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Objective To develop a visual rating scale for posterior atrophy (PA) assessment and to analyse whether this scale aids in the discrimination between Alzheimer’s disease (AD) and other dementias. Methods Magnetic resonance imaging of 118 memory clinic patients were analysed for PA (range 0–3), medial temporal lobe atrophy (MTA) (range 0–4) and global cortical atrophy (range 0–3) by different raters. Weighted-kappas were calculated for inter- and intra-rater agreement. Relationships between PA and MTA with the MMSE and age were estimated with linear-regression analysis. Results Intra-rater agreement ranged between 0.93 and 0.95 and inter-rater agreement between 0.65 and 0.84. Mean PA scores were higher in AD compared to controls (1.6 ± 0.9 and 0.6 ± 0.7, p  < 0.01), and other dementias (0.8 ± 0.8, p  < 0.01). PA was not associated with age compared to MTA ( B  = 1.1 (0.8) versus B  = 3.1 (0.7), p  < 0.01)). PA and MTA were independently negatively associated with the MMSE ( B  = −1.6 (0.5), p  < 0.01 versus B  = −1.4 (0.5), p  < 0.01). Conclusion This robust and reproducible scale for PA assessment conveys independent information in a clinical setting and may be useful in the discrimination of AD from other dementias.

Purpose Brain perfusion imaging is of enormous importance for various neurological diseases. Fast gradient-echo sequences offering flow-related enhancement (FREE) could present a basis to generate perfusion-weighted maps. In this study, we obtained perfusion-weighted maps without contrast media by a previously described postprocessing algorithm from the field of functional lung MRI. At first, the perfusion signal was analyzed in fast low-angle shot (FLASH) and balanced steady-state free precession (bSSFP) sequences. Secondly, perfusion maps were compared to pseudo-continuous arterial spin labeling (pCASL) MRI in a healthy cohort. Thirdly, the feasibility of the new technique was demonstrated in a small selected group of patients with metastases and acute stroke. Methods One participant was examined with bSSFP and FLASH sequences at 1.5T and 3T, different flip angles and slice thicknesses. Twenty-five volunteers had bSSFP imaging and pCASL MRI. Three patients with cerebral metastases and one with acute ischemic stroke had bSSFP imaging and were compared to T1 post-contrast images and CT perfusion. Frequency analyses, SNR and perfusion contrast were compared at different flip angles and slice thicknesses. Regional correlations and Sorensen-Dice overlap were calculated in the healthy cohort. Dice overlap of the pathologies in the patient cohort were calculated. Results The bSSFP sequence presented detectable perfusion signal within brain vessel and parenchyma together with superior SNR compared to FLASH. Perfusion contrast and its corticomedullary differentiation increased with flip angle. Mean regional correlation was 0.36 and highly significant between FREE maps and pCASL and grey and white matter Dice match were 72% and 60% in the healthy cohort. Pathologies presented good overlap between FREE perfusion-weighted and T1 post-contrast images. Conclusion The feasibility of FREE brain perfusion imaging has been shown in a healthy cohort and selected patient cases with brain metastases and acute stroke. The study demonstrates a new approach for non-contrast brain perfusion imaging.

Objectives To investigate arterial spin-labelling (ASL) cerebral blood flow (CBF) changes in predementia stages of Alzheimer’s disease (AD). Methods Data were obtained from 177 patients with subjective complaints, mild cognitive impairment and AD from the Amsterdam Dementia Cohort. AD stages were based on diagnosis and cerebrospinal fluid biomarkers amyloid-β (Aβ) and total-tau (tau). General-linear-models were used to assess relationships between AD stages and total and regional CBF, correcting for age and sex. Results Decreasing CBF was related to more advanced AD stages in all supratentorial regions (p for trend < 0.05). Post-hoc testing revealed that CBF was lower in AD compared to controls and stage-1 predementia patients (i.e. abnormal Aβ and normal tau) in temporal and parietal regions, and compared to stage-2 predementia patients (i.e. abnormal Aβ and tau) in temporal regions. CBF values of stage-2 predementia patients were numerically in between those of stage-1 predementia patients and AD. Conclusion The continuing decrease of CBF along the continuum of AD indicates the potential of ASL-CBF as a measure for disease progression. Key Points • Decreasing CBF relates to more advanced AD stages in all supratentorial regions . • The reduction of CBF does not reach a bottom level . • ASL-CBF has potential as a measure for disease progression in AD .

ObjectiveAlzheimer's disease (AD) is a heterogeneous disorder with complex underlying neuropathology that is still not completely understood. For better understanding of this heterogeneity, we aimed to identify cognitive subtypes using latent class analysis (LCA) in a large sample of patients with AD dementia. In addition, we explored the relationship between the identified cognitive subtypes, and their demographical and neurobiological characteristics.MethodsWe performed LCA based on neuropsychological test results of 938 consecutive probable patients with AD dementia using Mini-Mental State Examination as the covariate. Subsequently, we performed multinomial logistic regression analysis with cluster membership as dependent variable and dichotomised demographics, APOE genotype, cerebrospinal fluid biomarkers and MRI characteristics as independent variables.ResultsLCA revealed eight clusters characterised by distinct cognitive profile and disease severity. Memory-impaired clusters—mild-memory (MILD-MEM) and moderate-memory (MOD-MEM)—included 43% of patients. Memory-spared clusters mild-visuospatial-language (MILD-VILA), mild-executive (MILD-EXE) and moderate-visuospatial (MOD-VISP) —included 29% of patients. Memory-indifferent clusters mild-diffuse (MILD-DIFF), moderate-language (MOD-LAN) and severe-diffuse (SEV-DIFF) —included 28% of patients. Cognitive clusters were associated with distinct demographical and neurobiological characteristics. In particular, the memory-spared MOD-VISP cluster was associated with younger age, APOE e4 negative genotype and prominent atrophy of the posterior cortex.ConclusionsUsing LCA, we identified eight distinct cognitive subtypes in a large sample of patients with AD dementia. Cognitive clusters were associated with distinct demographical and neurobiological characteristics.

To assess the associations of age and diagnosis with visual ratings of medial temporal lobe atrophy (MTA), parietal atrophy (PA), global cortical atrophy (GCA), and white matter hyperintensities (WMH) and to investigate their clinical value in a large memory clinic cohort. We included 2,934 patients (age 67 ± 9 years; 1,391 [47%] female; MMSE 24 ± 5) from the Amsterdam Dementia Cohort (1,347 dementia due to Alzheimer's disease [AD]; 681 mild cognitive impairment [MCI]; 906 controls with subjective cognitive decline). We analyzed the effect of age, APOE e4 and diagnosis on visual ratings using linear regression analyses. Subsequently, we compared diagnostic and predictive value in three age-groups (<65 years, 65-75 years, and >75 years). Linear regression analyses showed main effects of age and diagnosis and an interaction age diagnosis for MTA, PA, and GCA. For MTA the interaction effect indicated steeper age effects in MCI and AD than in controls. PA and GCA increased with age in MCI and controls, while AD patients have a high score, regardless of age. For WMH we found a main effect of age, but not of diagnosis. For MTA, GCA and PA, diagnostic value was best in patients <65 years (optimal cut-off: ≥1). PA and GCA only discriminated in patients <65 years and MTA in patients <75 years. WMH did not discriminate at all. Taking into account APOE did not affect the identified optimal cut-offs. When we used these scales to predict progression in MCI using Cox proportional hazard models, only MTA (cut-off ≥2) had any predictive value, restricted to patients >75 years. Visual ratings of atrophy and WMH were differently affected by age and diagnosis, requiring an age-specific approach in clinical practice. Their diagnostic value seems strongest in younger patients.

Objectives We examined whether providing a quantitative report (QReport) of regional brain volumes improves radiologists’ accuracy and confidence in detecting volume loss, and in differentiating Alzheimer’s disease (AD) and frontotemporal dementia (FTD), compared with visual assessment alone. Methods Our forced-choice multi-rater clinical accuracy study used MRI from 16 AD patients, 14 FTD patients, and 15 healthy controls; age range 52–81. Our QReport was presented to raters with regional grey matter volumes plotted as percentiles against data from a normative population ( n  = 461). Nine raters with varying radiological experience (3 each: consultants, registrars, ‘non-clinical image analysts’) assessed each case twice (with and without the QReport). Raters were blinded to clinical and demographic information; they classified scans as ‘normal’ or ‘abnormal’ and if ‘abnormal’ as ‘AD’ or ‘FTD’. Results The QReport improved sensitivity for detecting volume loss and AD across all raters combined ( p  = 0.015* and p  = 0.002*, respectively). Only the consultant group’s accuracy increased significantly when using the QReport ( p =  0.02*) . Overall, raters’ agreement (Cohen’s κ ) with the ‘gold standard’ was not significantly affected by the QReport; only the consultant group improved significantly ( κ s 0.41➔0.55, p =  0.04*). Cronbach’s alpha for interrater agreement improved from 0.886 to 0.925, corresponding to an improvement from ‘good’ to ‘excellent’. Conclusion Our QReport referencing single-subject results to normative data alongside visual assessment improved sensitivity, accuracy, and interrater agreement for detecting volume loss. The QReport was most effective in the consultants, suggesting that experience is needed to fully benefit from the additional information provided by quantitative analyses. Key Points • The use of quantitative report alongside routine visual MRI assessment improves sensitivity and accuracy for detecting volume loss and AD vs visual assessment alone. • Consultant neuroradiologists’ assessment accuracy and agreement (kappa scores) significantly improved with the use of quantitative atrophy reports. • First multi-rater radiological clinical evaluation of visual quantitative MRI atrophy report for use as a diagnostic aid in dementia.

Optic neuritis is often an initial symptom in multiple sclerosis (MS) or clinically isolated syndrome (CIS), yet comprehensive studies using the 2017 McDonald criteria for MS are scarce. Patient records from our academic centre (2010–2018) were reviewed. Using the 2017 McDonald criteria, three groups were formed: MS optic neuritis (optic neuritis with confirmed MS), CIS optic neuritis (optic neuritis without confirmed MS) and suspected optic neuritis (sON). We compared clinical and paraclinical findings among the groups to identify predictors for CIS- or MS-optic neuritis. The study included 129 MS, 108 CIS, and 44 sON cases. The combination of visual impairment, dyschromatopsia, and retrobulbar pain was observed in 47% of MS patients, 42% of CIS patients, and 30% of sON patients. Dyschromatopsia was the strongest indicator of MS or CIS diagnosis in the backward regression model. 56% of MS patients had relative afferent pupillary defect, 61% optic nerve anomalies within magnetic resonance imaging, and 81% abnormal visual evoked potentials. Our results emphasize the challenges in diagnosing optic neuritis, as not all patients with objectively diagnosed MS exhibit the triad of typical symptoms. To address potentially missing clinical features, incorporating additional paraclinical findings is proposed.

To analyze cerebral arteriovenous pulse propagation and to generate phase-resolved pulse amplitude maps from a fast gradient-echo sequence offering flow-related enhancement (FREE). Brain MRI was performed using a balanced steady-state free precession sequence at 3T followed by retrospective k-space gating. The time interval of the pulse wave between anterior-, middle- and posterior cerebral artery territories and the superior sagittal sinus were calculated and compared between and older and younger groups within 24 healthy volunteers. Pulse amplitude maps were generated and compared to pseudo-Continuous Arterial Spin Labeling (pCASL) MRI maps by voxel-wise Pearson correlation, Sørensen-Dice maps and in regards to signal contrast. The arteriovenous delays between all vascular territories and the superior sagittal sinus were significantly shorter in the older age group (11 individuals, ≥ 31 years) ranging between 169 ± 112 and 246 ± 299 ms versus 286 ± 244 to 419 ± 299 ms in the younger age group (13 individuals) (P ≤ 0.04). The voxel-wise pulse wave amplitude values and perfusion-weighted pCASL values correlated significantly (Pearson-r = 0.33, P < 0.01). Mean Dice overlaps of high (gray) and low (white matter) regions were 73 ± 3% and 59 ± 5%. No differences in image contrast were seen in the whole brain and the white matter, but significantly higher mean contrast of 0.73 ± 0.23% in cortical gray matter in FREE-MRI compared to 0.52 ± 0.12% in pCASL-MRI (P = 0.01). The dynamic information of flow-related enhancement allows analysis of the cerebral pulse wave propagation potentially providing information about the (micro)circulation on a regional level. However, the pulse wave amplitude reveals weaknesses in comparison to true perfusion-weighting and could rather be used to calculate a pulsatility index.

ObjectiveDifferentiation between progressive multifocal leukoencephalopathy (PML) and new multiple sclerosis (MS) lesions on brain MRI during natalizumab pharmacovigilance in the absence of clinical signs and symptoms is challenging but is of substantial clinical relevance. We aim to define MRI characteristics that can aid in this differentiation.MethodsReference and follow-up brain MRIs of natalizumab-treated patients with MS with asymptomatic PML (n=21), or asymptomatic new MS lesions (n=20) were evaluated with respect to characteristics of newly detected lesions by four blinded raters. We tested the association with PML for each characteristic and constructed a multivariable prediction model which we analysed using a receiver operating characteristic (ROC) curve.ResultsPresence of punctate T2 lesions, cortical grey matter involvement, juxtacortical white matter involvement, ill-defined and mixed lesion borders towards both grey and white matter, lesion size of >3 cm, and contrast enhancement were all associated with PML. Focal lesion appearance and periventricular localisation were associated with new MS lesions. In the multivariable model, punctate T2 lesions and cortical grey matter involvement predict for PML, while focal lesion appearance and periventricular localisation predict for new MS lesions (area under the curve: 0.988, 95% CI 0.977 to 1.0, sensitivity: 100%, specificity: 80.6%).InterpretationThe MRI characteristics of asymptomatic natalizumab-associated PML lesions proved to differ from new MS lesions. This led to a prediction model with a high discriminating power. Careful assessment of the presence of punctate T2 lesions, cortical grey matter involvement, focal lesion appearance and periventricular localisation allows for an early diagnosis of PML.

The implementation of a variety of immunosuppressive therapies has made drug-associated progressive multifocal leukoencephalopathy (PML) an increasingly prevalent clinical entity. The purpose of this study was to investigate its diagnostic characteristics and to determine whether differences herein exist between the multiple sclerosis (MS), neoplasm, post-transplantation, and autoimmune disease subgroups. Reports of possible, probable, and definite PML according to the current diagnostic criteria were obtained by a systematic search of PubMed and the Dutch pharmacovigilance database. Demographic, epidemiologic, clinical, radiological, cerebrospinal fluid (CSF), and histopathological features were extracted from each report and differences were compared between the disease categories. In the 326 identified reports, PML onset occurred on average 29.5 months after drug introduction, varying from 14.2 to 37.8 months in the neoplasm and MS subgroups, respectively. The most common overall symptoms were motor weakness (48.6 %), cognitive deficits (43.2 %), dysarthria (26.3 %), and ataxia (24.1 %). The former two also constituted the most prevalent manifestations in each subgroup. Lesions were more often localized supratentorially (87.7 %) than infratentorially (27.4 %), especially in the frontal (64.1 %) and parietal lobes (46.6 %), and revealed enhancement in 27.6 % of cases, particularly in the MS (42.9 %) subgroup. Positive JC virus results in the first CSF sample were obtained in 63.5 %, while conversion after one or more negative outcomes occurred in 13.7 % of cases. 52.2 % of patients died, ranging from 12.0 to 83.3 % in the MS and neoplasm subgroups, respectively. In conclusion, despite the heterogeneous nature of the underlying diseases, motor weakness and cognitive changes were the two most common manifestations of drug-associated PML in all subgroups. The frontal and parietal lobes invariably constituted the predilection sites of drug-related PML lesions.