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We aimed to identify features associated with different disease trajectories in Alzheimer's disease (AD)-related primary progressive aphasia (PPA). We considered 23 patients diagnosed with AD-related PPA. All patients underwent neuropsychological evaluation

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.

Immunosenescence, vascular aging, and brain aging, all characterized by elevated levels of inflammatory markers, are thought to share a common pathogenetic pathway: inflamm-aging. Retrospective cross-sectional analysis was conducted using data from the Mugello study (Tuscany, Italy), a representative Italian cohort of free-living nonagenarians. to assess the association between specific peripheral inflammation markers derived from white blood cell counts, and the diagnosis of dementia. All the variables of interest were reported for 411 subjects (110 males and 301 females) out of 475 enrolled in the study. Anamnestic dementia diagnosis was obtained from clinical certificate and confirmed by a General Practitioner, whereas leukocyte ratios were directly calculated from white blood cell counts. Body mass index and comorbidities were considered potential confounders. Diagnosis of any type dementia was certified in 73 cases (17.8%). Subjects affected by dementia were older, more frequently reported a previous stroke, had lower body mass index, and lower Mini-Mental-State-Examination score. Moreover, they had a higher lymphocyte count and lymphocyte-to-monocyte ratio compared to the non-demented nonagenarians. We found that higher levels of lymphocyte counts are cross-sectionally associated with a clinical diagnosis of dementia. Furthermore, lymphocyte-to-monocyte ratio is directly associated with any type of dementia, independently of age, sex, lymphocyte count, and comorbidities. Lymphocyte-to-monocyte ratio may be considered a marker of immunological changes in the brain of dementia patients; moreover, it is low-cost, and easily available, thus enabling comparisons among different studies and populations, although the timeline and the extent of lymphocyte-to-monocyte ratio role in dementia development must be further investigated.

As more and more persons live into their 90s and beyond, investigating causes of disability in the oldest-old population is relevant for public health implications to plan preventive strategies and rehabilitation interventions. A negative association between physically demanding work and midlife physical function has been shown, but there is a paucity of longitudinal studies investigating possible work-related long-term effects in the oldest old. This study investigates the relationship between physically demanding work exposure and late-life physical performances, disability, general health status, and quality of life in a sample of women aged 90 years and over inside the Mugello Study. Sociodemographic data, cognitive and functional status, lifestyle, medical history, drug use, and work history were collected from 236 participants. Farmers had a lower percentage of individuals with preserved independence in basic activities of daily living compared to other occupations. However, in the multivariate analysis, only a higher cognitive function remained associated with functional independence. While confirming the well-known association between cognitive and functional decline in very old age, our results do not support the hypothesis that the negative effects of physical work exposure observed in midlife are relevant to predict disability in nonagenarian women.

Background Alzheimer's disease (AD) has a high incidence in the elderly. Besides cognitive disorders, patients may also develop behavioural and psychological symptoms of dementia (BPSD), which can be particularly disabling for patients and families. BPSD encompass a wide range of symptoms, among which psychotic symptoms and disruptive behaviours often prompt the first related hospitalization and request for family support. The aetiological mechanism of BPSD has not yet been clarified, and no predictive or risk factors have been identified. The main objectives of our study are to describe the frequency of aggression/agitation and psychotic symptoms, defined 'positive BPSD', in a cohort of 60 AD patients, identify areas of the brain involved in behavioural symptomatology through brain 18 F-fluorodesoxyglucose-positron emission tomography (FDG-PET), and investigate a potential predictive role of brain FDG-PET in BPSD development. Methods A cohort of 60 AD patients was retrospectively enrolled and regularly followed for at least 3 years. Each subject underwent brain FDG-PET at the time of diagnosis. Patients were divided into three groups based on the presence of behavioural disturbances: present, absent, and developed later. Results Of the 60 AD patients in the cohort, 52% had positive BPSD: 17 at baseline and 14 during the 3-year follow-up. FDG-PET identified an association between hypometabolism in the bilateral temporal lobes and the presence of BPSD, and showed initial hypometabolism in the postero-temporal lobes 3 years before symptom onset. Conclusions Positive BPSD are frequently manifested in AD. Our study identified the temporal lobes as the neurobiological substrate of positive BPSD and FDG-PET as a potential instument to predict their developement. Temporal lobes are involved in processing facial expression and recognizing emotions; an impairment of these functions could cause delusions and agitated/aggressive behaviour. To confirm the potential predictive role of FDG-PET in the onset of BPSD in AD, further studies are needed.

Objective to identify the predictors of mortality in a cohort of nonagenarians inside the “Mugello study” after 10 years follow-up. Methods Information on sociodemographic data, cognitive and functional status, lifestyle, medical history, and drug use was collected from 433 non-selected participants aged 90-99 years, living in the Mugello area (Italy). Participants were followed over 10 years and their dates of death were retrieved from the municipal registers. Cox regression analysis was used to determine significant potential prognostic factors. Results The mortality rate was 96.5%. Cox proportional hazards analysis showed that a lower cognitive status was significantly associated with higher mortality as well as a poorer functional status, a higher comorbidity, and a higher number of drugs consumption. Discussion Impaired cognitive function, loss of functional independence, higher comorbidity, and higher drugs intake were the stronger predictors of mortality.

We aimed to detail language profiles, brain metabolic patterns and proportion of Alzheimer's disease biomarkers in a cohort of patients with mixed primary progressive aphasia (mPPA). We considered 58 patients with PPA: 10 with non-fluent/agrammatic variant (nfvPPA), 16 with semantic variant (svPPA), 21 with logopenic variant (lvPPA) and 9 with mPPA. Patients with mPPA were further classified as 4 nf/lvPPA (with prevailing features for nfvPPA and lvPPA) and 5 s/lvPPA (with prevailing features for svPPA and lvPPA). Nf/lvPPA patients were characterized by higher proportion of Naming impairment compared to nfvPPA and more frequent Grammatical Errors and Phonologic Errors than lvPPA. S/lvPPA had higher proportion of impairment in Sentences Repetition compared to svPPA and in Single-word Comprehension compared to lvPPA. 100% of nf/lvPPA and 40% of s/lvPPA had Aβ positive biomarkers. Brain hypometabolic pattern in Nf/lvPPA was consistent with lvPPA, while s/lvPPA had a brain metabolism resembling svPPA. We concluded that nf/lvPPA patients might be considered as PPA variant due to Alzheimer's disease and s/lvPPA group mainly included patients with svPPA.

Background The early differential diagnosis among neurodegenerative parkinsonian disorders becomes essential to set up the correct clinical-therapeutic approach. The increased utilization of [18F] fluoro-deoxy-glucose positron emission tomography (FDG PET) and the pressure for cost-effectiveness request a systematic evaluation and a validation of its utility in clinical practice. This retrospective study aims to consider the contribution, in terms of increasing accuracy and increasing diagnostic confidence, of voxel-based FDG PET analyses in the differential diagnosis of these disorders, including Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, and cortico-basal syndrome. Method Eighty-three subjects with a clinically confirmed diagnosis of degenerative parkinsonian disorders who underwent FDG brain PET/CT were selected. A voxel-based analysis was set up using statistical parametric mapping (SPM) on MATLAB to produce maps of brain hypometabolism and relative hypermetabolism. Four nuclear physicians (two expert and two not expert), blinded to the patients’ symptoms, other physicians’ evaluations, and final clinical diagnosis, independently evaluated all data by visual assessment and by adopting metabolic maps. Results In not-expert evaluators, the support of both hypometabolism and hypermetabolism maps results in a significant increase in diagnostic accuracy as well as clinical confidence. In expert evaluators, the increase in accuracy and in diagnostic confidence is mainly supported by hypometabolism maps alone. Conclusions In this study, we demonstrated the additional value of combining voxel-based analyses with qualitative assessment of brain PET images. Moreover, maps of relative hypermetabolism can also make their contribution in clinical practice, particularly for less experienced evaluators.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary Information: Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; Additional file 2 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; both files are available online at https://doi.org/10.1186/s13024-021-00499-4 Copyright © The Author(s) 2021. Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD. This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.

Background Primary progressive aphasia (PPA) has been described as a neurodegenerative language disorder mainly affecting the left hemisphere. Few cases of right hemisphere damage in right-handed PPA subjects have been reported. This condition, named crossed aphasia in dextral (CAD), is relatively rare and probably related to an alteration during neurodevelopment of language networks. Objective To explore the prevalence of CAD in an Italian cohort of 68 PPA patients, in order to evaluate whether right hemisphere language lateralization could be a risk factor for PPA. Methods Clinical-demographic and cerebral [18F]-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) scan were analyzed, resulting in 23 logopenic variant (lvPPA) patients, 26 non-fluent variant (nfvPPA) patients, and 19 semantic variant (svPPA) patients. SPM single subject routine was performed for diagnostic purposes in order to identify the hypometabolic pattern of each patient. Based on brain metabolic profile, PPA patients were divided in right and left lvPPA, nfvPPA, and svPPA. [18F]FDG-PET group analyses were performed with SPM two-sample t-test routine. Results 26% of lvPPA cases were identified as CAD based on right hypometabolic pattern. CAD patients did not differ from left lvPPA regarding demographic features and general cognitive performance; however, they performed better in specific working memory tasks and showed brain hypometabolism limited to the superior, middle, and supramarginal temporal gyri. Conclusion Atypical lateralization of language function could determine a vulnerability of the phonological language loop and in that way could be a risk factor for lvPPA.

Lipoproteins are the complexes of different lipids and proteins, which are devoted to the transport and clearance of lipids or lipid-related molecules in the circulation. Lipoproteins have been found to play a crucial role in brain function and may influence myelination process. Among lipoproteins, high-density lipoproteins (HDLs) and their major protein component, apoA-I, are directly involved in cholesterol efflux in the brain. It has been suggested that inadequate or dysfunctional brain HDLs may contribute to cerebrovascular dysfunctions, neurodegeneration, or neurovascular instability. HDL deficiency could also promote cognitive decline through impacting on atherosclerotic risk. The focus of this review is to discuss knowledge on HDL dysregulation in neurological disorders. A better understanding on how changes in cellular HDL and apolipoprotein homeostasis affect central nervous system function may provide promising novel avenues for the treatment of specific HDL-related neurological disorders.

BACKGROUND Alzheimer's disease (AD) diagnosis can be hindered by amyloid biomarkers discordances. OBJECTIVE We aim to interpret discordances between amyloid positron emission tomography (Amy-PET) and cerebrospinal fluid (CSF) (Aβ42 and Aβ42/40), using Amy-PET semiquantitative analysis, [18F]fluorodeoxyglucose (FDG)-PET pattern, and CSF assays. METHOD Thirty-six subjects with dementia or mild cognitive impairment, assessed by neuropsychological tests, structural and functional imaging, and CSF assays (Aβ42, Aβ42/40, p-tau, t-tau), were retrospectively examined. Amy-PET and FDG-PET scans were analyzed by visual assessment and voxel-based analysis. SUVR were calculated on Amy-PET scans. RESULTS Groups were defined basing on the agreement among CSF Aβ42 (A), CSF Aβ42/40 Ratio (R), and Amy-PET (P) dichotomic results ( ±). In discordant groups, CSF assays, Amy-PET semiquantification, and FDG-PET patterns supported the diagnosis suggested by any two agreeing amyloid biomarkers. In groups with discordant CSF Aβ42, the ratio always agrees with Amy-PET results, solving both false-negative and false-positive Aβ42 results, with Aβ42 levels close to the cut-off in A + R-P- subjects. The A + R + P- group presented high amyloid deposition in relevant areas, such as precuneus, posterior cingulate cortex (PCC) and dorsolateral frontal inferior cortex at semiquantitative analysis. CONCLUSION The amyloid discordant cases could be overcome by combining CSF Aβ42, CSF ratio, and Amy-PET results. The concordance of any 2 out of the 3 biomarkers seems to reveal the remaining one as a false result. A cut-off point review could avoid CSF Aβ42 false-negative results. The regional semiquantitative Amy-PET analysis in AD areas, such as precuneus and PCC, could increase the accuracy in AD diagnosis.

Alzheimer's disease (AD) has a high incidence in the elderly. Besides cognitive disorders, patients may also develop behavioural and psychological symptoms of dementia (BPSD), which can be particularly disabling for patients and families. BPSD encompass a wide range of symptoms, among which psychotic symptoms and disruptive behaviours often prompt the first related hospitalization and request for family support. The aetiological mechanism of BPSD has not yet been clarified, and no predictive or risk factors have been identified. The main objectives of our study are to describe the frequency of aggression/agitation and psychotic symptoms, defined 'positive BPSD', in a cohort of 60 AD patients, identify areas of the brain involved in behavioural symptomatology through brainA cohort of 60 AD patients was retrospectively enrolled and regularly followed for at least 3 years. Each subject underwent brain FDG-PET at the time of diagnosis. Patients were divided into three groups based on the presence of behavioural disturbances: present, absent, and developed later.Of the 60 AD patients in the cohort, 52% had positive BPSD: 17 at baseline and 14 during the 3-year follow-up. FDG-PET identified an association between hypometabolism in the bilateral temporal lobes and the presence of BPSD, and showed initial hypometabolism in the postero-temporal lobes 3 years before symptom onset.Positive BPSD are frequently manifested in AD. Our study identified the temporal lobes as the neurobiological substrate of positive BPSD and FDG-PET as a potential instument to predict their developement. Temporal lobes are involved in processing facial expression and recognizing emotions; an impairment of these functions could cause delusions and agitated/aggressive behaviour. To confirm the potential predictive role of FDG-PET in the onset of BPSD in AD, further studies are needed.

Background: The aims of this study were to compare the diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of different cerebrospinal fluid (CSF) amyloid biomarkers and amyloid-Positron Emission Tomography (PET) in patients with a clinical diagnosis of Alzheimer&rsquo, s disease (AD) and Frontotemporal Dementia (FTD), to compare concordance between biomarkers, and to provide an indication of their use and interpretation. Methods: We included 148 patients (95 AD and 53 FTD), who underwent clinical evaluation, neuropsychological assessment, and at least one amyloid biomarker (CSF analysis or amyloid-PET). Thirty-six patients underwent both analyses. One-hundred-thirteen patients underwent Apolipoprotein E (ApoE) genotyping. Results: Amyloid-PET presented higher diagnostic accuracy, sensitivity, and NPV than CSF A&beta, 1&ndash, 42 but not A&beta, 42/40 ratio. Concordance between CSF biomarkers and amyloid-PET was higher in FTD patients compared to AD cases. None of the AD patients presented both negative A&beta, biomarkers. Conclusions: CSF A&beta, 42/40 ratio significantly increased the diagnostic accuracy of CSF biomarkers. On the basis of our current and previous data, we suggest a flowchart to guide the use of biomarkers according to clinical suspicion: due to the high PPV of both amyloid-PET and CSF analysis including A&beta, 42/40, in cases of concordance between at least one biomarker and clinical diagnosis, performance of the other analysis could be avoided. A combination of both biomarkers should be performed to better characterize unclear cases. If the two amyloid biomarkers are both negative, an underlying AD pathology can most probably be excluded.

Background: Discordance among amyloid biomarkers is a challenge to overcome in order to increase diagnostic accuracy in dementia. Objectives: 1) To verify that cerebrospinal fluid (CSF) Aβ42/Aβ40 ratio (AβR) better agrees with Amyloid PET (Amy-PET) results compared to CSF Aβ42; 2) to detect differences among concordant positive, concordant negative, and discordant cases, basing the concordance definition on the agreement between CSF AβR and Amy-PET results; 3) to define the suspected underlying pathology of discordant cases using in vivo biomarkers. Method: We retrospectively enrolled 39 cognitively impaired participants in which neuropsychological tests, apolipoprotein E genotype determination, TC/MRI, FDG-PET, Amy-PET, and CSF analysis had been performed. In all cases, CSF analysis was repeated using the automated Lumipulse method. In discordant cases, FDG-PET scans were evaluated visually and using automated classifiers. Results: CSF AβR better agreed with Amy-PET compared to CSF Aβ42 (Cohen’s K 0.431 versus 0.05). Comparisons among groups did not show any difference in clinical characteristics except for age at symptoms onset that was higher in the 6 discordant cases with abnormal CSF AβR values and negative Amy-PET (CSF AβR+/AmyPET–). FDG-PET and all CSF markers (Aβ42, AβR, p-Tau, t-Tau) were suggestive of Alzheimer’s disease (AD) in 5 of these 6 cases. Conclusion: 1) CSF AβR is the CSF amyloid marker that shows the better level of agreement with Amy-PET results; 2) The use of FDG-PET and CSF-Tau markers in CSFAβR+/Amy-PET–discordant cases can support AD diagnosis; 3) Disagreement between positive CSF AβR and negative Amy-PET in symptomatic aged AD patients could be due to the variability in plaques conformation and a negative Amy-PET scan cannot be always sufficient to rule out AD.

Background Mild cognitive impairment (MCI) due to Alzheimer's disease is the symptomatic predementia phase of Alzheimer's disease dementia, characterised by cognitive and functional impairment not severe enough to fulfil the criteria for dementia. In clinical samples, people with amnestic MCI are at high risk of developing Alzheimer's disease dementia, with annual rates of progression from MCI to Alzheimer's disease estimated at approximately 10% to 15% compared with the base incidence rates of Alzheimer's disease dementia of 1% to 2% per year. Objectives To assess the diagnostic accuracy of structural magnetic resonance imaging (MRI) for the early diagnosis of dementia due to Alzheimer's disease in people with MCI versus the clinical follow-up diagnosis of Alzheimer's disease dementia as a reference standard (delayed verification). To investigate sources of heterogeneity in accuracy, such as the use of qualitative visual assessment or quantitative volumetric measurements, including manual or automatic (MRI) techniques, or the length of follow-up, and age of participants. MRI was evaluated as an add-on test in addition to clinical diagnosis of MCI to improve early diagnosis of dementia due to Alzheimer's disease in people with MCI. Search methods On 29 January 2019 we searched Cochrane Dementia and Cognitive Improvement's Specialised Register and the databases, MEDLINE, Embase, BIOSIS Previews, Science Citation Index, PsycINFO, and LILACS. We also searched the reference lists of all eligible studies identified by the electronic searches. Selection criteria We considered cohort studies of any size that included prospectively recruited people of any age with a diagnosis of MCI. We included studies that compared the diagnostic test accuracy of baseline structural MRI versus the clinical follow-up diagnosis of Alzheimer's disease dementia (delayed verification). We did not exclude studies on the basis of length of follow-up. We included studies that used either qualitative visual assessment or quantitative volumetric measurements of MRI to detect atrophy in the whole brain or in specific brain regions, such as the hippocampus, medial temporal lobe, lateral ventricles, entorhinal cortex, medial temporal gyrus, lateral temporal lobe, amygdala, and cortical grey matter. Data collection and analysis Four teams of two review authors each independently reviewed titles and abstracts of articles identified by the search strategy. Two teams of two review authors each independently assessed the selected full-text articles for eligibility, extracted data and solved disagreements by consensus. Two review authors independently assessed the quality of studies using the QUADAS-2 tool. We used the hierarchical summary receiver operating characteristic (HSROC) model to fit summary ROC curves and to obtain overall measures of relative accuracy in subgroup analyses. We also used these models to obtain pooled estimates of sensitivity and specificity when sufficient data sets were available. Main results We included 33 studies, published from 1999 to 2019, with 3935 participants of whom 1341 (34%) progressed to Alzheimer's disease dementia and 2594 (66%) did not. Of the participants who did not progress to Alzheimer's disease dementia, 2561 (99%) remained stable MCI and 33 (1%) progressed to other types of dementia. The median proportion of women was 53% and the mean age of participants ranged from 63 to 87 years (median 73 years). The mean length of clinical follow-up ranged from 1 to 7.6 years (median 2 years). Most studies were of poor methodological quality due to risk of bias for participant selection or the index test, or both. Most of the included studies reported data on the volume of the total hippocampus (pooled mean sensitivity 0.73 (95% confidence interval (CI) 0.64 to 0.80); pooled mean specificity 0.71 (95% CI 0.65 to 0.77); 22 studies, 2209 participants). This evidence was of low certainty due to risk of bias and inconsistency. Seven studies reported data on the atrophy of the medial temporal lobe (mean sensitivity 0.64 (95% CI 0.53 to 0.73); mean specificity 0.65 (95% CI 0.51 to 0.76); 1077 participants) and five studies on the volume of the lateral ventricles (mean sensitivity 0.57 (95% CI 0.49 to 0.65); mean specificity 0.64 (95% CI 0.59 to 0.70); 1077 participants). This evidence was of moderate certainty due to risk of bias. Four studies with 529 participants analysed the volume of the total entorhinal cortex and four studies with 424 participants analysed the volume of the whole brain. We did not estimate pooled sensitivity and specificity for the volume of these two regions because available data were sparse and heterogeneous. We could not statistically evaluate the volumes of the lateral temporal lobe, amygdala, medial temporal gyrus, or cortical grey matter assessed in small individual studies. We found no evidence of a difference between studies in the accuracy of the total hippocampal volume with regards to duration of follow-up or age of participants, but the manual MRI technique was superior to automatic techniques in mixed (mostly indirect) comparisons. We did not assess the relative accuracy of the volumes of different brain regions measured by MRI because only indirect comparisons were available, studies were heterogeneous, and the overall accuracy of all regions was moderate. Authors' conclusions The volume of hippocampus or medial temporal lobe, the most studied brain regions, showed low sensitivity and specificity and did not qualify structural MRI as a stand-alone add-on test for an early diagnosis of dementia due to Alzheimer's disease in people with MCI. This is consistent with international guidelines, which recommend imaging to exclude non-degenerative or surgical causes of cognitive impairment and not to diagnose dementia due to Alzheimer's disease. In view of the low quality of most of the included studies, the findings of this review should be interpreted with caution. Future research should not focus on a single biomarker, but rather on combinations of biomarkers to improve an early diagnosis of Alzheimer's disease dementia.

Background: Circadian and sleep disturbances are associated with increased risk of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Wearable activity trackers could provide a new approach in diagnosis and prevention. Objective: To evaluate sleep and circadian rhythm parameters, through wearable activity trackers, in MCI and AD patients as compared to controls, focusing on sex dissimilarities. Methods: Based on minute level data from consumer wearable devices, we analyzed actigraphic sleep parameters by applying an electromedical type I registered algorithm, and the corresponding circadian variables in 158 subjects: 86 females and 72 males (42 AD, 28 MCI, and 88 controls). Moreover, we used a confusion-matrix chart method to assess accuracy, precision, sensitivity, and specificity of two decision-tree models based on actigraphic data in predicting disease or health status. Results: Wake after sleep onset (WASO) was higher (p

An early differentiation between Alzheimer’s Disease (AD) and other dementias is crucial for an adequate patients’ management, albeit it may result difficult for the occurrence of “atypical presentations.” Current diagnostic criteria recognize the importance of biomarkers for AD diagnosis, but still an optimal diagnostic work-up isn’t available. Evaluate the utility and reproducibility of biomarkers and propose an “optimal” diagnostic work-up in atypical dementia. (1) a retrospective selection of “atypical dementia cases”; (2) a repetition of diagnostic assessment by two neurologists following two different diagnostic work-ups, each consisting of multiple steps; (3) a comparison between diagnostic accuracy and confidence reached at each step by both neurologists and evaluation of the inter-rater agreement. In AD, regardless of the undertaken diagnostic work-up, a significant gain in accuracy was reached by both neurologists after the second step, whereas in frontotemporal dementia (FTD), adding subsequent steps was not always sufficient to increase significantly the baseline accuracy. A relevant increment in diagnostic confidence was detectable after studying pathophysiological markers in AD, and after assessing brain metabolism in FTD. The inter-rater agreement was higher at the second step for the AD group when the pathophysiological markers were available and for the FTD group when the results of FDG-PET were accessible. In atypical cases of dementia, biomarkers significantly raise diagnostic accuracy, confidence, and agreement. This study introduces a proof of diagnostic work-up that combines imaging and CSF biomarkers and suggests distinct ways to proceed on the basis of a greater diagnostic likelihood.

Purpose: To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images. Materials and Methods: Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test. Results: CBF-pGM outperformed M0-T1w (CC improvement 47.2% ± 22.0%; P < 0.001), and the non-rigid transformation outperformed rigid-body (20.6% ± 5.3%; P < 0.001). Masking only improved the M0-T1w rigid-body registration (14.5% ± 15.5%; P = 0.007). Conclusion: The choice of image registration strategy impacts ASL group analyses. The non-rigid transformation is promising but requires validation. CBF-pGM rigid-body registration without masking can be used as a default strategy. In patients with expansive perfusion deficits, M0-T1w may outperform CBF-pGM in sequences with high effective spatial resolution. BET-masking only improves M0-T1w registration when the M0 image has sufficient contrast. Level of Evidence: 1. Technical Efficacy: Stage 1. J. Magn. Reson. Imaging 2018;47:131–140.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial. ispartof: NEUROIMAGE-CLINICAL vol:24 ispartof: location:Netherlands status: published

Background/aims Few longitudinal studies have explored the progression of cognitive and functional impairment of patients with primary progressive aphasia (PPA). The aims of the study were to describe the clinical, neuroimaging, and genetic features of a cohort of 68 PPA patients, and to outline the natural history of the disease. Materials and methods A sample of 23 patients with the logopenic variant, 26 with the nonfluent/agrammatic variant, and 19 with the semantic variant was retrospectively collected and followed-up for a maximum of 6 years. Clinical-neuropsychological assessment, fluorodeoxyglucose positron emission tomographic imaging, and genetic analyses were acquired at baseline. Disease progression was evaluated in terms of language impairment, global cognitive decline, and functional dependency. Results During follow-up, one third of subjects presented total language loss, and 20% severe functional dependency. Global cognitive decline after the first year (hazard ratio, 5.93; confidence interval, 1.63-21.56) and high schooling (hazard ratio, 0.07; confidence interval, 0.008-0.74) represented risk factors for functional impairment. The apolipoprotein E status was associated with the progression of cognitive decline. Positive family history for dementia was frequent and 3 genetic autosomal dominant mutations were identified. Conclusions There were no differences in the progression of PPA subtypes. Genetics plays an important role in disease onset and progression.

BACKGROUND: Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. We aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia.METHODS: We recruited participants from 14 centres collaborating in the Genetic Frontotemporal Dementia Initiative (GENFI), which is a multicentre cohort study of families with genetic frontotemporal dementia done across Europe and Canada. Eligible participants (aged ≥18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more. Participants were excluded if they had neurological comorbidities that were likely to affect NfL, including cerebrovascular events. We measured NfL longitudinally in serum samples collected between June 8, 2012, and Dec 8, 2017, through follow-up visits annually or every 2 years, which also included MRI and neuropsychological assessments. Using mixed-effects models, we analysed NfL changes over time and correlated them with longitudinal imaging and clinical parameters, controlling for age, sex, and study site. The primary outcome was the course of NfL over time in the various stages of genetic frontotemporal dementia.FINDINGS: We included 59 symptomatic carriers and 149 presymptomatic carriers of a mutation in GRN, C9orf72, or MAPT, and 127 non-carriers. Nine presymptomatic carriers became symptomatic during follow-up (so-called converters). Baseline NfL was elevated in symptomatic carriers (median 52 pg/mL [IQR 24-69]) compared with presymptomatic carriers (9 pg/mL [6-13]; pINTERPRETATION: Our findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy. The characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker.FUNDING: ZonMw and the Bluefield project.

The neuropathological processes eventually leading to Alzheimer's disease (AD) are thought to start decades before the appearance of clinical symptoms and the clinical diagnosis of AD dementia. The term "preclinical AD" has been recently introduced to identify this "silent stage" of AD, when the disease is already present, but symptoms are not yet clinically evident. Advances in AD biomarkers have dramatically improved the ability to detect AD pathological processes in vivo in cognitively intact subjects, thus demonstrating the presence of AD pathology in the preclinical phase. This review focuses on the recent advances in the field of neuroimaging and CSF AD biomarkers specifically in the preclinical phase of AD, and aims to discuss the significance that such biomarkers could have in cognitively intact subjects. Even though the use of such biomarkers in AD preclinical phase has contributed to improve our understanding of AD early pathological processes, it raised also a number of new challenges that still remain to be overcome, such as a better definition of the clinical and individual significance of currently known biomarkers in preclinical stages and the development of novel biomarkers of different early AD-related events.

Background Alzheimer's disease (AD) patients present high variability in the rate of cognitive decline. Despite the wide knowledge on factors influencing dementia risk, little is known on what accounts for AD progression. Previous studies on this topic have mainly analyzed each factor separately without taking into account the interaction between genetic and non-genetic factors. Objective The aim of the present study is to evaluate the role of demographic, clinical, therapeutic, and genetic factors and their interaction on cognitive decline among newly diagnosed AD patients. Methods We retrospectively selected 160 AD patients diagnosed at the Neurology Unit of Careggi University Hospital of Florence. We evaluated the occurrence of rapid cognitive changes defined as the worsening of more than four points at the Mini-Mental State Examination after 2-year follow up period. Results Among the 160 AD patients, 50% presented rapid disease progression. Extrapyramidal signs at disease onset were predictors of worse outcome (OR 2.2), especially among Apolipoprotein E (APOE) ɛ4 allele carriers, while the presence of family history for dementia decreased the risk of rapid progression by about 50%. Higher educated ɛ4-carriers showed a slower AD progression. We identified the chronic use of aspirin as potential secondary preventative strategy for the non ɛ4-carriers. Conclusion At dementia onset, some clinical and demographic data can be predictors of future progression. The outcomes of the present study support the already hypothesized interaction between genetic and non-genetic factors during disease course and suggest genetic-based approaches.

According to the literature, the APP Ala713Thr mutation is associated with Alzheimer's disease and cerebral amyloid angiopathy. We describe a case of dementia clinically compatible with frontotemporal dementia in an APP Ala713Thr mutation carrier in which both [18F]Florbetapir PET uptake and Aβ1-42 cerebrospinal fluid levels were normal. Further evidences are required to establish if this association is only incidental.

Clinical assessment and management of sleep disturbances in patients with mild cognitive impairment and dementia has important clinical and social implications. Poor sleep results in an increased risk of morbidities and mortality in demented patients and is a source of stress for caregivers. Sleep disturbances show high prevalence in mild cognitive impairment and dementia patients and they are often associated one to another in the same patient. A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of individuals with cognitive decline. The Sleep Study Group of the Italian Dementia Research Association (SINDem) reviewed evidence from original research articles, meta-analyses and systematic reviews published up to December 2013. The evidence was classified in quality levels (I, II, III) and strength of recommendations (A, B, C, D, E). Where there was a lack of evidence, but clear consensus, good practice points were provided. These recommendations may not be appropriate for all circumstances and should therefore be adopted only after a patient's individual characteristics have been carefully evaluated.

There is strong evidence that Alzheimer's disease (AD) pathology starts decades before clinical onset. Cognitive reserve (CR) and brain reserve can be a good predictive model for AD development. Neuroimaging can help in describing cerebral reserves, as well as in detecting AD brain pathology before the onset of clinical dementia. Education and occupation act as proxies for CR and are associated with a lower risk of AD and delayed onset of symptoms. The apolipoprotein E (ApoE)-ε4 allele is a strong risk factor for AD and is associated with lower hippocampal volume even in normal aging. A fluorodeoxyglucose positron emission tomography study of brain metabolism shows different metabolic phenotypes among subjects with different educational levels and ApoE genotypes. More highly educated subjects reach a clinical level when the cerebral areas involved in coping with network disruption are seriously impaired, and the AD-ε4 carriers show more global metabolic brain impairment compared with non-ε4 carriers. Thus, CR can counteract a genetically unfavorable background, suggesting a possible preventive strategy. AD research findings have already produced results, since recent epidemiological studies report a decreasing incidence of AD in the last years.

Background/Aims: Sleep disturbances are common in the elderly and in persons with cognitive decline. The aim of this study was to describe frequency and characteristics of insomnia, excessive daytime sleepiness, sleep-disordered breathing, REM behavior disorder and restless legs syndrome in a large cohort of persons with mild cognitive impairment or dementia. Methods: 431 consecutive patients were enrolled in 10 Italian neurological centers: 204 had Alzheimer’s disease, 138 mild cognitive impairment, 43 vascular dementia, 25 frontotemporal dementia and 21 Lewy body dementia or Parkinson’s disease dementia. Sleep disorders were investigated with a battery of standardized questions and questionnaires. Results: Over 60% of persons had one or more sleep disturbances almost invariably associated one to another without any evident and specific pattern of co-occurrence. Persons with Alzheimer’s disease and those with mild cognitive impairment had the same frequency of any sleep disorder. Sleep-disordered breathing was more frequent in vascular dementia. REM behavior disorder was more represented in Lewy body or Parkinson’s disease dementia. Conclusion: A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of persons with cognitive decline. Instrumental supports should be used only in selected patients.