Olof Strandberg

Increased basal ganglia binding of 18F‐AV‐1451 in patients with progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is difficult to diagnose accurately. The recently developed tau PET tracers may improve the diagnostic work‐up of PSP.

Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease

Objective: We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity. Methods: In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [18F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE. Results: Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [18F] flutemetamol tracer ( = 0.44, p = 0.02 and = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = −0.16, p = 0.02), independently of amyloid pathology. Conclusions: mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology.

Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity

It is not known exactly where amyloid-β (Aβ) fibrils begin to accumulate in individuals with Alzheimer’s disease (AD). Recently, we showed that abnormal levels of Aβ42 in cerebrospinal fluid (CSF) can be detected before abnormal amyloid can be detected using PET in individuals with preclinical AD. Using these approaches, here we identify the earliest preclinical AD stage in subjects from the ADNI and BioFINDER cohorts. We show that Aβ accumulation preferentially starts in the precuneus, medial orbitofrontal, and posterior cingulate cortices, i.e., several of the core regions of the default mode network (DMN). This early pattern of Aβ accumulation is already evident in individuals with normal Aβ42 in the CSF and normal amyloid PET who subsequently convert to having abnormal CSF Aβ42. The earliest Aβ accumulation is further associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism. Our results suggest that Aβ fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity.Abnormal levels of Aβ42 in the cerebrospinal fluid occur prior to a positive amyloid PET scan in the brain of individuals with Alzheimer’s disease and here the authors use this temporal pattern to identify individuals with very early stage AD. They show that Aβ fibrils start to accumulate in some of the regions of the default mode network and affect brain connectivity before neurodegeneration occurs.

18F‐AV‐1451 and CSF T‐tau and P‐tau as biomarkers in Alzheimer's disease

To elucidate the relationship between cerebrospinal fluid (CSF) total‐tau (T‐tau) and phosphorylated tau (P‐tau) with the tau PET ligand 18F‐AV‐1451 in Alzheimers disease (AD), we examined 30 cognitively healthy elderly (15 with preclinical AD), 14 prodromal AD, and 39 AD dementia patients. CSF T‐tau and P‐tau were highly correlated (R = 0.92, P < 0.001), but they were only moderately associated with retention of 18F‐AV‐1451, and mainly in demented AD patients. 18F‐AV‐1451, but not CSF T‐tau or P‐tau, was strongly associated with atrophy and cognitive impairment. CSF tau was increased in preclinical AD, despite normal 18F‐AV‐1451 retention. However, not all dementia AD patients exhibited increased CSF tau, even though 18F‐AV‐1451 retention was always increased at this disease stage. We conclude that CSF T‐tau and P‐tau mainly behave as biomarkers of “disease state”, since they appear to be increased in many cases of AD at all disease stages, already before the emergence of tau aggregates. In contrast, 18F‐AV‐1451 is a biomarker of “disease stage”, since it is increased in clinical stages of the disease, and is associated with brain atrophy and cognitive decline.

Modeling strategies for quantification of in vivo 18F-AV1451 binding in patients with tau pathology

Aggregation of hyperphosphorylated tau is a major hallmark of many neurodegenerative diseases, including Alzheimer disease (AD). In vivo imaging with PET may offer important insights into pathophysiologic mechanisms, diagnosis, and disease progression. We describe different strategies for quantification of 18F-AV-1451 (T807) tau binding, including models with blood sampling and noninvasive alternatives. Methods: Fifteen subjects (4 controls, 6 AD, 3 progressive supranuclear palsy, 2 cortico basal syndrome) underwent 180-min PET with 18F-AV-1451 and arterial blood sampling. Modeling with arterial input functions included 1-, 2-, and 3-tissue-compartment models and the Logan plot. Using the cerebellum as reference region, we applied the simplified reference tissue model 2 and Logan reference plot. Finally, simplified outcome measures were calculated as ratio, with reference to cerebellar concentrations (SUV ratio [SUVR]) and SUVs. Results: Tissue compartment models were not able to describe the kinetics of 18F-AV-1451, with poor fits in 33%–53% of cortical regions and 80% in subcortical areas. In contrast, the Logan plot showed excellent fits and parameter variance (total volume of distribution SE < 5%). Compared with the 180-min arterial-based Logan model, strong agreement was obtained for the Logan reference plot also for a reduced scan time of 100 min (R2 = 0.91) and SUVR 100–120 min (R2 = 0.94), with 80–100 min already representing a reasonable compromise between duration and accuracy (R2 = 0.93). Time–activity curves and kinetic parameters were equal for cortical regions and the cerebellum in control subjects but different in the putamen. Cerebellar total volumes of distribution were higher in controls than patients. For these methods, increased cortical binding was observed for AD patients and to some extent for cortico basal syndrome, but not progressive supranuclear palsy. Conclusion: The Logan plot provided the best estimate of tau binding using arterial input functions. Assuming that the cerebellum is a valid reference region, simplified methods seem to provide robust alternatives for quantification, such as the Logan reference plot with 100-min scan time. Furthermore, SUVRs between target and cerebellar activities obtained from an 80- to 100-min static scan offer promising potential for clinical routine application.

Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer's disease

&NA; Patients with Alzheimers disease can present with different clinical phenotypes. Individuals with late‐onset Alzheimers disease (>65 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early‐onset Alzheimers disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early‐onset Alzheimers disease, 21 with late‐onset Alzheimers disease, three with prodromal early‐onset Alzheimers disease and 13 with prodromal late‐onset Alzheimers disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F‐AV‐1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early‐ and late‐onset Alzheimers disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F‐AV‐1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early‐onset Alzheimers disease with controls resulted in significantly higher 18F‐AV‐1451 retention throughout the neocortex, while comparing healthy controls with late‐onset Alzheimers disease patients yielded a distinct pattern of higher 18F‐AV‐1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early‐onset Alzheimers disease group exhibited greater uptake than the late‐onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimers disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimers disease.

Comparing18F-AV-1451 with CSF t-tau and p-tau for diagnosis of Alzheimer disease

Objective To compare PET imaging of tau pathology with CSF measurements (total tau [t-tau] and phosphorylated tau [p-tau]) in terms of diagnostic performance for Alzheimer disease (AD). Methods We compared t-tau and p-tau and 18F-AV-1451 in 30 controls, 14 patients with prodromal AD, and 39 patients with Alzheimer dementia, recruited from the Swedish BioFINDER study. All patients with AD (prodromal and dementia) were screened for amyloid positivity using CSF β-amyloid 42. Retention of 18F-AV-1451 was measured in a priori specified regions, selected for known associations with tau pathology in AD. Results Retention of 18F-AV-1451 was markedly elevated in Alzheimer dementia and moderately elevated in prodromal AD. CSF t-tau and p-tau was increased to similar levels in both AD dementia and prodromal AD. 18F-AV-1451 had very good diagnostic performance for Alzheimer dementia (area under the receiver operating characteristic curve [AUROC] ∼1.000), and was significantly better than t-tau (0.876), p-tau (0.890), hippocampal volume (0.824), and temporal cortical thickness (0.860). For prodromal AD, there were no significant AUROC differences between CSF tau and 18F-AV-1451 measures (0.836–0.939), but MRI measures had lower AUROCs (0.652–0.769). Conclusions CSF tau and 18F-AV-1451 have equal performance in early clinical stages of AD, but 18F-AV-1451 is superior in the dementia stage, and exhibits close to perfect diagnostic performance for mild to moderate AD. Classification of evidence This study provides Class III evidence that CSF tau and 18F-AV-1451 PET have similar performance in identifying early AD, and that 18F-AV-1451 PET is superior to CSF tau in identifying mild to moderate AD.

Discriminative Accuracy of [18F]flortaucipir Positron Emission Tomography for Alzheimer Disease vs Other Neurodegenerative Disorders

Importance The positron emission tomography (PET) tracer [18F]flortaucipir allows in vivo quantification of paired helical filament tau, a core neuropathological feature of Alzheimer disease (AD), but its diagnostic utility is unclear. Objective To examine the discriminative accuracy of [18F]flortaucipir for AD vs non-AD neurodegenerative disorders. Design, Setting, and Participants In this cross-sectional study, 719 participants were recruited from 3 dementia centers in South Korea, Sweden, and the United States between June 2014 and November 2017 (160 cognitively normal controls, 126 patients with mild cognitive impairment [MCI], of whom 65.9% were amyloid-&bgr; [A&bgr;] positive [ie, MCI due to AD], 179 patients with AD dementia, and 254 patients with various non-AD neurodegenerative disorders). Exposures The index test was the [18F]flortaucipir PET standardized uptake value ratio (SUVR) in 5 predefined regions of interest (ROIs). Cut points for tau positivity were determined using the mean +2 SDs observed in controls and Youden Index for the contrast AD dementia vs controls. Main Outcomes and Measures The reference standard was the clinical diagnosis determined at the specialized memory centers. In the primary analysis, the discriminative accuracy (ie, sensitivity and specificity) of [18F]flortaucipir was examined for AD dementia vs all non-AD neurodegenerative disorders. In secondary analyses, the area under the curve (AUC) of [18F]flortaucipir SUVR was compared with 3 established magnetic resonance imaging measures (hippocampal volumes and AD signature and whole-brain cortical thickness), and sensitivity and specificity of [18F]flortaucipir in MCI due to AD vs non-AD neurodegenerative disorders were determined. Results Among 719 participants, the overall mean (SD) age was 68.8 (9.2) years and 48.4% were male. The proportions of patients who were amyloid-&bgr; positive were 26.3%, 65.9%, 100%, and 23.8% among cognitively normal controls, patients with MCI, patients with AD dementia, and patients with non-AD neurodegenerative disorders, respectively. [18F]flortaucipir uptake in the medial-basal and lateral temporal cortex showed 89.9% (95% CI, 84.6%-93.9%) sensitivity and 90.6% (95% CI, 86.3%-93.9%) specificity using the threshold based on controls (SUVR, 1.34), and 96.8% (95% CI, 92.0%-99.1%) sensitivity and 87.9% (95% CI, 81.9%-92.4%) specificity using the Youden Index–derived cutoff (SUVR, 1.27) for distinguishing AD dementia from all non-AD neurodegenerative disorders. The AUCs for all 5 [18F]flortaucipir ROIs were higher (AUC range, 0.92-0.95) compared with the 3 volumetric MRI measures (AUC range, 0.63-0.75; all ROIs P < .001). Diagnostic performance of the 5 [18F]flortaucipir ROIs were lower in MCI due to AD (AUC range, 0.75-0.84). Conclusions and Relevance Among patients with established diagnoses at a memory disorder clinic, [18F]flortaucipir PET was able to discriminate AD from other neurodegenerative diseases. The accuracy and potential utility of this test in patient care require further research in clinically more representative populations.

Effects of APOE ε4 on neuroimaging, cerebrospinal fluid biomarkers, and cognition in prodromal Alzheimer's disease

Apolipoprotein (APOE) ε4 is a major genetic risk factor for Alzheimers disease (AD), but its importance for the clinical and biological heterogeneity in AD is unclear, particularly at the prodromal stage. We analyzed 151 prodromal AD patients (44 APOE ε4-negative and 107 APOE ε4-positive) from the BioFINDER study. We tested cognition, 18F-flutemetamol β-amyloid (Aβ) positron emission tomography, cerebrospinal fluid biomarkers of Aβ, tau and neurodegeneration, and magnetic resonance imaging of white matter pathology and brain structure. Despite having similar cortical Aβ-load and baseline global cognition (mini mental state examination), APOE ε4-negative prodromal AD had more nonamnestic cognitive impairment, higher cerebrospinal fluid levels of Aβ-peptides and neuronal injury biomarkers, more white matter pathology, more cortical atrophy, and faster decline of mini mental state examination, compared to APOE ε4-positive prodromal AD. The absence of APOE ε4 is associated with an atypical phenotype of prodromal AD. This suggests that APOE ε4 may impact both the diagnostics of AD in early stages and potentially also effects of disease-modifying treatments.

ASSOCIATIONS BETWEEN TAU, Aβ AND CORTICAL THICKNESS WITH COGNITION IN ALZHEIMER’S DISEASE

five novel risk loci for LOAD: NICN1 (p1⁄42.2E-07), RAB43 (p1⁄42.0E-06), VKORC1 (p1⁄43.5E-09), HPR (p1⁄43.0E-07), and PARD6G (p1⁄43.6E-07). Our analysis also highlighted LIMS2 (p1⁄49.4E-12) near BIN1, IL10 (p1⁄43.7E-07) which is 700kb upstream of CR1, and two novel genes ADRA1A (p1⁄41.3E-09) and EXTL3 (p1⁄45.1E-12) at the CLU-PTK2B locus. Conclusions: Cross-tissue transcriptome-wide association analysis identified multiple novel loci for LOAD and suggested novel risk genes at known risk loci. Many of our newly identified genes have been implicated in AD pathophysiology in prior studies. Several genes, including IL10 and ADRA1A, also have therapeutic potential to improve neurodegeneration. These results provide insights into the genetic basis of LOAD and may guide functional studies in the future.