Search

Purpose To examine [18F]RO948 retention in FTD, sampling the underlying protein pathology heterogeneity. Methods A total of 61 individuals with FTD (n = 35), matched cases of AD (n = 13) and Aβ-negative cognitively unimpaired individuals (n = 13) underwent [18F]RO948PET and MRI. FTD included 21 behavioral variant FTD (bvFTD) cases, 11 symptomatic C9orf72 mutation carriers, one patient with non-genetic bvFTD-ALS, one individual with bvFTD due to a GRN mutation, and one due to a MAPT mutation (R406W). Tracer retention was examined using a region-of-interest and voxel-wise approaches. Two individuals (bvFTD due to C9orf72) underwent postmortem neuropathological examination. Tracer binding was additionally assessed in vitro using [3H]RO948 autoradiography in six separate cases. Results [18F]RO948 retention across ROIs was clearly lower than in AD and comparable to that in Aβ-negative cognitively unimpaired individuals. Only minor loci of tracer retention were seen in bvFTD; these did not overlap with the observed cortical atrophy in the cases, the expected pattern of atrophy, nor the expected or verified protein pathology distribution. Autoradiography analyses showed no specific [3H]RO948 binding. The R406W MAPT mutation carriers were clear exceptions with AD-like retention levels and specific in-vitro binding. Conclusion [18F]RO948 uptake is not significantly increased in the majority of FTD patients, with a clear exception being specific MAPT mutations.

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer’s disease neuropathological hallmarks (that is, amyloid-β plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T− and A−T− groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+ (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9–33.7), A+TMTL+ (HR = 14.6, 95% CI = 8.1–26.4) and A+T− (HR = 2.4, 95% CI = 1.4–4.3) groups versus the A−T− (reference) group. Both A+TMTL+ (HR = 6.0, 95% CI = 3.4–10.6) and A+TNEO-T+ (HR = 7.9, 95% CI = 4.7–13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T− group. Linear mixed-effect models indicated that the A+TNEO-T+ (β = −0.056 ± 0.005, T = −11.55, P +TMTL+ (β = −0.024 ± 0.005, T = −4.72, P +T− (β = −0.008 ± 0.002, T = −3.46, P −T− (reference) group (all P +TNEO-T+ (P +TMTL+ (P = 0.002) groups also progressed faster than the A+T− group. In summary, evidence of advanced Alzheimer’s disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3–5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.

ObjectiveThe clinical phenotype of the rare behavioural variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination.MethodsFor the tau PET study, seven amyloid-β positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a ‘typical’ memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7).ResultsIndividual regional W-scores ≥1.96 (corresponding to p0.05).ConclusionsBoth in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

The neuropathologic changes underlying Alzheimer disease (AD) start before overt cognitive symptoms arise, but it is not well-known how they relate to the first subtle cognitive changes. The objective for this study was to examine the independent associations of the AD hallmarks β-amyloid (Aβ), tau, and neurodegeneration with different cognitive domains in cognitively unimpaired (CU) individuals.In this cross-sectional study, CU participants from the prospective BioFINDER-2 study were included. All had CSF biomarkers (Aβ42 and phosphorylated tau [p-tau]181), MRI (cortical thickness of AD-susceptible regions), Aβ-PET (neocortical uptake), tau-PET (entorhinal uptake), and cognitive test data for memory, executive function, verbal function, and visuospatial function. Multivariable linear regression models were performed using either CSF Aβ42, p-tau181, and cortical thickness or Aβ-PET, tau-PET, and cortical thickness as predictors of cognitive function. The results were validated in an independent cohort (Alzheimer's Disease Neuroimaging Initiative [ADNI]).A total of 316 CU participants were included from the BioFINDER-2 study. Abnormal Aβ status was independently associated with the executive measure, regardless of modality (CSF Aβ42, β = 0.128,These findings suggest that Aβ is independently associated with worse performance on an executive measure but not with memory performance, which instead is associated with tau pathology. This may have implications for early preclinical AD screening and outcome measures in AD trials targeting Aβ pathology.

A combination of plasma phospho-tau (P-tau) and other accessible biomarkers may provide accurate prediction about the risk of developing Alzheimer’s disease (AD) dementia. We examined this in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) who were consecutively recruited in the BioFINDER study (n=340). The results were validated in SCD/MCI participants in the ADNI study (n=543). Plasma P-tau, plasma Aβ42/Aβ40, plasma neurofilament light, APOE genotype, brief cognitive tests and MRI (cortical thickness in AD-specific regions) were examined as predictors of progression to AD dementia primarily within 4 years. The accuracy was determined using the area under the ROC curve (AUC) from logistic regression models. Within 4 years, plasma P-tau217 predicted AD dementia accurately (AUC 0.83) in BioFINDER. A model of plasma P-tau217, memory, executive function, and APOE had higher accuracy (AUC 0.91, p

ObjectiveThe clinical phenotype of the rare behavioral variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using PET and postmortem examination.MethodsFor the tau PET study, seven amyloid-P positive bvAD patients underwent [18F]flortaucipir or [18F]RO948 PET. We converted tau PET uptake values into standardized (W-)scores, by adjusting for age, sex and MMSE in a “typical” memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed bvAD (n=8) and typical AD (n=7) patients.ResultsRegional W-scores ≥1.96 (corresponding to p0.05).ConclusionBoth in-vivo and ex-vivo, bvAD patients showed heterogeneous patterns of tau pathology. Since key regions involved in behavioral regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD.

Objective To investigate health-related quality of life (HrQoL) and adaptive behavior in young people with narcolepsy and stress among their parents. Methods In a cross-sectional exploratory quantitative study design, 37 young people with narcolepsy (8–20 years of age) and their parents were recruited. Thirty-one had post-H1N1 vaccination-related narcolepsy (PHV) and six had narcolepsy not related to PHV (nPHV). In addition, 40 age- and gender-matched controls (aged 5–20 years) were recruited. Results Thirty-one patients completed the generic HrQoL questionnaire KIDSCREEN and the disease-specific NARQoL-21. HrQoL was found to be significantly diminished in all domains in the PHV group (p = 0.001) and in the School/Concentration domain (p = 0.004) in the nPHV group compared to age- and gender-matched controls. The Adaptive Behavior Assessment System was completed by parents of 32 patients. They rated their children significantly lower in the General adaptive composite (p = 0.026) and the Conceptual (p = 0.050) and Social composite scores (p = 0.001) compared with reference data on healthy Swedish children's and young people's adaptive behavior. Parents of 36 patients filled in the 36-item short form of the Parenting Stress Index questionnaire. They rated significantly higher Total stress, Parent-child dysfunctional interaction, and Difficult child scores compared with parents of controls (p = 0.001, p = 0.005, p Conclusions Children with narcolepsy have diminished HrQoL compared with controls. Parents of children with narcolepsy experience impaired adaptive behavior in their children and high levels of parenting stress. Identifying the contributory factors is necessary, and early intervention is crucial in order to improve the HrQoL of these children and their families.

Objectives: To evaluate psychiatric comorbidity and the cognitive profile in children and adolescents with narcolepsy in western Sweden and the relationship of these problems to H1N1 vaccination. Patients: Thirty-eight patients were included in the study. Design: We performed a population-based, cross-sectional study to investigate psychiatric comorbidity using a test battery of semistructured interviews generating Diagnostic and Statistical Manual of Mental Disorders, 4th Edition diagnoses, including the Development and Well-Being Assessment and the attention deficit hyperactivity disorder rating scale. The Autism Spectrum Screening Questionnaire and the Positive and Negative Syndrome Scale were used to screen for autistic traits and psychotic symptoms, respectively. The cognitive assessments were made by a clinical psychologist using the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, the Wechsler Intelligence Scale for Children, Fourth Edition, or the Wechsler Adult Intelligence Scale, Fourth Edition. Measurements and Results: In the post-H1N1 vaccination (PHV) narcolepsy group (n = 31), 43% of patients had psychiatric comorbidity, 29% had attention deficit hyperactivity disorder (ADHD) inattentive type, 20% had major depression, 10% had general anxiety disorder, 7% had oppositional defiant disorder (ODD), 3% had pervasive developmental disorder not otherwise specified (i.e., atypical autism), and 3% had eating disorder not otherwise specified (anorectic type). In the non–post-H1N1 vaccination (nPHV) narcolepsy group, one of seven patients had ADHD, inattentive type and ODD. The most frequent psychiatric symptom was temper tantrums, which occurred in 94% of the patients in the PHV group and 71% of the patients in the nPHV narcolepsy group. The cognitive assessment profile was similar in both groups and showed normal results for mean full-scale IQ and perceptual speed but decreased verbal comprehension and working memory. Patients with psychiatric comorbidity had a significantly lower full-scale IQ compared to those without. Conclusion: Our study indicates increased psychiatric comorbidity in children and adolescents with narcolepsy. The identified cognitive profile with significantly lower verbal comprehension and working memory compared with the normal mean index could have important implications for social relations and schooling. The small numbers of patients with nPHV narcolepsy make it difficult to draw firm conclusions about the possible