing values and test results in the Visual Association Test (VAT) and the 15 Word Test (15WT). RESULTS: A strict adherence to the test protocol resulted in a 10-fold decrease in the number of missing values in the VAT. For the 15WT this could not be realized mostly because the test was deemed too demanding for 1 in 6 patients. CONCLUSIONS: This study is one of the few examining the applicability of well-known episodic memory tests in older subjects. A strict adherence to the test protocol reduced the number of missing values. Floor effects were stronger for the 15WT than for the VAT. Results favor the use of the VAT in senior subjects and show the unsuitability of the 15WT in this group.

Clinician-patient communication during the diagnostic workup: The ABIDE project.

INTRODUCTION: We aimed to describe clinician-patient communication in the diagnostic process of memory clinics, specifically clinician behavior known to facilitate knowledgeable participation of patients during consultations. METHODS: In this multicenter, observational study, we audio-recorded routine diagnostic consultations of 41 clinicians and 136 patients/caregivers at eight memory clinics. Patients/caregivers completed surveys after each audiotaped consultation. We used a study-specific coding scheme to categorize communication behavior. RESULTS: Clinicians often provided information on (results of) diagnostic testing. They infrequently invited questions and/or checked understanding. Clinician behavior to involve patients in decision-making about diagnostic testing was limited. Of note, patients/caregivers rarely expressed their information or involvement preferences. Yet, approximately, one quarter of them would have liked to receive more information. DISCUSSION: Involving patients more explicitly by means of shared decision-making could benefit the quality of care provided in memory clinics because it enables clinicians to attune the diagnostic workup to the individual patient's needs.

Diagnostic performance of Elecsys immunoassays for cerebrospinal fluid Alzheimer's disease biomarkers in a nonacademic, multicenter memory clinic cohort: The ABIDE project.

INTRODUCTION: We compared the automated Elecsys and manual Innotest immunoassays for cerebrospinal fluid (CSF) Alzheimer's disease biomarkers in a multicenter diagnostic setting. METHODS: We collected CSF samples from 137 participants in eight local memory clinics. Amyloid ß(1-42) (Aß42), total tau (t-tau), and phosphorylated tau (p-tau) were centrally analyzed with Innotest and Elecsys assays. Concordances between methods were assessed. RESULTS: Biomarker results strongly correlated between assays with Spearman's ρ 0.94 for Aß42, 0.98 for t-tau, and 0.98 for p-tau. Using Gaussian mixture modeling, cohort-specific cut-points were estimated at 1092 pg/mL for Aß42, 235 pg/mL for t-tau, and 24 pg/mL for p-tau. We found an excellent concordance of biomarker abnormality between assays of 97% for Aß42 and 96% for both t-tau and p-tau. DISCUSSION: The high concordances between Elecsys and Innotest in this nonacademic, multicenter cohort support the use of Elecsys for CSF Alzheimer's disease diagnostics and allow conversion of results between methods.

Does MRI Increase the Diagnostic Confidence of Physicians in an Outpatient Memory Clinic.

BACKGROUND AND AIM: Data showing the usefulness of MRI to improve the accuracy of the diagnostic process in cognitive disorders were derived from studies in tertiary referral centers. MRI is widely used as a diagnostic tool in everyday practice, but it is unknown what the actual added value of MRI is. We studied the usefulness of MRI in the diagnostic process by measuring the change of confidence of the physician. METHODS: Physicians indicated confidence in their diagnosis before and after presentation of MR images using a visual analogue scale from 0-100%. RESULTS: Use of MRI increased the level of confidence by 3% in experienced clinicians and by 9% in inexperienced physicians. In 2/125 cases, MRI showed an unexpected finding. CONCLUSION: MRI is a useful diagnostic tool in everyday practice of diagnosing cognitive disorders.

Visual associations cued recall A Paradigm for Measuring Episodic Memory Decline in Alzheimer's Disease.

Repeated measurements of episodic memory are needed for monitoring amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD). Most episodic memory tests may pose a challenge to patients, even when they are in the milder stages of the disease. This cross-sectional study compared floor effects of the Visual Association Test (VAT) and the Rey Auditory Verbal Learning Test (RAVLT) in healthy elderly controls and in patients with aMCI or AD (N = 125). A hierarchical multiple regression analysis was used to examine whether linear or quadratic trends best fitted the data of cognitive test performance across global cognitive impairment. Results showed that VAT total scores decreased linearly across the range of global cognitive impairment, whereas RAVLT total scores showed a quadratic trend, with total scores levelling off for 90% of aMCI patients and 94% of AD patients. We conclude that the VAT shows few if any floor effects in patients with aMCI and mild AD and is therefore a potentially promising cognitive test for monitoring episodic memory impairment.

[Self-neglect in older adults--a complex problem]. / Zelfverwaarlozing bij ouderen, een complex probleem.

A 76-year-old man presented at the emergency department with functional decline and extreme self-neglect. He died after a few days. The probable cause of death was pneumonia. His family consented to autopsy. Surprisingly, the neuropathological findings showed a tauopathy consistent with fronto-temporal dementia. Self-neglect in the elderly is a common and complex problem associated with high mortality and morbidity. This syndrome requires a thorough workup to detect possible causes. The most common etiologies are neurodegenerative disorders, psychiatric illness and alcohol abuse. It is important to elucidate the cause of self-neglect in order to give the proper treatment and support to the patient and family.