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Background: Brain imaging with [18F]FDG-PET can support the diagnostic work-up of patients with α-synucleinopathies. Validated data analysis approaches are necessary to evaluate disease-specific brain metabolism patterns in neurodegenerative disorders. This study compared the univariate Statistical Parametric Mapping (SPM) single-subject procedure and the multivariate Scaled Subprofile Model/Principal Component Analysis (SSM/PCA) in a cohort of patients with α-synucleinopathies., Methods: We included [18F]FDG-PET scans of 122 subjects within the α-synucleinopathy spectrum: Parkinson's Disease (PD) normal cognition on long-term follow-up (PD - low risk to dementia (LDR); n = 28), PD who developed dementia on clinical follow-up (PD - high risk of dementia (HDR); n = 16), Dementia with Lewy Bodies (DLB; n = 67), and Multiple System Atrophy (MSA; n = 11). We also included [18F]FDG-PET scans of isolated REM sleep behaviour disorder (iRBD; n = 51) subjects with a high risk of developing a manifest α-synucleinopathy. Each [18F]FDG-PET scan was compared with 112 healthy controls using SPM procedures. In the SSM/PCA approach, we computed the individual scores of previously identified patterns for PD, DLB, and MSA: PD-related patterns (PDRP), DLBRP, and MSARP. We used ROC curves to compare the diagnostic performances of SPM t-maps (visual rating) and SSM/PCA individual pattern scores in identifying each clinical condition across the spectrum. Specifically, we used the clinical diagnoses ("gold standard") as our reference in ROC curves to evaluate the accuracy of the two methods. Experts in movement disorders and dementia made all the diagnoses according to the current clinical criteria of each disease (PD, DLB and MSA)., Results: The visual rating of SPM t-maps showed higher performance (AUC: 0.995, specificity: 0.989, sensitivity 1.000) than PDRP z-scores (AUC: 0.818, specificity: 0.734, sensitivity 1.000) in differentiating PD-LDR from other α-synucleinopathies (PD-HDR, DLB and MSA). This result was mainly driven by the ability of SPM t-maps to reveal the limited or absent brain hypometabolism characteristics of PD-LDR. Both SPM t-maps visual rating and SSM/PCA z-scores showed high performance in identifying DLB (DLBRP = AUC: 0.909, specificity: 0.873, sensitivity 0.866; SPM t-maps = AUC: 0.892, specificity: 0.872, sensitivity 0.910) and MSA (MSARP: AUC: 0.921, specificity: 0.811, sensitivity 1.000; SPM t-maps: AUC: 1.000, specificity: 1.000, sensitivity 1.000) from other α-synucleinopathies. PD-HDR and DLB were comparable for the brain hypo and hypermetabolism patterns, thus not allowing differentiation by SPM t-maps or SSM/PCA. Of note, we found a gradual increase of PDRP and DLBRP expression in the continuum from iRBD to PD-HDR and DLB, where the DLB patients had the highest scores. SSM/PCA could differentiate iRBD from DLB, reflecting specifically the differences in disease staging and severity (AUC: 0.938, specificity: 0.821, sensitivity 0.941)., Conclusions: SPM-single subject maps and SSM/PCA are both valid methods in supporting diagnosis within the α-synucleinopathy spectrum, with different strengths and pitfalls. The former reveals dysfunctional brain topographies at the individual level with high accuracy for all the specific subtype patterns, and particularly also the normal maps; the latter provides a reliable quantification, independent from the rater experience, particularly in tracking the disease severity and staging. Thus, our findings suggest that differences in data analysis approaches exist and should be considered in clinical settings. However, combining both methods might offer the best diagnostic performance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: 2-Deoxy-2-[ 18 F]fluoroglucose (FDG) PET is an important tool for the identification of Alzheimer's disease (AD) patients through the characteristic neurodegeneration pattern that these patients present. Regional cerebral blood flow (rCBF) images derived from dynamic 11 C-labelled Pittsburgh Compound B (PIB) have been shown to present a similar pattern as FDG. Moreover, multivariate analysis techniques, such as scaled subprofile modelling using principal component analysis (SSM/PCA), can be used to generate disease-specific patterns (DP) that may aid in the classification of subjects. Therefore, the aim of this study was to compare rCBF AD-DPs with FDG AD-DP and their respective performances. Therefore, 52 subjects were included in this study. Fifteen AD and 16 healthy control subjects were used to generate four AD-DP: one based on relative cerebral trace blood (R 1 ), two based on time-weighted average of initial frame intervals (ePIB), and one based on FDG images. Furthermore, 21 subjects diagnosed with mild cognitive impairment were tested against these AD-DPs., Results: In general, the rCBF and FDG AD-DPs were characterized by a reduction in cortical frontal, temporal, and parietal lobes. FDG and rCBF methods presented similar score distribution., Conclusion: rCBF images may provide an alternative for FDG PET scans for the identification of AD patients through SSM/PCA., (© 2022. The Author(s).)

Background: Individuals with a parental family history of dementia have an increased risk of developing dementia because they share their genes as well as their psychosocial behaviour. Due to this increased risk and their experience with dementia, they may be particularly eager to receive information regarding dementia risk reduction (DRR). This study evaluated the knowledge, beliefs and attitudes towards dementia and DRR among descendants of people with dementia., Method: Using a semi-structured topic guide, three focus group discussions were conducted consisting of 12 female (80%) and 3 male (20%) descendants of people with dementia with a mean (± SD) age of 48.8 (± 12) years. Focus group discussions were audio recorded and transcribed. Each transcript was analysed thoroughly, and where appropriate, a code was generated and assigned by two researchers independently. Then, similar codes were grouped together and categorized into themes., Results: The items in the topic guide could only be addressed after participants had been given the opportunity to share their experiences of having a parent with dementia. Participants were unaware or uncertain about the possibility of reducing the risk of developing dementia and therefore hesitant to assess their dementia risk without treatment options in sight. Moreover, participants indicated that their general practitioner only gave some information on heritability, not on DRR. Although participants identified a large number of modifiable risk factors as a group during the group discussions, they were eager to receive more information on dementia and DRR. In the end, participants adopted a more positive attitude towards a DRR programme and provided suggestions for the development of future DRR programmes., Conclusions: Although the research aim was to evaluate the knowledge, beliefs and attitudes towards dementia and DRR, sharing experiences of having a parent with dementia seemed a prerequisite for considering participants' own risk of developing dementia and participating in a DRR programme. Knowledge of dementia and DRR was limited. Due to unawareness of the possibility of reducing dementia risk, participants were hesitant about assessing their dementia risk. Group discussions positively changed the perception of dementia risk assessment and participants' willingness to participate in a DRR programme.

Quantification of amyloid load with positron emission tomography can be useful to assess Alzheimer's Disease in-vivo. However, quantification can be affected by the image processing methodology applied. This study's goal was to address how amyloid quantification is influenced by different semi-automatic image processing pipelines. Images were analysed in their Native Space and Standard Space; non-rigid spatial transformation methods based on maximum a posteriori approaches and tissue probability maps (TPM) for regularisation were explored. Furthermore, grey matter tissue segmentations were defined before and after spatial normalisation, and also using a population-based template. Five quantification metrics were analysed: two intensity-based, two volumetric-based, and one multi-parametric feature. Intensity-related metrics were not substantially affected by spatial normalisation and did not significantly depend on the grey matter segmentation method, with an impact similar to that expected from test-retest studies (≤10%). Yet, volumetric and multi-parametric features were sensitive to the image processing methodology, with an overall variability up to 45%. Therefore, the analysis should be carried out in Native Space avoiding non-rigid spatial transformations. For analyses in Standard Space, spatial normalisation regularised by TPM is preferred. Volumetric-based measurements should be done in Native Space, while intensity-based metrics are more robust against differences in image processing pipelines., Competing Interests: The authors have declared that no competing interests exist.

Scaled subprofile model using principal component analysis (SSM/PCA) is a multivariate analysis technique used, mainly in [ 18 F]-2-fluoro-2-deoxy-d-glucose (FDG) PET studies, for the generation of disease-specific metabolic patterns (DP) that may aid with the classification of subjects with neurological disorders, like Alzheimer's disease (AD). The aim of this study was to explore the feasibility of using quantitative parametric images for this type of analysis, with dynamic [ 11 C]-labelled Pittsburgh Compound B (PIB) PET data as an example. Therefore, 15 AD patients and 15 healthy control subjects were included in an SSM/PCA analysis to generate four AD-DPs using relative cerebral blood flow (R 1 ), binding potential (BP ND ) and SUVR images derived from dynamic PIB and static FDG-PET studies. Furthermore, 49 new subjects with a variety of neurodegenerative cognitive disorders were tested against these DPs. The AD-DP was characterized by a reduction in the frontal, parietal, and temporal lobes voxel values for R 1 and SUVR-FDG DPs; and by a general increase of values in cortical areas for BP ND and SUVR-PIB DPs. In conclusion, the results suggest that the combination of parametric images derived from a single dynamic scan might be a good alternative for subject classification instead of using 2 independent PET studies., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Apathy is recognized as a prevalent behavioral symptom of amnestic Mild Cognitive Impairment (aMCI). In aMCI, apathy is associated with an increased risk and increases the risk of progression to Alzheimer's Disease (AD). Previous DTI study in aMCI showed that apathy has been associated with white matter alterations in the cingulum, middle and inferior longitudinal fasciculus, fornix, and uncinate fasciculus. However, the underlying white matter correlates associated with apathy in aMCI are still unclear. We investigated this relationship using whole-brain diffusion tensor imaging (DTI). Twenty-nine aMCI patients and 20 matched cognitively healthy controls were included. Apathy severity was assessed using the Apathy Evaluation Scale Clinician version. We applied the tract-based spatial statistics analyses to DTI parameters: fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity to investigate changes in white matter pathways associated with the severity of apathy. No significant difference was found in any of the DTI parameters between aMCI and the control group. In aMCI, higher severity of apathy was associated with lower FA in various white matter pathways including the left anterior part of inferior fronto-occipital fasciculus/uncinate fasciculus, genu and body of the corpus callosum, superior and anterior corona radiata, anterior thalamic radiation of both hemispheres and in the right superior longitudinal fasciculus/anterior segment of arcuate fasciculus (p < .05, TFCE-corrected) after controlling for age, gender and GDS non-apathy. A trend association was observed in the right posterior corona radiata and corticospinal tract/internal capsule, and bilateral forceps minor (p < .065, TFCE-corrected). In conclusion, in aMCI, severity of apathy is associated with aberrant white matter integrity in widely distributed pathways, within and between hemispheres., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Descendants of patients with dementia have a higher risk to develop dementia. This study aims to investigate the uptake and effectiveness of an online tailor-made lifestyle programme for dementia risk reduction (DRR) among middle-aged descendants of people with recently diagnosed late-onset dementia., Methods and Analysis: Demin is a cluster randomised controlled trial, aiming to include 21 memory clinics of which 13 will be randomly allocated to the passive (poster and flyer in a waiting room) and 8 to the active recruitment strategy (additional personal invitation by members of the team of the memory clinic). We aim to recruit 378 participants (40-60 years) with a parent who is recently diagnosed with Alzheimer's disease or vascular dementia at one of the participating memory clinics. All participants receive a dementia risk assessment (online questionnaire, physical examination and blood sample) and subsequently an online tailor-made lifestyle advice regarding protective (Mediterranean diet, low/moderate alcohol consumption and high cognitive activity) and risk factors (physical inactivity, smoking, loneliness, cardiovascular diseases (CVD), hypertension, high cholesterol, diabetes, obesity, renal dysfunction and depression) for dementia. The primary outcome is the difference in uptake between the two recruitment strategies. Secondary outcomes are change(s) in (1) the Lifestyle for Brain Health score, (2) individual health behaviours, (3) health beliefs and attitudes towards DRR and (4) compliance to the tailor-made lifestyle advice. Outcomes will be measured at 3, 6, 9 and 12 months after baseline. The effectiveness of this online tailor-made lifestyle programme will be evaluated by comparing Demin participants to a matched control group (lifelines cohort)., Ethics and Dissemination: This study has been approved by the Dutch Ministry of Health, Welfare and Sport according to the Population Screening Act. All participants have to give online informed consent using SMS-tan (transaction authentication number delivered via text message). Findings will be disseminated through peer-reviewed journals and (inter)national conferences., Trial Registration Number: NTR7434., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: In clinical practice, visual assessment of glucose metabolism images is often used for the diagnosis of Alzheimer's disease (AD) through 2-[ 18 F]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scans. However, visual assessment of the characteristic AD hypometabolic pattern relies on the expertise of the reader. Therefore, user-independent pipelines are preferred to evaluate the images and to classify the subjects. Moreover, glucose consumption is highly correlated with cerebral perfusion. Regional cerebral blood flow (rCBF) images can be derived from dynamic 11 C-labelled Pittsburgh Compound B PET scans, which are also used for the assessment of the deposition of amyloid-β plaques on the brain, a fundamental characteristic of AD. The aim of this study was to explore whether these rCBF PIB images could be used for diagnostic purposes through the PMOD Alzheimer's Discrimination Tool., Results: Both tracer relative cerebral flow (R 1 ) and early PIB (ePIB) (20-130 s) uptake presented a good correlation when compared to FDG standardized uptake value ratio (SUVR), while ePIB (1-8 min) showed a worse correlation. All receiver operating characteristic curves exhibited a similar shape, with high area under the curve values, and no statistically significant differences were found between curves. However, R 1 and ePIB (1-8 min) had the highest sensitivity, while FDG SUVR had the highest specificity., Conclusion: rCBF images were suggested to be a good surrogate for FDG scans for diagnostic purposes considering an adjusted threshold value.

In Alzheimer's Disease (AD) dual-tracer positron emission tomography (PET) studies with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) and 11C-labelled Pittsburgh Compound B (PIB) are used to assess metabolism and cerebral amyloid-β deposition, respectively. Regional cerebral metabolism and blood flow (rCBF) are closely coupled, both providing an index for neuronal function. The present study compared PIB-derived rCBF, estimated by the ratio of tracer influx in target regions relative to reference region (R1) and early-stage PIB uptake (ePIB), to FDG scans. Fifteen PIB positive (+) patients and fifteen PIB negative (-) subjects underwent both FDG and PIB PET scans to assess the use of R1 and ePIB as a surrogate for FDG. First, subjects were classified based on visual inspection of the PIB PET images. Then, discriminative performance (PIB+ versus PIB-) of rCBF methods were compared to normalized regional FDG uptake. Strong positive correlations were found between analyses, suggesting that PIB-derived rCBF provides information that is closely related to what can be seen on FDG scans. Yet group related differences between method's distributions were seen as well. Also, a better correlation with FDG was found for R1 than for ePIB. Further studies are needed to validate the use of R1 as an alternative for FDG studies in clinical applications., Competing Interests: The authors have declared that no competing interests exist.

Apathy is a common symptom in patients with amnestic mild cognitive impairment (aMCI) and is associated with an increased risk of progression to Alzheimer's disease (AD). The neural substrates underlying apathy in aMCI may involve multiple brain regions, including the anterior cingulate cortex and the temporo-parietal region. Here we investigated neurometabolites in brain regions that may underlie apathy in aMCI patients using proton magnetic resonance spectroscopy ( 1 H-MRS). Twenty-eight aMCI patients with varying degrees of apathy and 20 matched controls underwent 1 H-MRS. Spectra were acquired from single voxels in the posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (DACC), right dorsolateral prefrontal cortex (DLPFC), and right temporo-parietal cortex (TPC). Apathy was measured with the Apathy Evaluation Scale (AES). Spearman partial correlations between metabolite concentrations in each region and severity of apathy were determined. Additionally, analyses of covariance (ANCOVA) were performed to determine whether metabolite changes differed between patients with or without clinically-diagnosed apathy. The degree of apathy was found to be negatively correlated with choline and myo-inositol (mI) in the TPC. Additional exploratory analyses suggested that N-acetylaspartate (NAA)/mI ratio was reduced in aMCI without clinical apathy but not in aMCI with clinical apathy. In the DACC, glutamate and glutamine (Glx) levels tended to be higher in the aMCI with apathy group compared to controls and reduced in association with depression scores. In conclusion, apathy in aMCI patients was associated with neurometabolite changes indicative of altered membranal integrity and glial function in the right TPC. Findings also indicated that in a clinically-diagnosed aMCI cohort, apathy symptoms may be suggestive of neural changes that are distinct from aMCI without apathy.