Brain age as a biomarker for pathological versus healthy ageing - a REMEMBER study.

OBJECTIVES: This study aimed to evaluate the potential clinical value of a new brain age prediction model as a single interpretable variable representing the condition of our brain. Among many clinical use cases, brain age could be a novel outcome measure to assess the preventive effect of life-style interventions. METHODS: The REMEMBER study population (N = 742) consisted of cognitively healthy (HC,N = 91), subjective cognitive decline (SCD,N = 65), mild cognitive impairment (MCI,N = 319) and AD dementia (ADD,N = 267) subjects. Automated brain volumetry of global, cortical, and subcortical brain structures computed by the CE-labeled and FDA-cleared software icobrain dm (dementia) was retrospectively extracted from T1-weighted MRI sequences that were acquired during clinical routine at participating memory clinics from the Belgian Dementia Council. The volumetric features, along with sex, were combined into a weighted sum using a linear model, and were used to predict 'brain age' and 'brain predicted age difference' (BPAD = brain age-chronological age) for every subject. RESULTS: MCI and ADD patients showed an increased brain age compared to their chronological age. Overall, brain age outperformed BPAD and chronological age in terms of classification accuracy across the AD spectrum. There was a weak-to-moderate correlation between total MMSE score and both brain age (r = -0.38,p < .001) and BPAD (r = -0.26,p < .001). Noticeable trends, but no significant correlations, were found between BPAD and incidence of conversion from MCI to ADD, nor between BPAD and conversion time from MCI to ADD. BPAD was increased in heavy alcohol drinkers compared to non-/sporadic (p = .014) and moderate (p = .040) drinkers. CONCLUSIONS: Brain age and associated BPAD have the potential to serve as indicators for, and to evaluate the impact of lifestyle modifications or interventions on, brain health.

A short and simple bedside test to detect cognitive fluctuations in patients with dementia with Lewy bodies.

BACKGROUND AND PURPOSE: The establishment of cognitive fluctuations is important when dementia with Lewy bodies (DLB) is suspected but can be especially difficult in the absence of a caregiver who lives with the patient. We examined the possibility of using fluctuating scores on a forward (FDS) and a backward digit span (BDS) test as a marker for cognitive fluctuation. METHODS: Patients with DLB (21), other forms of dementia (14 with Alzheimer's disease, 8 with vascular dementia) and 20 controls were asked to perform an FDS and BDS twice, with an interval of 20 min. RESULTS: Seventy percent of patients with DLB showed evidence of cognitive fluctuations for at least one test, while less than 10% of controls and patients with other dementias did. Evidence of cognitive fluctuations on at least one of both tests classified 83% of patients correctly (i.e. DLB or not), with a sensitivity of 70% and a specificity of 90%. CONCLUSIONS: Repeated forward and backward digit span tests seem a valid, short, easy and inexpensive bedside tool to detect cognitive fluctuations in the diagnostic work-up of DLB, even in the absence of a caregiver, which limits the use of questionnaires.

Diagnostic Performance of Automated MRI Volumetry by icobrain dm for Alzheimer's Disease in a Clinical Setting: A REMEMBER Study.

BACKGROUND: Magnetic resonance imaging (MRI) has become important in the diagnostic work-up of neurodegenerative diseases. icobrain dm, a CE-labeled and FDA-cleared automated brain volumetry software, has shown potential in differentiating cognitively healthy controls (HC) from Alzheimer's disease (AD) dementia (ADD) patients in selected research cohorts. OBJECTIVE: This study examines the diagnostic value of icobrain dm for AD in routine clinical practice, including a comparison to the widely used FreeSurfer software, and investigates if combined brain volumes contribute to establish an AD diagnosis. METHODS: The study population included HC (n = 90), subjective cognitive decline (SCD, n = 93), mild cognitive impairment (MCI, n = 357), and ADD (n = 280) patients. Through automated volumetric analyses of global, cortical, and subcortical brain structures on clinical brain MRI T1w (n = 820) images from a retrospective, multi-center study (REMEMBER), icobrain dm's (v.4.4.0) ability to differentiate disease stages via ROC analysis was compared to FreeSurfer (v.6.0). Stepwise backward regression models were constructed to investigate if combined brain volumes can differentiate between AD stages. RESULTS: icobrain dm outperformed FreeSurfer in processing time (15-30 min versus 9-32 h), robustness (0 versus 67 failures), and diagnostic performance for whole brain, hippocampal volumes, and lateral ventricles between HC and ADD patients. Stepwise backward regression showed improved diagnostic accuracy for pairwise group differentiations, with highest performance obtained for distinguishing HC from ADD (AUC = 0.914; Specificity 83.0%; Sensitivity 86.3%). CONCLUSION: Automated volumetry has a diagnostic value for ADD diagnosis in routine clinical practice. Our findings indicate that combined brain volumes improve diagnostic accuracy, using real-world imaging data from a clinical setting.

Dementia with Lewy bodies in first-generation immigrants in a European memory clinic.

We wanted to explore possible differences in disease presentation, frequency, and age of onset of dementia with Lewy bodies (DLB) between first-generation immigrants (FGI) and patients born in Belgium (PBIB). We conducted a retrospective study on all patients of our Memory Clinic between June 1, 2010 and January 31, 2020. A synucleinopathy was diagnosed in 150 of 2702 patients (5.5%): 91 received a diagnosis of DLB (3.4%). FGI were two times more likely to receive a diagnosis of DLB, due to a higher prevalence in North-Africans and Latin-Americans. Visual hallucinations were less frequent in North-Africans than in other immigrants. FGI were younger than PBIB and reported more often parasomnia. Our data suggest a higher risk for DLB in certain immigrant groups. Especially for North-African patients, a genetic factor can be suspected, namely mutations in Leucine-rich repeat kinase 2 (LRRK2). Memory clinics with a high rate of FGI may provide interesting data and insights into the prevalence of DLB, genetic and environmental differences.

Frontotemporal dementia patients exhibit deficits in predictive saccades.

Prediction and time estimation are all but required for motor function in everyday life. In the context of eye movements, for instance, they allow predictive saccades and eye re-acceleration in anticipation of a target re-appearance. While the neural pathways involved are not fully understood, it is known that the frontal lobe plays an important role. As such, neurological disorders that affect it, such as frontotemporal (FTD) dementia, are likely to induce deficits in such movements. In this work, we study the performances of frontotemporal dementia patients in an oculomotor task designed to elicit predictive saccades at different rates, and compare them to young and older adults. Clear deficits in the production of predictive saccades were found in patients, in particular when the time between saccades was short (~500 ms). Furthermore, one asymptomatic C9ORF72 mutation bearer showed patterns of oculomotor behavior similar to FTD patients. He exhibited FTD symptoms within 3 years post-measure, suggesting that an impairment of oculomotor function could be an early clinical sign. Taken together, these results argue in favor of a role of the frontal lobe in predictive movements timing over short timescales, and suggest that predictive saccades in FTD patients warrant further investigation to fully assess their potential as a diagnostic aid.

Serous Tubal Intraepithelial Carcinoma-Like and Pagetoid Tubal Metastasis of an Ovarian Large Cell Neuroendocrine Carcinoma: Peculiar Metastatic Growth Patterns of a Rare Tumor.

A large cell neuroendocrine carcinoma of the ovary is presented because of tubal metastases with peculiar growth patterns: pagetoid and serous tubal intraepithelial carcinoma-like. The possibility that a tubal intraepithelial carcinoma could represent a metastasis should be considered by pathologists.

West Nile Virus Neuroinvasive Disease Accelerating Probable Dementia With Lewy Bodies.

We describe a case of dementia with Lewy bodies immediately following encephalitis due to West Nile virus (WNV). The patient had rapid eye movement-sleep behavior disorder and constipation before the onset of encephalitis, which suggests that he would have ultimately developed dementia with Lewy bodies even without WNV infection. Our case illustrates the interactions between α-synuclein and WNV, as observed in mouse models, wherein synuclein expression augments after WNV infection and protects neurons against the virus.

Practices and opinions about disclosure of the diagnosis of Alzheimer's disease to patients with MCI or dementia: a survey among Belgian medical experts in the field of dementia.

Previous surveys revealed that only a minority of clinicians routinely disclosed the diagnosis of Alzheimer's disease (AD) to their patients. Many health professionals fear that the disclosure could be harmful to the patient. Recent advances in the development of biomarkers and new diagnostic criteria allow for an earlier diagnosis of AD at the mild cognitive impairment (MCI) stage. The Belgian Dementia Council, a group of Belgian experts in the field of dementia, performed a survey among its 44 members about their opinions and practices regarding disclosure of the diagnosis of AD, including MCI due to AD, and its consequences. Twenty-six respondents declared that they often or always disclose the diagnosis of AD to patients with dementia and to patients with MCI when AD CSF biomarkers are abnormal. The majority observed that the disclosure of AD is rarely or never harmful to the patients. Their patients and their caregivers rarely or never demonstrated animosity towards the clinicians following disclosure of the diagnosis of AD. These results should reassure clinicians about the safety of AD diagnosis disclosure in most cases whether the patient is at the MCI or the dementia stage.

Pregabalin as a Treatment for Anxiety in Patients With Dementia With Lewy Bodies: A Case Series.

BACKGROUND: Anxiety is a common and invalidating symptom of dementia with Lewy bodies (DLB). METHODS: To evaluate the efficacy of pregabalin as a treatment for anxiety in DLB, we screened all medical files of our patients with DLB for the use of pregabalin in this context. FINDINGS: Overall, pregabalin was well tolerated. Ten (62.5%) of 16 patients showed an improvement of anxiety, whereas in 3 of them, anxiety disappeared completely, at respectively 3, 11, and 22 months of follow-up, with total daily doses ranging from 75 to 150 mg. Positive response to pregabalin was associated with a significant reduction in benzodiazepine use. CONCLUSIONS: Pregabalin seems a useful and safe tool for treating anxiety in patients with DLB.

Anxiety symptoms are quantitatively and qualitatively different in dementia with Lewy bodies than in Alzheimer's disease in the years preceding clinical diagnosis.

AIM: Dementia with Lewy bodies (DLB) is a common but underdiagnosed type of cognitive impairment and dementia. The current diagnostic criteria for research purposes have a high specificity but lack sensitivity. Moreover, patients who live alone are not always aware that they have core clinical features such as cognitive fluctuations, visual hallucinations, and parasomnia. Anxiety is a common and early manifestation in DLB. METHODS: We matched 41 DLB patients with 41 patients with Alzheimer's disease (AD) according to gender, age, and cognitive status and retrospectively analyzed their files for the presence of anxiety, depression, constipation, and the core clinical features of DLB in the documented period before diagnosis. RESULTS: Anxiety, but not depression, occurred significantly more frequently in DLB than in AD (63.4% vs 26.8%). It appears up to 4-5 years before the diagnosis of DLB and is associated with depression and living at home. Anxiety in DLB was often described as intermittent panic attacks without reason or during states of delirium; it was also severe enough to require medical treatment and inpatient or outpatient psychiatric care. It was often mistaken for a psychiatric illness or a manifestation of other common forms of dementia. Anxiety in AD seemed much milder, was often related to the patient's coping with cognitive dysfunction, and was never cited as a specific reason for medical help. The concomitant presence of anxiety with at least one core clinical criterion of DLB enabled us to differentiate it from AD in our study, with a sensitivity of 63.4% but a specificity of 100%. CONCLUSIONS: In all patients over 50 who present with cognitive problems and anxiety, DLB should be considered. Patients and informants should be carefully questioned regarding the presence of other typical signs and symptoms of DLB.

Dramatic Response to First Line Single Agent Pembrolizumab in Anaplastic Thyroid Carcinoma.

Anaplastic thyroid carcinoma (ATC) is a deadly disease with very limited therapeutic options. There is an urgent need for new and efficacious drugs. Unfortunately accrual in clinical trials is problematic because of the rarity of the disease and often poor performance status at diagnosis. Recently some data have emerged suggesting a role for immunotherapy in the treatment of ATC. We describe the case of a 75-year-old patient with poor performance status and compromised airway and oesophagus at diagnosis, showing a rapid and dramatic response to first line single agent pembrolizumab. Disease progression in the brain occurred 16 months after initial diagnosis. At that time there was ongoing extracranial disease control.

Dementia, End of Life, and Euthanasia: A Survey Among Dementia Specialists Organized by the Belgian Dementia Council.

BACKGROUND: Palliative care and Advance Care Planning (ACP) are increasingly recommended for an optimal management of late-stage dementia. In Belgium, euthanasia has been decriminalized in 2002 for patients who are "mentally competent" (interpreted as non-demented). It has been suggested that advance directives for euthanasia (ADE) should be made possible for dementia patients. OBJECTIVE: This study presents the results of an internet survey among Belgian dementia specialists. METHODS: In 2013, the Belgian Dementia Council (BeDeCo) organized a debate on end of life decisions in dementia. Participants were medical doctors who are specialists in the dementia field. After the debate, an anonymous internet survey was organized. The participation rate was 55%. The sample was representative of the BeDeCo members. RESULTS: The results showed consensus in favor of palliative care and ACP, although ACP is not systematically addressed in practice. Few patients with dementia have requested euthanasia, but for those who did the participants had agreed to implement it for some patients. A majority of participants (94%) believe that most patients and their families are poorly informed about euthanasia. Although most participants (77%) said they approved the Law on euthanasia, 65% said they were against an extension of the Law to allow ADE for dementia. CONCLUSION: Palliative care and ACP are clearly accepted by professionals, although a gap between recommendation and practice remain. Euthanasia is a much more debated issue, even if a majority of professionals are, in principle, in favor of the current Law and seem to disapprove with a Law change allowing ADE for dementia. A better education for both health professionals and the lay public will be a key element in the future.

Validation of a brief Multicultural Cognitive Examination (MCE) for evaluation of dementia.

BACKGROUND: The aims of this study were to present the psychometric properties of a newly designed cognitive screening instrument, the Multicultural Cognitive Examination (MCE), and to compare it with the Rowland Universal Dementia Assessment Scale (RUDAS) in a multicultural population. METHODS: The study was a Western European cross-sectional multicenter study. The MCE consists of four components evaluating separate cognitive functions and was constructed by adding measures of memory, verbal fluency, and visuospatial function to the RUDAS to create a scale with 0 to 100 points. RESULTS: A total of 66 patients with dementia and 123 cognitively intact participants were included across six memory clinics; 96 had minority ethnic background, and 93 had majority ethnic background. Moderate to large differences were present between patients with dementia and control participants on all MCE components. The MCE significantly improved diagnostic accuracy compared with using the RUDAS alone, with area under the curves of .918, .984, and .991 for the RUDAS, MCE composite, and demographically corrected composite scores, respectively. Diagnostic accuracy of the MCE did not significantly differ between minority and majority ethnic groups. Across MCE subcomponents, patients with Alzheimer's disease (AD) dementia performed significantly poorer on the memory component compared with those with non-AD dementia. CONCLUSIONS: The MCE is a brief cross-cultural cognitive screening instrument that expands evaluation of the cognitive functions covered by the RUDAS, does not require any specialized training, and may be useful for classification of mild dementia or dementia subtypes.

Validation of the Rowland Universal Dementia Assessment Scale (RUDAS) in a multicultural sample across five Western European countries: diagnostic accuracy and normative data.

ABSTRACTBackground:With increasing cultural diversity and growing elderly immigrant populations in Western European countries, the availability of brief cognitive screening instruments adequate for assessment of dementia in people from diverse backgrounds becomes increasingly important. The aim of the present study was to investigate diagnostic accuracy of the Rowland Universal Dementia Assessment Scale (RUDAS) in a multicultural sample and to calculate normative data as a basis for demographic adjustment of RUDAS scores. METHODS: The study was a prospective international cross-sectional multi-center study. Receiver operating characteristic curve analysis was used to examine diagnostic accuracy. Regression analysis was used to assess the impact of demographic variables. RESULTS: Data was collected from 341 cognitively intact participants and 80 people with dementia with a wide age- and educational range. Of the 421 included participants, 239 (57%) had immigrant background. The RUDAS had high diagnostic accuracy with an area under the curve (AUC) of 0.93. The optimal cut-off score was <25 (sensitivity 0.80, specificity 0.90). Regression analysis revealed that RUDAS scores were mainly affected by education and were unrelated to data collection site and immigrant status. Education-adjusted normative data was calculated as a basis for education adjustment of RUDAS scores. Applying education-adjusted RUDAS scores slightly but significantly improved diagnostic accuracy with an AUC of 0.95. CONCLUSION: We found the RUDAS to have excellent diagnostic properties in our multicultural sample. However, we suggest that RUDAS scores should be adjusted for education to increase diagnostic accuracy and that the choice of cut-off score should be considered based on the clinical context and expected base rate of dementia.

Validation of a European Cross-Cultural Neuropsychological Test Battery (CNTB) for evaluation of dementia.

BACKGROUND: The aims of this study were to establish the diagnostic accuracy of the European Cross-Cultural Neuropsychological Test Battery (CNTB) for dementia in different ethnic populations in Western Europe, to examine its ability to differentiate cognitive impairment profiles for dementia subtypes, and to assess the impact of demographic variables on diagnostic properties. METHODS: The study was a Western European cross-sectional multi-center study. A total of 66 patients with dementia and 118 cognitively intact participants were included across six memory clinics; 93 had ethnic minority background and 91 had ethnic majority background. Tests in the CNTB cover global cognitive function, memory, language, executive functions, and visuospatial functions. RESULTS: Significant differences with moderate to large effect sizes were present between patients with dementia and control participants on all CNTB measures. Area under the curves (AUC) ranged from .62 to .99 with a mean AUC across all measures of .83. Comparison of ethnic minority and majority groups generally revealed higher sensitivity in the minority group but no significant difference in the mean AUC's across all measures (.84 vs78, P = .42). Comparison of impairment profiles for patients with Alzheimer's disease (AD) and non-AD dementia revealed that AD patients were significantly more impaired on the memory domain, whereas patients with non-AD dementia were more impaired on the executive functions domain. CONCLUSIONS: The CNTB was found to have promising cross-cultural diagnostic properties for evaluation of dementia in the targeted minority and majority populations and could represent a valid cross-cultural alternative to other well-established neuropsychological test batteries when assessing patients from these populations.

A Retrospective Belgian Multi-Center MRI Biomarker Study in Alzheimer's Disease (REMEMBER).

BACKGROUND: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer's disease (AD). OBJECTIVE: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression. METHODS: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available. RESULTS: The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment. CONCLUSION: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.

Performance of middle-aged and elderly European minority and majority populations on a Cross-Cultural Neuropsychological Test Battery (CNTB).

OBJECTIVE: The aim of this study was to examine test performance on a cross-cultural neuropsychological test battery for assessment of middle-aged and elderly ethnic minority and majority populations in western Europe, and to present preliminary normative data. METHOD: The study was a cross-sectional multi-center study. Tests in the European Cross-Cultural Neuropsychological Test Battery (CNTB) cover several cognitive domains, including global cognitive function, memory, executive functions, and visuospatial functions. RESULTS: A total of 330 participants were included: 14 Moroccan, 45 Pakistani/Indian Punjabi, 41 Polish, 66 Turkish, and 19 former Yugoslavian minority participants, and 145 western European majority participants. Significant differences between ethnic groups were found on most CNTB measures. However, ethnic groups differed greatly in demographic characteristics and differences in test scores were mainly related to educational differences, explaining an average of 15% of the variance. Preliminary multicultural CNTB normative data dichotomized by education and age were constructed using overlapping cells. Applying this normative data across the whole sample resulted in an acceptable number of participants scoring in the impaired range across all ethnic groups. Factor analyses found the CNTB to have a stable and clinically meaningful factor structure. CONCLUSIONS: The CNTB represents the first European joint effort to establish neuropsychological measures appropriate for ethnic minority populations in western Europe. The CNTB can be applied in approximately 60 min, covers several cognitive domains, and appears appropriate for assessment of the targeted populations. However, due to the small sample size in some ethnic groups further studies are needed replicate and support this.