Patients carrying the mutation p.R406W in MAPT present with non-conforming phenotypic spectrum.

The missense mutation p.R406W in microtubule-associated protein tau leads to frontotemporal lobar degeneration with an amnestic, Alzheimer's disease-like phenotype with an autosomal dominant pattern of inheritance. In 2003, we described the pedigree of a Belgian family, labelled ADG, with 28 p.R406W patients. Over 18 years follow-up, we extended the family with 10 p.R406W carriers and provided an in-depth clinical description of the patients. Additionally, genetic screening was used to identify p.R406W carriers in Belgian cohorts of frontotemporal dementia and Alzheimer's disease patients and to calculate p.R406W frequency. In the frontotemporal dementia cohort, we found four p.R406W carriers (n = 647, 0.62%) and three in the Alzheimer's disease cohort (n = 1134, 0.26%). Haplotype sharing analysis showed evidence of a shared haplotype suggesting that they are descendants of a common ancestor. Of the p.R406W patients, we describe characteristics of neuropsychological, imaging and fluid biomarkers as well as neuropathologic examination. Intriguingly, the phenotypic spectrum among the p.R406W patients ranged from typical behavioural variant frontotemporal dementia to clinical Alzheimer's disease, based on CSF biomarker analysis and amyloid PET scan. Heterogeneous overlap syndromes existed in between, with highly common neuropsychiatric symptoms like disinhibition and aggressiveness, which occurred in 100% of frontotemporal dementia and 58% of clinical Alzheimer's disease patients. This was also the case for memory problems, 89% in frontotemporal dementia and 100% in clinical Alzheimer's disease patients. Median age at death was significantly lower in patients with frontotemporal dementia (68 years) compared to clinical Alzheimer's disease patients (79 years), although the sizes of the sub-cohorts are limited and do not allow prognostic predictions. Post-mortem brain analysis of one p.R406W patient with behavioural variant frontotemporal dementia revealed frontotemporal lobar degeneration with tau pathology. Notably, neuropathological investigation showed only 3R tau isoforms in the absence of 4R tau reactivity, an unusual finding in microtubule-associated protein tau-related frontotemporal lobar degeneration. No traces of amyloid pathology were present. Prevalence of the p.R406W mutation was relatively high in both frontotemporal dementia and Alzheimer's disease Belgian patient cohorts. These findings grant new insights into genotype-phenotype correlations of p.R406W carriers. They may help in further unravelling of the pathophysiology of this tauopathy and in facilitating the identification of patients with p.R406W-related frontotemporal lobar degeneration, both in clinical diagnostic and research settings.

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.

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.

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.

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.

A Belgian consensus protocol for autologous hematopoietic stem cell transplantation in multiple sclerosis.

Multiple sclerosis is considered to be an immune mediated inflammatory disorder of the central nervous system. It mainly affects young, socioeconomic active patients. Although our armamentarium for this disease has significantly evolved in recent years some patients remain refractory to conventional therapies. In these cases, autologous hematopoietic stem cell transplantation can be considered as a therapeutic option. Decreasing morbidity, mortality, and increasing patient awareness have led to rising inquiry by our patients about this treatment option. With the aim of a standardized protocol and data registration, a Belgian working party on stem cell therapy in multiple sclerosis was established. In this paper, we report the consensus protocol of this working party on autologous hematopoietic stem cell transplantation in multiple sclerosis.

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.

Alzheimer's disease and driving: review of the literature and consensus guideline from Belgian dementia experts and the Belgian road safety institute endorsed by the Belgian Medical Association.

Alzheimer's disease (AD) is a highly prevalent condition and its prevalence is expected to further increase due to the aging of the general population. It is obvious that the diagnosis of AD has implications for driving. Finally, driving discussions are also emotionally charged because driving is associated with independence and personal identity. However, it is not clear how to implement this in clinical practice and the Belgian law on driving is rather vague in its referral to neurodegenerative brain diseases in general nor does it provide clear-cut instructions for dementia or AD compared to for example driving for patients with epilepsy and as such does not prove to be very helpful. The present article reviews what is known from both literature and existing guidelines and proposes a consensus recommendation tailored to the Belgian situation agreed by both AD experts and the Belgian Road Safety Institute endorsed by the Belgian Medical Association. It is concluded that the decision about driving fitness should be considered as a dynamic process where the driving fitness is assessed and discussed early after diagnosis and closely monitored by the treating physician. The diagnosis of AD on itself definitely does not imply the immediate and full revocation of a driving license nor does it implicate a necessary referral for a formal on-road driving assessment. There is no evidence to recommend a reduced exposure or a mandatory co-pilot. A MMSE-based framework to trichotomise AD patients as safe, indeterminate or unsafe is presented. The final decision on driving fitness can only be made after careful history taking and clinical examination, neuropsychological, functional and behavioral evaluation and, only for selected cases, a formal assessment of driving performance.

Clinical Evidence of Disease Anticipation in Families Segregating a C9orf72 Repeat Expansion.

Importance: Patients carrying a C9orf72 repeat expansion leading to frontotemporal dementia and/or amyotrophic lateral sclerosis have highly variable ages at onset of disease, suggesting the presence of modifying factors. Objective: To provide clinical-based evidence for disease anticipation in families carrying a C9orf72 repeat expansion by analyzing age at onset, disease duration, and age at death in successive generations. Design, Setting, and Participants: This cohort study was performed from June 16, 2000, to June 1, 2016, in 36 extended Belgian families in which a C9orf72 repeat expansion was segregating. The generational effect on age at onset, disease duration, and age at death was estimated using a mixed effects Cox proportional hazards regression model, including random-effects terms for within-family correlation and kinship. Time until disease onset or last examination, time from disease onset until death or last examination, or age at death was collected for for 244 individuals (132 proven or obligate C9orf72 carriers), of whom 147 were clinically affected (89 proven or obligate C9orf72 carriers). Main Outcomes and Measures: Generational effect on age at onset, disease duration, and age at death. Results: Among the 111 individuals with age at onset available (66 men and 45 women; mean [SD] age, 57.2 [9.1] years), the mean (SD) age at onset per generation (from earliest-born to latest-born generation) was 62.5 (8.3), 57.1 (8.2), 54.6 (10.2), and 49.3 (7.5) years. Censored regression analysis on all affected and unaffected at-risk relatives confirmed a decrease in age at onset in successive generations (P < .001). No generational effect was observed for disease duration or age at death. Conclusions and Relevance: The clinical data provide supportive evidence for the occurrence of disease anticipation in families carrying a C9orf72 repeat expansion by means of a decrease in age at onset across successive generations. This finding may help clinicians decide from which age onward it may be relevant to clinically follow presymptomatic individuals who carry a C9orf72 repeat expansion.

Clinical characteristics and long term prognosis in early onset multiple sclerosis.

The clinical features, disease course and long term prognosis of early onset multiple sclerosis (EOMS) are variable. A preponderance of female sex, a high incidence of visual and brainstem symptoms at onset and a relapsing-remitting disease course with slower progression rate all have been considered relatively frequent in this subgroup of MS patients. Unfortunately, follow-up in previous studies has usually been limited to less than 10 years, precluding general statements on the long term evolution and prognosis in EOMS. In this retrospective study of EOMS with a substantially longer follow-up of 20.8 years, clinical characteristics, disease course and long term prognosis are described in 49 EOMS patients. In a representative subgroup of 28 patients disability was scored using Kurtzke's Functional System (FS) and Expanded Disability Status Scale (EDSS). The mean period of follow- up for these patients was 28.7 years. The present study confirms that several specific clinical characteristics can be identified in EOMS patients, such as a mainly relapsing-remitting disease onset and frequent presentation with brainstem- cerebellar dysfunction (28.6 %), pyramidal symptoms (18.4 %) and optic neuritis (14.3%). However, after a long period of follow-up the overall disease course and prognosis do not seem to differ from that in adult onset MS. By consequence a young age at onset in MS cannot be considered a favourable prognostic factor.

Clinical utility and applicability of biomarker-based diagnostic criteria for Alzheimer's disease: a BeDeCo survey.

We conducted a survey regarding the medical care of patients with dementia in expert settings in Belgium. Open, unrestricted and motivated answers were centralized, blindly interpreted and structured into categories. The report of the results was then submitted to the participants in subsequent plenary meetings and through email. Fourteen experts responded to the questionnaire, confirming that recent propositions to modify Alzheimer's disease (AD) diagnostic criteria and options have stirred up debate among well-informed and dedicated experts in the field. The opinions were not unanimous and illustrate how difficult it is to find a standardized method of diagnosing this disease. The responses to the survey suggest that application of a step-by-step pragmatic method is used in practice. Only when the combination of clinical findings and classical structural neuro-imaging is insufficient for a diagnosis or suggests an atypical presentation, additional biomarkers are considered. Interestingly, few differences, if any, were observed between the use of biomarkers in MCI and in AD. In conclusion, the Belgian experts consulted in this survey were generally in agreement with the new diagnostic criteria for AD, although some concern was expressed about them being too "amyloidocentric". Although the clinical examination, including a full neuropsychological evaluation, is still considered as the basis for diagnosis, most experts also stated that they use biomarkers to help with diagnosis.

Pseudotumoral rebound of multiple sclerosis in a pregnant patient after stopping natalizumab.

Natalizumab is a highly efficacious treatment for active relapsing-remitting multiple sclerosis, dramatically reducing both clinical and radiological signs of inflammation in most patients. The disease course after stopping treatment and especially the emergence of rebound activity are still a matter of debate. We present a case of dramatic reactivation of clinical disease activity with newly emerging pseudotumoral lesions in a patient who stopped treatment due to pregnancy. Both the clinical and radiological presentation suggest a rebound and necessitate close monitoring of patients stopping their treatment during pregnancy, even after a long period of stable disease.

MRI characteristics of trigeminal nerve involvement in patients with multiple sclerosis.

BACKGROUND: Trigeminal neuralgia and central sensory disturbances are common in patients with multiple sclerosis. The anatomic correlation to lesions in the trigeminal nuclei in the brainstem is not well studied. OBJECTIVE: We studied the anatomical characteristics of demyelinating lesions of the trigeminal complex in the brainstem on MRI in patients with MS and Clinically Isolated syndrome (CIS). MATERIALS AND METHODS: 43 Patients with MS or CIS and MRI lesions in the trigeminal complex in the brainstem were selected from a large database of patients referred for MRI because of trigeminal symptoms. RESULTS AND CONCLUSION: A linear plaque involving the intrapontine fascicular part of the trigeminal nerve and lesions of the spinal trigeminal nucleus and tract seem to be distinctive MRI findings in patients with RRMS or CIS.

Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort.

OBJECTIVE: To characterize patients with frontotemporal lobar degeneration (FTLD) with a repeat expansion mutation in the gene C9orf72, and to determine whether there are differences in the clinical presentation compared with FTLD carriers of a mutation in GRN or MAPT or with patients with FTLD without mutation. DESIGN: Patient series. SETTING: Dementia clinics in Flanders, Belgium. PATIENTS: Two hundred seventy-five genetically and phenotypically thoroughly characterized patients with FTLD. MAIN OUTCOME MEASURES: Clinical and demographic characteristics of 26 C9orf72 expansion carriers compared with patients with a GRN or MAPT mutation, as well as patients with familial and sporadic FTLD without mutation. RESULTS: C9orf72 expansion carriers developed FTLD at an early age (average, 55.3 years; range, 42-69 years), significantly earlier than in GRN mutation carriers or patients with FTLD without mutation. Mean survival (6.2 years; range, 1.5-17.0 years) was similar to other patient groups. Most developed behavioral variant frontotemporal dementia (85%), with disinhibited behavior as the prominent feature. Concomitant amyotrophic lateral sclerosis is a strong distinguishing feature for C9orf72 -associated FTLD. However, in most patients (73%), amyotrophic lateral sclerosis symptoms were absent. Compared with C9orf72 expansion carriers, nonfluent aphasia and limb apraxia were significantly more common in GRN mutation carriers. CONCLUSIONS: C9orf72 -associated FTLD most often presents with early-onset behavioral variant frontotemporal dementia with disinhibition as the prominent feature, with or without amyotrophic lateral sclerosis. Based on the observed genotype-phenotype correlations between the different FTLD syndromes and different genetic causes, we propose a decision tree to guide clinical genetic testing in patients clinically diagnosed as having FTLD.