To study the effect of disease duration on the clinical, neuropsychological and [18F]-deoxyglucose (FDG) PET findings in patients with mixed type multiple system atrophy (MSA), this study included 16 controls and 37 mixed-type MSA patients with a shorter than a 3-year history of cerebellar or parkinsonian symptoms. We classified the patients into three groups according to the duration of parkinsonian or cerebellar symptoms (Group I = ≤1 year; II = 13–24 months; III = 25–36 months). We performed UPDRS, international cooperative ataxia rating scale (ICARS), and a neuropsychological test battery. We compared the FDG PET findings of each group of patients with controls. Group I patients frequently had memory and frontal executive dysfunction. They showed hypometabolism in the frontal cortex, anterior cerebellar hemisphere and vermis. They had parkinsonian motor deficits, but no basal ganglia hypometabolism. Group II and III patients frequently had multiple domain cognitive impairments, and showed hypometabolism in the frontal and parieto-temporal cortices. Hypometabolism of the bilateral caudate and the left posterolateral putamen was observed in Group II, and whole striatum in Group III. In summary, the cortical hypometabolism begins in the frontal cortex and spreads to the parieto-temporal cortex in MSA. This spreading pattern coincides with the progressive cognitive decline. Early caudate hypometabolism may also contribute to the cognitive impairment. Parkinsonian motor deficits precede putaminal hypometabolism that begins in its posterolateral part. Cerebellar hypometabolism occurs early in the clinical courses and seems to be a relevant metabolic descriptor of cerebellar deficits.
Abstract Background To investigate prognostic value of amyloid (A) and tau (T) imaging biomarkers in a long term follow up cohort study. Method We included 273 AD spectrum participants [96 cognitive unimpaired (CU), 106 mild cognitive impairment (MCI) and 71 AD dementia (DEM)] who completed 18 F‐florbetaben, 18 F‐flortaucipir PET and T1‐weighted MRI. Global cortical standardized uptake value ratios (SUVR) of 18 F‐florbetaben, temporal meta‐region‐of‐interest SUVR of 18 F‐flortaucipir and hippocampal atrophy of T1‐weighted MRI were used to define AT(N) classification. Longitudinal cognitive change was evaluated by repeated Mini‐Mental State Examination (MMSE) and Clinical Dementia Rating Sum of Boxes (CDR‐SB). Participants were categorized according to their A/T imaging biomarker, 18 F‐florbetaben PET positive/negative (A+/A‐) and 18 F‐flortaucipir PET positive/negative (T+/T‐) profiles. For measuring prognosis, we investigated the nursing care facility admission rate for all participants and the AD conversion rate for CU and MCI over 60 months. Result Participants were included CU (77/96 A‐T‐, 1/96 A‐T+, 11/96 A+T‐ and 7/96 A+T+), MCI (59/106 A‐T‐, 2/106 A‐T+, 18/106 A+T‐ and 27/106 A+T+) and DEM (20/71 A‐T‐, 1/71 A‐T+, 16/71 A+T‐ and 34/71 A+T+). Annual cognitive function change of all participants was correlated with A+ (MMSE: B=‐0.5944, p <0.000; CDR‐SB: B=0.6288, p <0.000), T+ (MMSE: ‐0.8187, p <0.000; CDR‐SB: B=0.7524, p <0.000), hippocampal atrophy (MMSE: B=‐0.3940, p <0.000; CDR‐SB: B=0.5577, p <0.000) and A+T+ compared with A‐T‐ (MMSE: B=‐0.8917, p <0.000; CDR‐SB: 0.8680, p <0.000, Figure 1). Admission rate of nursing care facility of all participants was higher with A+ (HR=2.37, p =0.026), T+ (HR=2.65, p =0.006) and A+T+ (HR=3.06, p=0.006). AD conversion rate in CU and MCI (n=202) was higher with A+ (HR=2.98, p=0.003), T+ (HR=3.19, p<0.000) and A+T+ (HR=3.897, p <0.000, Figure 2). Conclusion A/T imaging biomarkers have prognostic value for annual cognitive decline rate, anticipating admission rates to nursing care facility, and AD conversion rate.
Abstract Background Tau PET tracers have proven useful for diagnostic purposes, but their prognostic utility for predicting future cognitive changes over time is unclear. We aimed to examine the prognostic accuracy of [ 18 F]flortaucipir and [ 18 F]RO948 (tau) PET in individuals across the Alzheimer’s disease (AD) spectrum. Method We included 673 cognitively unimpaired individuals (CU, 277/673 amyloid‐β+), 443 participants with mild cognitive impairment (MCI, 279/443 amyloid‐β+) and 315 amyloid‐β+ participants with AD dementia. Amyloid‐β status was determined by PET and/or CSF. The participants underwent [ 18 F]flortaucipir (n=1135, discovery cohort) or [ 18 F]RO948 (n=296, replication cohort) PET, T1‐weighted MRI and repeated Mini‐Mental State Examination (MMSE). Baseline [ 18 F]flortaucipir/[ 18 F]RO948 PET standardized uptake value ratios (SUVR) within in a temporal region‐of‐interest (ROI)and an MRI‐based AD‐signature cortical thickness ROI were used to predict longitudinal changes of MMSE using linear mixed effect models. Additionally, we performed mediation analyses to test whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures, and examined whether age, sex and APOE genotype modified the association between baseline tau PET and cognitive change. Result Tau PET in a temporal ROI predicted changes in MMSE, and associations were stronger than for AD‐signature cortical thickness across all participants (R 2 : 0.34 vs 0.24, bootstrapped p‐value for difference: <0.001), in amyloid‐β+ MCI (R 2 : 0.27 vs 0.13, p<0.001) and in amyloid‐β+ CU (R 2 : 0.14 vs 0.04, p<0.001, Figure‐1). AD signature cortical thickness only modestly mediated the association between tau PET and MMSE scores over time in amyloid‐β+ AD dementia (34.2%[95%CI: 16.8%‐59.0%] of the total effect, p<0.001) and in amyloid‐β+ MCI (11.6%[0‐25.0%], p=0.044), but not in amyloid‐β+ CU (p=0.848, Figure‐2). Age (T=‐2.24, p=0.025), but not sex (T=0.95, p=0.341) or APOE genotype (T=1.32, p=0.188), modified the association between baseline tau PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels (Figure‐3). Most results were replicated in the [ 18 F]RO948 PET cohort. Conclusion Tau PET is a promising tool for predicting future cognitive change and could support the prognostic process in preclinical(i.e. amyloid‐β+ CU) and prodromal (i.e. amyloid‐β+ MCI) stages of Alzheimer’s disease.
Abstract Purpose This study aims to determine whether comparable target regions of interest (ROIs) and cut-offs can be used across [ 18 F]flortaucipir, [ 18 F]RO948, and [ 18 F]MK6240 tau positron emission tomography (PET) tracers for differential diagnosis of Alzheimer’s disease (AD) dementia vs either cognitively unimpaired (CU) individuals or non-AD neurodegenerative diseases. Methods A total of 1755 participants underwent tau PET using either [ 18 F]flortaucipir ( n = 975), [ 18 F]RO948 ( n = 493), or [ 18 F]MK6240 ( n = 287). SUVR values were calculated across four theory-driven ROIs and several tracer-specific data-driven (hierarchical clustering) regions of interest (ROIs). Diagnostic performance and cut-offs for ROIs were determined using receiver operating characteristic analyses and the Youden index, respectively. Results Comparable diagnostic performance (area under the receiver operating characteristic curve [AUC]) was observed between theory- and data-driven ROIs. The theory-defined temporal meta-ROI generally performed very well for all three tracers (AUCs: 0.926–0.996). An SUVR value of approximately 1.35 was a common threshold when using this ROI. Conclusion The temporal meta-ROI can be used for differential diagnosis of dementia patients with [ 18 F]flortaucipir, [ 18 F]RO948, and [ 18 F]MK6240 tau PET with high accuracy, and that using very similar cut-offs of around 1.35 SUVR. This ROI/SUVR cut-off can also be applied across tracers to define tau positivity.
The degree to which individuals cope with Alzheimer's disease (AD)-like tau pathology in terms of cognition (cognitive resilience, CR) and brain structure (brain resilience, BR) is unknown. We aimed to examine whether and which demographic (age, sex, education), genetic (APOEe4 status) and imaging (white matter hyperintensities [WMHs] and cortical atrophy) factors could explain inter-individual differences in CR and BR to tau pathology, as well as predict changes in global cognition over time. In 260 Aβ-positive patients with MCI/AD dementia (Table-1), we determined the amount of tau pathology across the whole cortex using [18F]flortaucipir-PET. We performed (separate) linear regression models between whole cortex [18F]flortaucipir uptake and MMSE (CRMMSE), delayed episodic memory recall (CRMEM) and category fluency (CRFLUENCY) scores, and used the standardized residuals as a measure of CR (Figure-1A). The same procedure was performed for whole cortex [18F]flortaucipir uptake versus cortical thickness to obtain a measure of BR (Figure-1B). Next, bivariable and multivariate linear regression models were conducted with age, sex, education, APOEe4 status, WMHs and cortical thickness (in CR models only) as predictors and CR and BR measures as dependent variables. We additionally performed linear mixed models to examine whether changes inMMSE scores over time differed as a function of a 4-level CR/BR variable. In multivariable models, higher global cortical thickness was associated with greater CRMMSE (β=0.23, p<0.001), CRMEM (β=0.16, p=0.028) and CRFLUENCY (β=0.27, p<0.001) to tau pathology (Table-2). Additionally, higher education was associated with greater CRMMSE (β=0.23, p<0.001), while APOEe4-positivity was associated with lower CRMEM (β=−0.17, p=0.013). Females (β=−0.15, p=0.022) and younger patients (β=−0.20, p=0.006) showed greater BR to tau pathology. Linear mixed models indicated a significant interaction time*CR/BR-status for MMSE (p<0.05, Figure-2), and showed the steepest slope for individuals with low CR and low BR (CR-/BR-) followed by CR+/BR+, CR+/BR-, and CR-/BR+.
Abstract Background The contribution of A/T/N neuroimaging biomarkers to impaired odor identification ability in the Alzheimer’s disease spectrum was investigated Method We analyzed data from 127 participants who completed Cross‐Cultural Smell Identification Test (CCSIT), brain magnetic resonance (MR) imaging, and 18 F‐flortaucipir and 18 F‐florbetaben positron emission tomography (PET) studies. We compared A/T/N neuroimaging biomarkers between normosmia and hyposmia groups, and performed correlation analysis between the biomarkers and CCSIT scores. Additionally, path analysis for odor identification ability was performed using cognitive function as a mediator. Result Individuals with hyposmia showed higher frequency of amyloid‐β (Aβ) positivity, and lower neuropsychological test performance than those with normosmia. After correction for covariates including total cognition scores, there was no difference in the Aβ or tau burden between the normosmia and hyposmia groups, and no correlation between CCSIT scores and Aβ or tau burden. Meanwhile, cortical volumes in the lateral and medial temporal cortices were smaller in the hyposmia group and decreased with the worsening of CCSIT scores. Path analysis showed that only neurodegeneration had a direct effect on odor identification, while Aβ and tau burden contributed to odor identification with the mediation of cognition. Conclusion In the Alzheimer’s disease spectrum, impaired odor identification ability may be attributable to neurodegeneration rather than the direct effect of Aβ or tau burden.
Odor identification ability may serve as an important diagnostic biomarker in Alzheimer's disease (AD). The aim of the study is to investigate the contribution of A/T/N neuroimaging biomarkers to impaired odor identification ability in the Alzheimer's disease spectrum. In 127 participants, we compared A/T/N neuroimaging biomarkers between normosmia and hyposmia groups, and performed correlation analysis between the biomarkers and Cross-Cultural Smell Identification Test (CCSIT) scores. Additionally, path analysis for odor identification ability was performed using cognitive function as a mediator. In between-group comparison, individuals with hyposmia showed higher frequency of amyloid-β (Aβ) positivity, and lower neuropsychological test performance than those with normosmia. After correction for covariates including total cognition scores, there was no difference in the Aβ or tau burden between the normosmia and hyposmia groups, and no correlation between CCSIT scores and Aβ or tau burden. Meanwhile, cortical volumes in the lateral and medial temporal cortices were smaller in the hyposmia group and decreased with the worsening of CCSIT scores. Path analysis showed that only neurodegeneration had a direct effect on odor identification, while Aβ and tau burden contributed to odor identification with the mediation of cognition. In the Alzheimer's disease spectrum, impaired odor identification ability may be attributable to neurodegeneration rather than the direct effect of Aβ or tau burden.
<b><i>Objective:</i></b> To define the significance of striatal cribriform state (SCS) observed in patients with primary progressive parkinsonism. <b><i>Methods:</i></b> We reviewed medical records and brain magnetic resonance imaging studies of 1,260 patients with primary progressive parkinsonism. We identified 23 patients with SCS and analyzed their clinical features. <b><i>Results</i></b>: All 23 patients had rapidly progressive parkinsonism predominated by postural instability and gait disturbance. Clinical features of 18 of the 23 patients were compatible with progressive supranuclear palsy (PSP); 2 patients were compatible with parkinsonian type multiple system atrophy; 2 patients were compatible with mixed clinical features of both; and 1 patient had PSP-like clinical features. <b><i>Conclusions:</i></b> Most parkinsonian patients with SCS present rapidly progressive parkinsonism predominated by postural instability and gait disturbance. SCS observed in patients with parkinsonism does not seem to be a coincidental finding associated with the generalized cerebrovascular process.
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