Objective
The hexanucleotide repeat expansion in C9orf72 is an associated genetic cause in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In the “ALS/FTD” spectrum prevails ...clinical heterogeneity and an in vivo knowledge of the underling brain dysfunction in patients carrying C9orf72 mutation remain limited and only described at group level. The study aimed to assess the brain metabolic alterations characterizing patients with C9orf72 mutation using FDG-PET in single individuals.
Methods
We applied a validated statistical parametric mapping (SPM) voxel-based procedure for FDG-PET data to obtain maps of brain relative hypometabolism and hypermetabolism at single-subject level in six FTD/ALS patients carrying the C9orf72 mutation.
Results
Clinical diagnoses classified the patients as right semantic variant of frontotemporal dementia (one case, C9svFTD), behavioral variant of frontotemporal dementia (two cases, C9bvFTD), and bulbar amyotrophic lateral sclerosis (three cases, C9bALS). The FDG-PET SPM revealed a prevalent frontal hypometabolism in C9bvFTD cases, and right temporal polar and lateral involvement in C9svFTD, consistent with the clinical diagnosis. There was a quite comparable occipital and cerebellar hypermetabolism in these cases. The three C9bALS patients showed variable patterns of hypo- and hypermetabolism.
Conclusions
The present work is the first in vivo FDG-PET study showing the heterogeneous patterns of brain regional hypo- and hypermetabolism in single patients sharing C9orf72 mutation. Brain hypometabolism was consistent with the clinical phenotypes, supporting the diagnostic importance of neuroimaging functional biomarkers to capture at single-subject level specific brain dysfunction.
INTRODUCTION
Amnestic mild cognitive impairment (aMCI) is emerging as a heterogeneous condition.
METHODS
We looked at a cohort of N = 207 aMCI subjects, with baseline fluorodeoxyglucose positron ...emission tomography (FDG‐PET), T1 magnetic resonance imaging, cerebrospinal fluid (CSF), apolipoprotein E (APOE), and neuropsychological assessment. An algorithm based on FDG‐PET hypometabolism classified each subject into subtypes, then compared biomarker measures and clinical progression.
RESULTS
Three subtypes emerged: hippocampal sparing–cortical hypometabolism, associated with younger age and the highest level of Alzheimer's disease (AD)‐CSF pathology; hippocampal/cortical hypometabolism, associated with a high percentage of APOE ε3/ε4 or ε4/ε4 carriers; medial–temporal hypometabolism, characterized by older age, the lowest AD‐CSF pathology, the most severe hippocampal atrophy, and a benign course. Within the whole cohort, the severity of temporo‐parietal hypometabolism, correlated with AD‐CSF pathology and marked the rate of progression of cognitive decline.
DISCUSSION
FDG‐PET can distinguish clinically comparable aMCI at single‐subject level with different risk of progression to AD dementia or stability. The obtained results can be useful for the optimization of pharmacological trials and automated‐classification models.
Highlights
Algorithm based on FDG‐PET hypometabolism demonstrates distinct subtypes across aMCI;
Three different subtypes show heterogeneous biological profiles and risk of progression;
The cortical hypometabolism is associated with AD pathology and cognitive decline;
MTL hypometabolism is associated with the lowest conversion rate and CSF‐AD pathology.
Brain hypometabolism patterns have been previously associated with cognitive decline in Parkinson's disease (PD). Our aim is to evaluate the impact of single-subject fluorodeoxyglucose (FDG)-PET ...brain hypometabolism on long-term cognitive and motor outcomes in PD.
Forty-nine non-demented PD patients with baseline brain FDG-PET data underwent an extensive clinical follow-up for 8 years. The ability of FDG-PET to predict long-term cognitive and motor progression was evaluated using Cox regression and mixed ANCOVA models.
Participants were classified according to FDG-PET pattern in PD with typical (n = 26) and atypical cortical metabolism (n = 23). Patients with atypical brain hypometabolic patterns showed higher incidence of dementia (60% vs 3%; HR = 18.3), hallucinations (56% vs 7%, HR = 7.3) and faster motor decline compared to typical pattern group.
This study argues for specific patterns of FDG-PET cortical hypometabolism in PD as a prognostic marker for long term cognitive and motor outcomes at single-subject level.
•Atypical FDG-PET patterns increase long-term risk for dementia conversion in PD.•Atypical FDG-PET patterns are associated with worse long-term motor progression.•Alzheimer's disease-like pattern is associated with the worst prognosis in PD.
The impairment of nigrostriatal dopaminergic network is a core feature of dementia with Lewy bodies (DLB). The involvement and reconfiguration of extranigrostriatal dopaminergic circuitries in the ...DLB continuum is still theme of debate. We aim to investigate in vivo the dynamic changes of local and long-distance dopaminergic networks across DLB continuum.
Forty-nine patients (including 29 with dementia and 20 prodromal cases) and fifty-two controls entered the study. Each subject underwent a standardized clinical and neurological examination and performed Brain SPECT to measuring brain dopamine transporter (DAT) density. Spatially normalized images underwent the occipital-adjusted specific binding to obtain parametric data. The ANCOVA was applied to assess 123I-FP-CIT differences between pDLB, overt-DLB and CG, considering age, gender, and motor impairment as variables of no interest. Between-nodes correlation analysis measured molecular connectivity within the ventral and dorsal dopaminergic networks.
Prodromal DLB and DLB patients showed comparable nigrostriatal deficits in basal ganglia regions compared with CG. Molecular connectivity analyses revealed extensive connectivity losses, more in ventral than in dorsal dopaminergic network in DLB dementia. Conversely, the prodromal group showed increased connectivity compared to CG, mostly putamen-thalamus-cortical and striatal-cortical connectivity.
This study indicates a comparable basal ganglia deficit in nigrostriatal projections in DLB continuum and supports a different reorganization of extra-striatal dopaminergic connectivity in the prodromal phases of DLB. The shift from an increased to a decreased bilateral putamen-thalamus-cortex connectivity might be a hallmark of transition from prodromal to dementia DLB stages.
•To assess the dynamic local and molecular connectivity changes across the DLB course.•Univariate analysis revealed similar DAT derangements in the two groups.•Multivariate connectivity approach showed substantial differences between the two groups.•Hyperconnectivity in dorsal and ventral dopaminergic networks characterized pDLB.•Whereas a widespread loss of connectivity was prominent in overt DLB.
Posterior cortical atrophy is a rare syndrome characterised by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing. The disorder has been associated with ...underlying neuropathological features of Alzheimer's disease, but large-scale biomarker and neuropathological studies are scarce. We aimed to describe demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy in a large international cohort.
We searched PubMed between database inception and Aug 1, 2021, for all published research studies on posterior cortical atrophy and related terms. We identified research centres from these studies and requested deidentified, individual participant data (published and unpublished) that had been obtained at the first diagnostic visit from the corresponding authors of the studies or heads of the research centres. Inclusion criteria were a clinical diagnosis of posterior cortical atrophy as defined by the local centre and availability of Alzheimer's disease biomarkers (PET or CSF), or a diagnosis made at autopsy. Not all individuals with posterior cortical atrophy fulfilled consensus criteria, being diagnosed using centre-specific procedures or before development of consensus criteria. We obtained demographic, clinical, biofluid, neuroimaging, and neuropathological data. Mean values for continuous variables were combined using the inverse variance meta-analysis method; only research centres with more than one participant for a variable were included. Pooled proportions were calculated for binary variables using a restricted maximum likelihood model. Heterogeneity was quantified using I2.
We identified 55 research centres from 1353 papers, with 29 centres responding to our request. An additional seven centres were recruited by advertising via the Alzheimer's Association. We obtained data for 1092 individuals who were evaluated at 36 research centres in 16 countries, the other sites having not responded to our initial invitation to participate to the study. Mean age at symptom onset was 59·4 years (95% CI 58·9–59·8; I2=77%), 60% (56–64; I2=35%) were women, and 80% (72–89; I2=98%) presented with posterior cortical atrophy pure syndrome. Amyloid β in CSF (536 participants from 28 centres) was positive in 81% (95% CI 75–87; I2=78%), whereas phosphorylated tau in CSF (503 participants from 29 centres) was positive in 65% (56–75; I2=87%). Amyloid-PET (299 participants from 24 centres) was positive in 94% (95% CI 90–97; I2=15%), whereas tau-PET (170 participants from 13 centres) was positive in 97% (93–100; I2=12%). At autopsy (145 participants from 13 centres), the most frequent neuropathological diagnosis was Alzheimer's disease (94%, 95% CI 90–97; I2=0%), with common co-pathologies of cerebral amyloid angiopathy (71%, 54–88; I2=89%), Lewy body disease (44%, 25–62; I2=77%), and cerebrovascular injury (42%, 24–60; I2=88%).
These data indicate that posterior cortical atrophy typically presents as a pure, young-onset dementia syndrome that is highly specific for underlying Alzheimer's disease pathology. Further work is needed to understand what drives cognitive vulnerability and progression rates by investigating the contribution of sex, genetics, premorbid cognitive strengths and weaknesses, and brain network integrity.
None.
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F–fluoro-deoxy-glucose Positron Emission Tomography (FDG-PET) allows early identification of neurodegeneration in dementia. The use of an optimized method based on the SPM software package highly ...improves diagnostic accuracy. However, the impact of different scanners for data acquisition on the SPM results and the effects of different pools of healthy subjects on the statistical comparison have not been investigated yet. Images from 144 AD patients acquired using six different PET scanners were analysed with an optimized single-subject SPM procedure to identify the typical AD hypometabolism pattern at single subject level. We compared between-scanners differences on the SPM outcomes in a factorial design. Single-subject SPM comparison analyses were also performed against a different group of healthy controls from the ADNI initiative. The concordance between the two analyses (112 vs. 157 control subjects) was tested using Dice scores. In addition, we applied the optimized single-subject SPM procedure to the FDG-PET data acquired with 3 different scanners in 57 MCI subjects, in order to assess for tomograph influence in early disease phase. All the patients showed comparable AD-like hypometabolic patterns, also in the prodromal phase, in spite of being acquired with different PET scanners. SPM statistical comparisons performed with the two different healthy control databases showed a high degree of concordance (76% average pattern volume overlap and 90% voxel-wise agreement in AD-related brain structures). The validated optimized SPM-based single-subject procedure is influenced neither by the scanners used for image acquisition, nor by differences in healthy control groups, thus implying a great reliability of this method for longitudinal and multicentre studies.
18F-fluoro-deoxy-glucose Positron Emission Tomography (FDG-PET) allows early identification of neurodegeneration in dementia. The use of an optimized method based on the SPM software package highly ...improves diagnostic accuracy. However, the impact of different scanners for data acquisition on the SPM results and the effects of different pools of healthy subjects on the statistical comparison have not been investigated yet. Images from 144 AD patients acquired using six different PET scanners were analysed with an optimized single-subject SPM procedure to identify the typical AD hypometabolism pattern at single subject level. We compared between-scanners differences on the SPM outcomes in a factorial design. Single-subject SPM comparison analyses were also performed against a different group of healthy controls from the ADNI initiative. The concordance between the two analyses (112 vs. 157 control subjects) was tested using Dice scores. In addition, we applied the optimized single-subject SPM procedure to the FDG-PET data acquired with 3 different scanners in 57 MCI subjects, in order to assess for tomograph influence in early disease phase. All the patients showed comparable AD-like hypometabolic patterns, also in the prodromal phase, in spite of being acquired with different PET scanners. SPM statistical comparisons performed with the two different healthy control databases showed a high degree of concordance (76% average pattern volume overlap and 90% voxel-wise agreement in AD-related brain structures). The validated optimized SPM-based single-subject procedure is influenced neither by the scanners used for image acquisition, nor by differences in healthy control groups, thus implying a great reliability of this method for longitudinal and multicentre studies.
F-fluoro-deoxy-glucose Positron Emission Tomography (FDG-PET) allows early identification of neurodegeneration in dementia. The use of an optimized method based on the SPM software package highly ...improves diagnostic accuracy. However, the impact of different scanners for data acquisition on the SPM results and the effects of different pools of healthy subjects on the statistical comparison have not been investigated yet. Images from 144 AD patients acquired using six different PET scanners were analysed with an optimized single-subject SPM procedure to identify the typical AD hypometabolism pattern at single subject level. We compared between-scanners differences on the SPM outcomes in a factorial design. Single-subject SPM comparison analyses were also performed against a different group of healthy controls from the ADNI initiative. The concordance between the two analyses (112 vs. 157 control subjects) was tested using Dice scores. In addition, we applied the optimized single-subject SPM procedure to the FDG-PET data acquired with 3 different scanners in 57 MCI subjects, in order to assess for tomograph influence in early disease phase. All the patients showed comparable AD-like hypometabolic patterns, also in the prodromal phase, in spite of being acquired with different PET scanners. SPM statistical comparisons performed with the two different healthy control databases showed a high degree of concordance (76% average pattern volume overlap and 90% voxel-wise agreement in AD-related brain structures). The validated optimized SPM-based single-subject procedure is influenced neither by the scanners used for image acquisition, nor by differences in healthy control groups, thus implying a great reliability of this method for longitudinal and multicentre studies.
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