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Introduction: Although frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance has been recognized, a uniform description of the syndrome is still missing. This multicenter study aims to establish a cohesive clinical phenotype., Methods: Retrospective clinical data from 18 centers across 12 countries yielded 360 FTD patients with predominant RATL atrophy through initial neuroimaging assessments., Results: Common symptoms included mental rigidity/preoccupations (78%), disinhibition/socially inappropriate behavior (74%), naming/word-finding difficulties (70%), memory deficits (67%), apathy (65%), loss of empathy (65%), and face-recognition deficits (60%). Real-life examples unveiled impairments regarding landmarks, smells, sounds, tastes, and bodily sensations (74%). Cognitive test scores indicated deficits in emotion, people, social interactions, and visual semantics however, lacked objective assessments for mental rigidity and preoccupations., Discussion: This study cumulates the largest RATL cohort unveiling unique RATL symptoms subdued in prior diagnostic guidelines. Our novel approach, combining real-life examples with cognitive tests, offers clinicians a comprehensive toolkit for managing these patients., Highlights: This project is the first international collaboration and largest reported cohort. Further efforts are warranted for precise nomenclature reflecting neural mechanisms. Our results will serve as a clinical guideline for early and accurate diagnoses., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

We rediscovered a phenotype of AD known in the early 1900s as presbyophrenia, but then forgotten, and renamed as confabulation-misidentification phenotype. The phenotype includes diencephalic amnesia whose prototype is Korsakoff syndrome. The main features are anterograde and retrograde amnesia with marked disorientation and confabulation, executive impairments, reduced insight and attention deficits, misidentification, minor hallucination and other delusions, behavioral disturbances, and early anxiety. In this article, we summarize what we have discovered about the new phenotype and what is still missing to confirm this diencephalic variant of AD., Competing Interests: The authors have no conflict of interest to report., (© 2024 – The authors. Published by IOS Press.)

Pharmacological treatments in Parkinson's disease (PD), albeit effective in alleviating many motor symptoms, have limited effects in non-motor signatures as cognitive impairment, as well as in other aspects included postural instability. Consequently, complementary interventions are nowadays a prerogative of clinical practice managing PD symptomatology. In this pilot longitudinal study, we recruited twenty-four PD patients participating in one of two interventions: adapted Argentine Tango or group-based physiotherapy. Participants underwent a motor and neuropsychological evaluation before and after four months of activities, carried out twice a week. We found a general stabilization of motor and cognitive abilities, with significant improvements in several motor skills, mainly pertaining to static and dynamic balance, similarly in both groups. At cognitive level, we measured a significant improvement in both groups in the Action Naming task. Interestingly, only PD patients in the Tango group improved their performance in the test measuring facial emotion recognition. These findings highlight the crucial role that physical activities have in the stabilization and slowdown of disease's progression in PD. They further highlight the beneficial effects of a group-based physical intervention, which, especially in the case of Tango, could lead to behavioral ameliorations in domains other than the motor, such as emotion recognition., (© 2024. The Author(s).)

Introduction: Differential diagnosis among subjects with Primary Progressive Aphasia (PPA) can be challenging. Structural MRI can support the clinical profile. Visual rating scales are a simple and reliable tool to assess brain atrophy in the clinical setting. The aims of the study were to establish to what extent the visual rating scales could be useful in the differential diagnosis of PPA, to compare the clinical diagnostic impressions derived from routine MRI interpretations with those obtained using the visual rating scale and to correlate results of the scales in a voxel-based morphometry (VBM) analysis., Method: Patients diagnosed with primary progressive aphasia (PPA) according to current criteria from two centers-Ospedale Maggiore Policlinico of Milan and Hospital Clínic de Barcelona-were included in the study. Two blinded clinicians evaluated the subjects MRIs for cortical atrophy and white matter hyperintensities using two protocols: routine readings and the visual rating scale. The diagnostic accuracy between patients and controls and within PPA subgroups were compared between the two protocols., Results: One hundred fifty Subjects were studied. All the scales showed a good to excellent intra and inter-rater agreement. The left anterior temporal scale could differentiate between semantic PPA and all other variants. The rater impression after the protocol can increase the accuracy just for the logopenic PPA. In the VBM analysis, the scores of visual rating scales correlate with the corresponding area of brain atrophy., Conclusion: The Left anterior temporal rating scale can distinguish semantic PPA from other variants. The rater impression after structured view improved the diagnostic accuracy of logopenic PPA compared to normal readings. The unstructured view of the MRI was reliable for identifying semantic PPA and controls. Neither the structured nor the unstructured view could identify the nonfluent and undetermined variants., (© 2024. The Author(s).)

Background: Predominant right temporal atrophy is a radiological sign usually associated with frontotemporal dementia but this sign can also be present in Alzheimer's disease. Given the overlap of clinical symptoms between the two conditions, it is important to know which characteristics allow them to be differentiated., Objectives: To compare clinical, neuropsychological and structural magnetic resonance imaging (MRI) data of subjects with prominent right anterior temporal atrophy, depending on the status of amyloid biomarkers., Methods: Among patients followed in the dementia center of Ospedale Maggiore Policlinico, subjects with right anterior temporal atrophy, defined as grade 3 or 4 on the corresponding visual rating scale, were identified. Only subjects with both an MRI scan and amyloid status available were considered. For selected subjects, data were extracted from clinical and neuropsychological records at initial presentation and at last available follow-up. Two raters applied a protocol of eight visual rating scales to compare brain atrophy and white matter hyperintensities., Results: Of 497 subjects, 17 fulfilled the inclusion criteria: 7 amyloid-positive and 10 amyloid-negative. At initial presentation, executive dysfunction and topographical disorientation were more common in amyloid-positive patients. At follow-up, behavioral symptoms, such as social awkwardness and compulsive attitude, were more frequent in the amyloid-negative patients. Amyloid-positive patients presented an overall worse neuropsychological performance, especially in the language and visuospatial domain, and had higher scores on the right anterior cingulate visual rating scale., Conclusion: Patients with predominant right temporal atrophy showed clinical, neuropsychological and radiological differences, depending on the status of amyloid biomarkers., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls., Methods: A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment., Results: The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p < 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p < 0.001). The addition of both markers further increased the AUC to 0.90 (p < 0.001)., Conclusions: The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD., (© 2024. The Author(s).)

Background: Perivascular spaces (PVS) are fluid-filled compartments that dilate in response to many different conditions. A high burden of enlarged PVS (EPVS) in the centrum semiovale (CSO) has been linked to neurodegeneration. Moreover, an increase in cerebrospinal fluid (CSF) levels of aquaporin-4 (AQP4), a water channel expressed on PVS-bounding astrocytes, has been described in patients with neurodegenerative dementia. Our aim was to investigate the relationship between neurodegenerative diseases and two putative glymphatic system biomarkers: AQP4 and EPVS., Methods: We included 70 individuals, 54 patients with neurodegenerative diseases and 16 subjects with non-degenerative conditions. EPVS were visually quantified on MRI-scans applying Paradise's scale. All subjects underwent lumbar puncture for the measurement of AQP4 levels in the cerebrospinal fluid (CSF). CSF levels of amyloid-β-1-42, phosphorylated and total tau (tTau) were also measured. Linear regression analyses were adjusted for age, sex, education and disease duration, after excluding outliers., Results: Cerebrospinal fluid (CSF)-AQP4 levels were independent predictors of total (β = 0.28, standard error [SE] = 0.08, p = 0.001), basal ganglia (β = 0.20, SE = 0.08, p = 0.009) and centrum semiovale EPVS (β = 0.37, SE = 0.12, p = 0.003). tTau levels predicted CSO-EPVS (β = 0.30, SE = 0.15, p = 0.046). Moreover, increased levels of AQP4 were strongly associated with higher levels of tTau in the CSF (β = 0.35, SE = 0.13, p = 0.008)., Conclusion: We provide evidence that CSO-EPVS and CSF-AQP4 might be clinically meaningful biomarkers of glymphatic dysfunction and associated neurodegeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sacchi, Arcaro, Carandini, Pietroboni, Fumagalli, Fenoglio, Serpente, Sorrentino, Visconte, Pintus, Conte, Contarino, Scarpini, Triulzi, Galimberti and Arighi.)

Recently, a fully automated instrument for the detection of the Cerebrospinal Fluid (CSF) biomarker for Alzheimer’s disease (AD) (low concentration of Amyloid-beta 42 (Aβ42), high concentration of total tau (T-tau) and Phosphorylated-tau (P-tau181)), has been implemented, namely CLEIA. We conducted a comparative analysis between ELISA and CLEIA methods in order to evaluate the analytical precision and the diagnostic performance of the novel CLEIA system on 111 CSF samples. Results confirmed a robust correlation between ELISA and CLEIA methods, with an improvement of the accuracy with the new CLEIA methodology in the detection of the single biomarkers and in their ratio values. For Aβ42 regression analysis with Passing−Bablok showed a Pearson correlation coefficient r = 0.867 (0.8120; 0.907% 95% CI p < 0.0001), T-tau analysis: r = 0.968 (0.954; 0.978% 95% CI p < 0.0001) and P-tau181: r = 0.946 (0.922; 0.962 5% 95% CI p < 0.0001). The overall ROC AUC comparison between ROC in ELISA and ROC in CLEIA confirmed a more accurate ROC AUC with the new automatic method: T-tau AUC ELISA = 0.94 (95% CI 0.89; 0.99 p < 0.0001) vs. AUC CLEIA = 0.95 (95% CI 0.89; 1.00 p < 0.0001), and P-tau181 AUC ELISA = 0.91 (95% CI 0.85; 0.98 p < 0.0001) vs. AUC CLEIA = 0.98 (95% CI 0.95; 1.00 p < 0.0001). The performance of the new CLEIA method in automation is comparable and, for tau and P-tau181, even better, as compared with standard ELISA. Hopefully, in the future, automation could be useful in clinical diagnosis and also in the context of clinical studies.

Aquaporin-4 (AQP4) is a channel protein that plays a fundamental role in glymphatic system, a newly described pathway for fluid exchange in the central nervous system, as well as a central figure in a fascinating new theory for the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). In this study, cerebrospinal fluid (CSF) concentration of AQP4, amyloid-β, total tau and P-tau were determined in 103 CSF samples from patients affected by neurodegenerative dementias (AD and FTD) or psychiatric diseases and 21 controls. Significantly higher levels of AQP4 were found in AD and FTD patients compared to subjects not affected by neurodegenerative diseases, and a significant, positive correlation between AQP4 and total tau levels was found. This evidence may pave the way for future studies focused on the role of this channel protein in the clinical assessment of the glymphatic function and degree of neurodegeneration., (© 2022. The Author(s).)

Primary progressive aphasia (PPA) damages the parts of the brain that control speech and language. There are three clinical PPA variants: nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). The pathophysiology underlying PPA variants is not fully understood, including the role of micro (mi)RNAs which were previously shown to play a role in several neurodegenerative diseases. Using a two-step analysis (array and validation through real-time PCR), we investigated the miRNA expression pattern in serum from 54 PPA patients and 18 controls. In the svPPA cohort, we observed a generalized upregulation of miRNAs with miR-106b-5p and miR-133a-3p reaching statistical significance (miR-106b-5p: 2.69 ± 0.89 mean ± SD vs. 1.18 ± 0.28, p < 0.0001; miR-133a-3p: 2.09 ± 0.10 vs. 0.74 ± 0.11 mean ± SD, p = 0.0002). Conversely, in lvPPA, the majority of miRNAs were downregulated. GO enrichment and KEGG pathway analyses revealed that target genes of both miRNAs are involved in pathways potentially relevant for the pathogenesis of neurodegenerative diseases. This is the first study that investigates the expression profile of circulating miRNAs in PPA variant patients. We identified a specific miRNA expression profile in svPPA that could differentiate this pathological condition from other PPA variants. Nevertheless, these preliminary results need to be confirmed in a larger independent cohort., Competing Interests: The authors declare no conflict of interest.

Purpose: Positron emission tomography (PET) with amyloid tracers (amy-PET) allows the quantification of pathological amyloid deposition in the brain tissues, including the white matter (WM). Here, we evaluate amy-PET uptake in WM lesions (WML) and in the normal-appearing WM (NAWM) of patients with Alzheimer's disease (AD) and non-AD type of dementia., Methods: Thirty-three cognitively impaired subjects underwent brain magnetic resonance imaging (MRI), Aβ 1-42 (Aβ) determination in the cerebrospinal fluid (CSF) and amy-PET. Twenty-three patients exhibiting concordant results in both CSF analysis and amy-PET for cortical amyloid deposition were recruited and divided into two groups, amyloid positive (A+) and negative (A-). WML quantification and brain volumes' segmentation were performed. Standardized uptake values ratios (SUVR) were calculated in the grey matter (GM), NAWM and WML on amy-PET coregistered to MRI images., Results: A+ compared to A- showed a higher WML load (p = 0.049) alongside higher SUVR in all brain tissues (p < 0.01). No correlations between CSF Aβ levels and WML and NAWM SUVR were found in A+, while, in A-, CSF Aβ levels were directly correlated to NAWM SUVR (p = 0.04). CSF Aβ concentration was the only predictor of NAWM SUVR (adj R 2  = 0.91; p = 0.04) in A-. In A+ but not in A- direct correlations were identified between WM and GM SUVR (p < 0.01)., Conclusions: Our data provide evidence on the role of amy-PET in the assessment of microstructural WM injury in non-AD dementia, whereas amy-PET seems less suitable to assess WM damage in AD patients due to a plausible amyloid accrual therein., (© 2022. The Author(s).)

Background: Diogenes syndrome is a neurobehavioural syndrome characterised by domestic squalor, hoarding and lack of insight. It is an uncommon but high-mortality condition, often associated with dementia., Aims: To describe the clinical features and treatment of Diogenes syndrome secondary to behavioural variant frontotemporal dementia (bvFTD)., Method: We describe a case of bvFTD in a 77-year-old man presenting with Diogenes syndrome., Results: The patient's medical and psychiatric histories were unremarkable, but in recent years he had begun packing his flat with 'art pieces'. Mental state examination revealed confabulation and more structured delusions. Neuropsychological evaluation outlined an impairment in selective attention and letter verbal fluency, but no semantic impairment, in the context of an overall preserved mental functioning. Brain magnetic resonance imaging and positron emission tomography (PET) with fluorodeoxyglucose showed mild bilateral temporo-insular atrophy and hypometabolism in the left-superior temporal gyrus respectively. An amyloid PET scan and genetic analysis covering the dementia spectrum were normal. A diagnosis of bvFTD was made., Conclusions: The clinical framing of behavioural symptoms of dementia such as hoarding poses a diagnostic challenge. This case illustrates the importance of a deeper understanding of Diogenes syndrome, leading to timelier diagnosis and effective therapeutic strategies.

Small extracellular vesicles (EVs) are able to pass from the central nervous system (CNS) into peripheral blood and contain molecule markers of their parental origin. The aim of our study was to isolate and characterize total and neural-derived small EVs (NDEVs) and their micro RNA (miRNA) cargo in Alzheimer's disease (AD) patients. Small NDEVs were isolated from plasma in a population consisting of 40 AD patients and 40 healthy subjects (CTRLs) using high throughput Advanced TaqMan miRNA OpenArrays ® , which enables the simultaneous determination of 754 miRNAs. MiR-23a-3p, miR-223-3p, miR-100-3p and miR-190-5p showed a significant dysregulation in small NDEVs from AD patients as compared with controls (1.16 ± 0.49 versus 7.54 ± 2.5, p = 0.026; 9.32 ± 2.27 versus 0.66 ± 0.18, p <0.0001; 0.069 ± 0.01 versus 0.5 ± 0.1, p < 0.0001 and 2.9 ± 1.2 versus 1.93 ± 0.9, p < 0.05, respectively). A further validation analysis confirmed that miR-23a-3p, miR-223-3p and miR-190a-5p levels in small NDEVs from AD patients were significantly upregulated as compared with controls ( p = 0.008; p = 0.016; p = 0.003, respectively) whereas miR-100-3p levels were significantly downregulated ( p = 0.008). This is the first study that carries out the comparison between total plasma small EV population and NDEVs, demonstrating the presence of a specific AD NDEV miRNA signature., Competing Interests: The authors declare no conflict of interest.

Objectives: Posterior Cortical Atrophy (PCA) is an atypical presentation of Alzheimer disease (AD) characterized by atrophy of posterior brain regions. This pattern of atrophy is usually evaluated with Koedam visual rating scale, a score developed to enable visual assessment of parietal atrophy on magnetic resonance imaging (MRI). However, Koedam scale is complex to assess and its utility in the differential diagnosis between PCA and typical AD has not been demonstrated yet. The aim of this study is therefore to spot a simple and reliable MRI element able to differentiate between PCA and typical AD using visual rating scales., Methods: 15 patients who presented with progressive complex visual disorders and predominant occipitoparietal hypometabolism on PET-FDG were selected from our centre and compared with 30 typical AD patients and 15 healthy subjects. We used previously validated visual rating scales including Koedam scale, which we divided into three major components: posterior cingulate, precuneus and parieto-occipital. Subsequently we validated the results using the automated software Brainvisa Morphologist and Voxel Based Morphometry (VBM)., Results: Patients with PCA, compared to typical AD, showed higher widening of the parieto-occipital sulcus, assessed both with visual rating scales and Brainvisa. In the corresponding areas, the VBM analysis showed an inverse correlation between the results obtained from the visual evaluation scales with the volume of the grey matter and a direct correlation between the same results with the cerebrospinal fluid volume., Conclusions: A visually based rating scale for parieto-occipital sulcus can distinguish Posterior Cortical Atrophy from typical Alzheimer disease., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: According to the 2018 NIA-AA research framework, Alzheimer's disease (AD) is not defined by the clinical consequences of the disease, but by its underlying pathology, measured by biomarkers. Evidence of both amyloid-β (Aβ) and phosphorylated tau protein (p-tau) deposition-assessed interchangeably with amyloid-positron emission tomography (PET) and/or cerebrospinal fluid (CSF) analysis-is needed to diagnose AD in a living person. Our aim was to test the new NIA-AA research framework in a large cohort of cognitively impaired patients to evaluate correspondence between the clinical syndromes and the underlying pathologic process testified by biomarkers., Methods: We retrospectively analysed 628 subjects referred to our centre in suspicion of dementia, who underwent CSF analysis, together with neuropsychological assessment and neuroimaging, and were diagnosed with different neurodegenerative dementias according to current criteria, or as cognitively unimpaired. Subjects were classified considering CSF biomarkers, and the prevalence of normal, AD-continuum and non-AD profiles in each clinical syndrome was calculated. The positivity threshold of each CSF biomarker was first assessed by receiver operating characteristic analysis, using Aβ-positive/negative status as determined by amyloid-PET visual reads. The agreement between CSF and amyloid-PET data was also evaluated., Results: Among patients with a clinical diagnosis of AD, 94.1% were in the AD-continuum, whereas 5.5% were classified as non-AD and 0.4% were normal. The AD-continuum profile was found also in 26.2% of frontotemporal dementia, 48.6% of Lewy body dementia, 25% of atypical parkinsonism and 44.7% of vascular dementia. Biomarkers' profile did not differ in amnestic and not amnestic mild cognitive impairment. CSF Aβ levels and amyloid-PET tracer binding negatively correlated, and the concordance between the two Aβ biomarkers was 89%., Conclusions: The examination of the 2018 NIA-AA research framework in our clinical setting revealed a good, but incomplete, correspondence between the clinical syndromes and the underlying pathologic process measured by CSF biomarkers. The AD-continuum profile resulted to be a sensitive, but non-specific biomarker with regard to the clinical AD diagnosis. CSF and PET Aβ biomarkers were found to be not perfectly interchangeable to quantify the Aβ burden, possibly because they measure different aspects of AD pathology.

Homozygous mutations in Triggering Receptor Expressed on Myeloid cells 2 gene (TREM2) are one of the major causes of Nasu Hakola Disease (NHD). We analysed Peripheral Blood Mononuclear Cells (PBMC) profile of 164 inflammatory factors in patients with NHD carrying the TREM2 Q33X mutation as compared with heterozygous and wild type individuals. Several molecules related to bone formation and angiogenesis were altered in NHD compared to non-carriers: Bone Morphogenetic Protein (BMP)-1 mRNA levels were significantly increased in PBMC (2.32 fold-increase; P = 0.01), as were Transforming Growth Factor Beta (TGFB)3 levels (1.51 fold-increase; P = 0.02). Conversely, CXCL5 and Pro Platelet Basic Protein (PPBP) were strongly downregulated (-28.26, -9.85 fold-decrease over non-carriers, respectively, P = 0.01), as well as Platelet Factor 4 Variant 1 (PF4V1; -41.44, P = 0.03). Among other inflammatory factors evaluated, Interleukin (IL)-15 and Tumor Necrosis Factor Superfamily Member (TNFSF)4 mRNA levels were decreased in NHD as compared with non-carriers (-2.25 and -3.87 fold-decrease, P = 0.01 and 0.001, respectively). In heterozygous individuals, no significant differences were observed, apart from IL-15 mRNA levels, that were decreased at the same extent as NHD (-2.05 fold-decrease over non-carriers, P = 0.002). We identified a signature in PBMC from patients with NHD consisting of strongly decreased mRNA levels of CXCL5, PPBP, PF4V1, mildly decreased IL-15 and TNFSF4 and mildly increased BMP-1 and TGFB3., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Fronto-temporal dementia (FTD) is the clinical-diagnostic term that is now preferred to describe patients with a range of progressive dementia syndromes associated with focal atrophy of the frontal and anterior temporal cerebral regions. Currently available FTD medications have been used to control behavioral symptoms, even though they are ineffective in some patients, expensive and may induce adverse effects. Alternative therapeutic approaches are worth pursuing, such as non-invasive brain stimulation with transcranial direct current (tDCS). tDCS has been demonstrated to influence neuronal excitability and reported to enhance cognitive performance in dementia. The aim of this study was to investigate whether applying Anodal tDCS (2 mA intensity, 20 min) over the fronto-temporal cortex bilaterally in five consecutive daily sessions would improve cognitive performance and behavior symptoms in FTD patients, also considering the neuromodulatory effect of stimulation on cortical electrical activity measured through EEG. We recruited 13 patients with FTD and we tested the effect of Anodal and Sham (i.e., placebo) tDCS in two separate experimental sessions. In each session, at baseline (T0), after 5 consecutive days (T1), after 1 week (T2), and after 4 weeks (T3) from the end of the treatment, cognitive and behavioral functions were tested. EEG (21 electrodes, 10-20 international system) was recorded for 5 min with eyes closed at the same time points in nine patients. The present findings showed that Anodal tDCS applied bilaterally over the fronto-temporal cortex significantly improves (1) neuropsychiatric symptoms (as measured by the neuropsychiatric inventory, NPI) in FTD patients immediately after tDCS treatment, and (2) simple visual reaction times (sVRTs) up to 1 month after tDCS treatment. These cognitive improvements significantly correlate with the time course of the slow EEG oscillations (delta and theta bands) measured at the same time points. Even though further studies on larger samples are needed, these findings support the effectiveness of Anodal tDCS over the fronto-temporal regions in FTD on attentional processes that might be correlated to a normalized EEG low-frequency pattern.

Background: In patients with frontotemporal dementia, it has been shown that brain atrophy occurs earliest in the anterior cingulate, insula and frontal lobes. We used visual rating scales to investigate whether identifying atrophy in these areas may be helpful in distinguishing symptomatic patients carrying different causal mutations in the microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame (C9ORF72) genes. We also analysed asymptomatic carriers to see whether it was possible to visually identify brain atrophy before the appearance of symptoms., Methods: Magnetic resonance imaging of 343 subjects (63 symptomatic mutation carriers, 132 presymptomatic mutation carriers and 148 control subjects) from the Genetic Frontotemporal Dementia Initiative study were analysed by two trained raters using a protocol of six visual rating scales that identified atrophy in key regions of the brain (orbitofrontal, anterior cingulate, frontoinsula, anterior and medial temporal lobes and posterior cortical areas)., Results: Intra- and interrater agreement were greater than 0.73 for all the scales. Voxel-based morphometric analysis demonstrated a strong correlation between the visual rating scale scores and grey matter atrophy in the same region for each of the scales. Typical patterns of atrophy were identified: symmetric anterior and medial temporal lobe involvement for MAPT, asymmetric frontal and parietal loss for GRN, and a more widespread pattern for C9ORF72. Presymptomatic MAPT carriers showed greater atrophy in the medial temporal region than control subjects, but the visual rating scales could not identify presymptomatic atrophy in GRN or C9ORF72 carriers., Conclusions: These simple-to-use and reproducible scales may be useful tools in the clinical setting for the discrimination of different mutations of frontotemporal dementia, and they may even help to identify atrophy prior to onset in those with MAPT mutations.

Background: The role of cerebrospinal fluid (CSF) biomarkers, and neuroimaging in the diagnostic process of Alzheimer's disease (AD) is not clear, in particular in the older patients., Objective: The aim of this study was to compare the clinical diagnosis of AD with CSF biomarkers and with cerebrovascular damage at neuroimaging in a cohort of geriatric patients., Methods: Retrospective analysis of medical records of ≥65-year-old patients with cognitive impairment referred to an Italian geriatric outpatient clinic, for whom the CSF concentration of amyloid-β (Aβ), total Tau (Tau), and phosphorylated Tau (p-Tau) was available. Clinical diagnosis (no dementia, possible and probable AD) was based on the following two sets of criteria: (1) the Diagnostic Statistical Manual of Mental Disorders ( DSM -IV) plus the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and (2) the National Institute on Aging-Alzheimer's Association (NIA-AA). The Fazekas visual scale was applied when a magnetic resonance imaging scan was available., Results: We included 94 patients, mean age 77.7 years, mean Mini Mental State Examination score 23.9. The concordance (kappa coefficient) between the two sets of clinical criteria was 70%. The mean CSF concentration (pg/ml) (±SD) of biomarkers was as follows: Aβ 687 (±318), Tau 492 (±515), and p-Tau 63 (±56). There was a trend for lower Aβ and higher Tau levels from the no dementia to the probable AD group. The percentage of abnormal liquor according to the local cutoffs was still 15 and 21% in patients without AD based on the DSM -IV plus NINCDS-ADRDA or the NIA-AA criteria, respectively. The exclusion of patient in whom normotensive hydrocephalus was suspected did not change these findings. A total of 80% of patients had the neuroimaging report describing chronic cerebrovascular damage, while the Fazekas scale was positive in 45% of patients overall, in 1/2 of no dementia or possible AD patients, and in about 1/3 of probable AD patients, with no difference across ages., Conclusion: We confirmed the expected discrepancy between different approaches to the diagnosis of AD in a geriatric cohort of patients with cognitive impairment. Further research is needed to understand how to interpret this discrepancy and provide clinicians with practical guidelines.

Accurately distinguishing between different degenerative dementias during life is challenging but increasingly important with the prospect of disease-modifying therapies. Molecular biomarkers of dementia pathology are becoming available, but are not widely used in clinical practice. Conversely, structural neuroimaging is recommended in the evaluation of cognitive impairment. Visual assessment remains the primary method of scan interpretation, but in the absence of a structured approach, diagnostically relevant information may be under-utilized. This definitive, multi-centre study uses post-mortem confirmed cases as the gold standard to: (i) assess the reliability of six visual rating scales; (ii) determine their associated pattern of atrophy; (iii) compare their diagnostic value with expert scan assessment; and (iv) assess the accuracy of a machine learning approach based on multiple rating scales to predict underlying pathology. The study includes T1-weighted images acquired in three European centres from 184 individuals with histopathologically confirmed dementia (101 patients with Alzheimer's disease, 28 patients with dementia with Lewy bodies, 55 patients with frontotemporal lobar degeneration), and scans from 73 healthy controls. Six visual rating scales (medial temporal, posterior, anterior temporal, orbito-frontal, anterior cingulate and fronto-insula) were applied to 257 scans (two raters), and to a subset of 80 scans (three raters). Six experts also provided a diagnosis based on unstructured assessment of the 80-scan subset. The reliability and time taken to apply each scale was evaluated. Voxel-based morphometry was used to explore the relationship between each rating scale and the pattern of grey matter volume loss. Additionally, the performance of each scale to predict dementia pathology both individually and in combination was evaluated using a support vector classifier, which was compared with expert scan assessment to estimate clinical value. Reliability of scan assessment was generally good (intraclass correlation coefficient > 0.7), and average time to apply all six scales was <3 min. There was a very close association between the pattern of grey matter loss and the regions of interest each scale was designed to assess. Using automated classification based on all six rating scales, the accuracy (estimated using the area under the receiver-operator curves) for distinguishing each pathological group from controls ranged from 0.86-0.97; and from one another, 0.75-0.92. These results were substantially better than the accuracy of any single scale, at least as good as expert reads, and comparable to previous studies using molecular biomarkers. Visual rating scores from magnetic resonance images routinely acquired as part of the investigation of dementias, offer a practical, inexpensive means of improving diagnostic accuracy., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.)

We analysed the expression levels of 84 key genes involved in the regulated degradation of cellular protein by the ubiquitin-proteasome system in peripheral cells from patients with frontotemporal dementia (FTD) due to C9ORF72 and GRN mutations, as compared with sporadic FTD and age-matched controls. A SABiosciences PCR array was used to investigate the transcription profile in a discovery population consisting of six patients each in C9ORF72, GRN, sporadic FTD and age-matched control groups. A generalized down-regulation of gene expression compared with controls was observed in C9ORF72 expansion carriers and sporadic FTD patients. In particular, in both groups, four genes, UBE2I, UBE2Q1, UBE2E1 and UBE2N, were down-regulated at a statistically significant (p < 0.05) level. All of them encode for members of the E2 ubiquitin-conjugating enzyme family. In GRN mutation carriers, no statistically significant deregulation of ubiquitination pathway genes was observed, except for the UBE2Z gene, which displays E2 ubiquitin conjugating enzyme activity, and was found to be statistically significant up-regulated (p = 0.006). These preliminary results suggest that the proteasomal degradation pathway plays a role in the pathogenesis of FTD associated with TDP-43 pathology, although different proteins are altered in carriers of GRN mutations as compared with carriers of the C9ORF72 expansion.