Davneet Minhas

The Centiloid Project: Standardizing quantitative amyloid plaque estimation by PET

Although amyloid imaging with PiB‐PET ([C‐11]Pittsburgh Compound‐B positron emission tomography), and now with F‐18‐labeled tracers, has produced remarkably consistent qualitative findings across a large number of centers, there has been considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention. In some cases this is as trivial as the choice of units, in some cases it is scanner dependent, and of course, different tracers yield different numbers. Our working group was formed to standardize quantitative amyloid imaging measures by scaling the outcome of each particular analysis method or tracer to a 0 to 100 scale, anchored by young controls (≤45 years) and typical Alzheimers disease patients. The units of this scale have been named “Centiloids.” Basically, we describe a “standard” method of analyzing PiB PET data and then a method for scaling any “nonstandard” method of PiB PET analysis (or any other tracer) to the Centiloid scale.

Modeling of Needle Steering via Duty-Cycled Spinning

As flexible bevel tip needles are inserted into tissue, a deflection force causes the needle to bend with a curvature dependent on relative stiffness and bevel angle. By constantly spinning the needle during insertion, the bevel angle is essentially negated and a straight trajectory can be achieved. Incorporating duty-cycled spinning during needle insertion provides proportional control of the curvature of the needle trajectory through tissue. This paper proposes a kinematic model for needle steering via duty-cycled spinning. Validation using experimental results is also presented.

Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study

BACKGROUND The biomarker model of Alzheimers disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimers disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed. METHODS For this prospective cohort study, carriers of autosomal dominant Alzheimers disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimers Disease Research Center every 1-2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using (11)C-Pittsburgh Compound-B PET, posterior cortical metabolism with (18)F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimers Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65-89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls). FINDINGS 16 people with mutations in PSEN1, PSEN2, or APP, aged 28-56 years, completed between two and eight assessments (a total of 83 assessments) over 2-11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6-11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline. INTERPRETATION Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimers disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimers disease-active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline-indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimers disease. FUNDING National Institutes of Health and Howard Hughes Medical Institute.

Percutaneous intracerebral navigation by duty-cycled spinning of flexible bevel-tipped needles.

BACKGROUND:Intracerebral drug delivery using surgically placed microcatheters is a growing area of interest for potential treatment of a wide variety of neurological diseases, including tumors, neurodegenerative disorders, trauma, epilepsy, and stroke. Current catheter placement techniques are limited to straight trajectories. The development of an inexpensive system for flexible percutaneous intracranial navigation may be of significant clinical benefit. OBJECTIVE:Utilizing duty-cycled spinning of a flexible bevel-tipped needle, the authors devised and tested a means of achieving nonlinear trajectories for the navigation of catheters in the brain, which may be applicable to a wide variety of neurological diseases. METHODS:Exploiting the bending tendency of bevel-tipped needles due to their asymmetry, the authors devised and tested a means of generating curvilinear trajectories by spinning a needle with a variable duty cycle (ie, in on-off fashion). The technique can be performed using image guidance, and trajectories can be adjusted intraoperatively via joystick. Fifty-eight navigation trials were performed during cadaver testing to demonstrate the efficacy of the needle-steering system and to test its precision. RESULTS:The needle-steering system achieved a target acquisition error of 2 ± 1 mm, while demonstrating the ability to reach multiple targets from one burr hole using trajectories of varying curvature. CONCLUSION:The accuracy of the needle-steering system was demonstrated in a cadaveric model. Future studies will determine the safety of the device in vivo.

Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals

IMPORTANCE Cerebral microbleeds (CMBs) are collections of blood breakdown products that are a common incidental finding in magnetic resonance imaging of elderly individuals. Cerebral microbleeds are associated with cognitive deficits, but the mechanism is unclear. Studies show that individuals with CMBs related to symptomatic cerebral amyloid angiopathy have abnormal vascular reactivity and cerebral blood flow (CBF), but, to our knowledge, abnormalities in cerebral blood flow have not been reported for healthy individuals with incidental CMBs. OBJECTIVE To evaluate the association of incidental CMBs with resting-state CBF, cerebral metabolism, cerebrovascular disease, β-amyloid (Aβ), and cognition. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study of 55 cognitively normal individuals with a mean (SD) age of 86.8 (2.7) years was conducted from May 1, 2010, to May 1, 2013, in an academic medical center in Pittsburgh; data analysis was performed between June 10, 2013, and April 9, 2015. INTERVENTIONS 3-Tesla magnetic resonance imaging was performed with susceptibility-weighted imaging or gradient-recalled echo to assess CMBs, arterial spin labeling for CBF, and T1- and T2-weighted imaging for atrophy, white matter hyperintensities, and infarcts. Positron emission tomography was conducted with fluorodeoxyglucose to measure cerebral metabolism and Pittsburgh compound B for fibrillar Aβ. Neuropsychological evaluation, including the Clinical Dementia Rating scale, was performed. MAIN OUTCOMES AND MEASURES Magnetic resonance images were rated for the presence and location of CMBs. Lobar CMBs were subclassified as cortical or subcortical. Measurements of CBF, metabolism, and Aβ were compared with the presence and number of CMBs with voxelwise and region-of-interest analyses. RESULTS The presence of cortical CMBs was associated with significantly reduced CBF in multiple regions on voxelwise and region-of-interest analyses (percentage difference in global CBF, -25.3%; P = .0003), with the largest reductions in the parietal cortex (-37.6%; P < .0001) and precuneus (-31.8%; P = .0006). Participants with any CMBs showed a nonsignificant trend toward reduced CBF. Participants with cortical CMBs had a significant association with greater prevalence of infarcts (24% vs 6%; P = .047) and demonstrated a trend to greater prevalence of deficits demonstrated on the Clinical Dementia Rating scale (45% vs 19%; P = .12). There was no difference in cortical amyloid (measured by Pittsburgh compound B positron emission tomography) between participants with and without CMBs (P = .60). CONCLUSIONS AND RELEVANCE In cognitively normal elderly individuals, incidental CMBs in cortical locations are associated with widespread reductions in resting-state CBF. Chronic hypoperfusion may put these people at risk for neuronal injury and neurodegeneration. Our results suggest that resting-state CBF is a marker of CMB-related small-vessel disease.

Cerebral perfusion alterations and cerebral amyloid in autosomal dominant Alzheimer disease

Objective: To evaluate alterations in cerebral blood flow (CBF) using arterial spin-labeled MRI in autosomal dominant Alzheimer disease (ADAD) mutation carriers (MCs) in relation to cerebral amyloid and compared with age-matched healthy controls. Background: Recent work has identified alterations in CBF in elderly subjects with mild cognitive impairment and Alzheimer dementia using MRI. However, similar studies are lacking in ADAD. Subjects with ADAD are generally free of significant vascular disease and offer the opportunity to measure CBF early in the pathologic process before significant symptom onset when unique markers might be identified. Methods: Fourteen MCs (presenilin-1 and amyloid beta precursor protein) (Clinical Dementia Rating [CDR] 0 = 9, CDR 0.5 = 4, CDR 1 = 1) and 50 controls underwent 3-tesla pulsed arterial spin-labeled MRI. SPM8 was used to test the effect of MC status at the voxel level on CBF before and after controlling for age and CDR. Results: MCs had decreased perfusion in the caudate and inferior striatum bilaterally even after controlling for age and CDR. In MCs, separate areas of decreased CBF were associated with increasing cerebral amyloid and to decreased performance of attention and executive function. Conclusions: Early CBF changes were identified in asymptomatic and mildly symptomatic subjects with ADAD, particularly in the anterior striatum. Furthermore, amyloid deposition was associated with decreased CBF in a number of regions including anterior and posterior cortical areas. Both amyloid and decreased CBF were associated with declines primarily in executive cognitive function.

Testing of neurosurgical needle steering via duty-cycled spinning in brain tissue in vitro

A technique for steering of flexible bevel-tipped needles through tissue, providing proportional control of trajectory curvature by means of duty-cycled rotation or spinning during insertion, has been presented previously, and tested in vitro in gelatin samples. The present paper presents the results of testing under more authentic conditions. Thirty-two needle insertions were performed in cadaver brain tissue. Needle insertion was controlled interactively by the surgeon, adjusting parameters intraoperatively as needed based on fluoroscope images acquired at intervals of 1–2 cm of insertion depth. The average target acquisition error was 1.80 ± 1.33 mm.

Dynamic PET imaging reveals heterogeneity of skeletal muscle insulin resistance.

PURPOSE Skeletal muscle insulin resistance (IR) often precedes hyperglycemia and type 2 diabetes. However, variability exists within different skeletal muscle types and can be influenced by 3 primary steps of control: glucose delivery, transport, and phosphorylation. We performed dynamic positron emission tomography imaging studies to determine the extent to which heterogeneity in muscle type and control of insulin action contribute to IR. METHODS Thirteen volunteers from normal weight to obese underwent dynamic positron emission tomography imaging of [15O]H2O, [11C]3-O-methylglucose, and [18F]fluorodeoxyglucose, measuring delivery, transport, and phosphorylation rates, respectively, in soleus and tibialis anterior muscle during a hyperinsulinemic-euglycemic clamp. Subjects were classified as insulin-sensitive (IS) or insulin-resistant (IR) based on the median systemic glucose infusion rate needed to maintain euglycemia. RESULTS In soleus, transport kinetic rates were significantly higher (P<.05) in IS (0.126±0.028 min(-1)) vs IR (0.051±0.008 min(-1)) subjects. These differences were not as evident in tibialis anterior. These differences were paralleled in overall insulin-stimulated tissue activity, higher in IS (0.017±0.001 mL·cm3·min(-1)) vs IR (0.011±0.002 mL·cm3·min(-1)) in soleus (P<.05), without significant differences in tibialis anterior. No significant differences were observed for either muscle in delivery or phosphorylation. Both muscle types displayed a control shift from an even distribution among the steps in IS to transport exerting greater control of systemic insulin sensitivity in IR. CONCLUSION Lower glucose transport rates are the major feature underlying IR preceding type 2 diabetes, although substantial heterogeneity in insulin action across muscle types highlight the complexity of skeletal muscle IR.

Reduced binding of Pittsburgh Compound-B in areas of white matter hyperintensities.

The amyloid imaging agent, Pittsburgh Compound-B, binds with high affinity to β-amyloid (Aβ) in the brain, and it is well established that PiB also shows non-specific retention in white matter (WM). However, little is known about retention of PiB in areas of white matter hyperintensities (WMH), abnormalities commonly seen in older adults. Further, it is hypothesized that WMH are related to both cognitive dysfunction and Aβ deposition. The goal of the present study was to explore PiB retention in both normal-appearing WM (NAWM) and WMH in a group of elderly, cognitively normal individuals. In a group of cognitively normal elderly (n = 64; 86.5 ± 2.6 years) two analyses were applied: (1) ROIs were placed over periventricular areas in which WMH caps are commonly seen on all subjects, regardless of WMH burden or size. (2) Subject-specific maps of NAWM and WMH were co-registered with the PiB-PET images and mean SUVR values were calculated in these NAWM and WMH maps. PiB retention was significantly reduced in the ROIs of subjects with high WMH compared to subjects with low WMH. Additionally, in subjects with high WMH, there was significantly lower PiB retention in subject-specific maps of WMH compared to NAWM, which was not observed in subjects with low WMH, likely because of the small size of WMH maps in this group. These data suggest that WM in areas of WMH binds PiB less effectively than does normal WM. Further exploration of this phenomenon may lead to insights about the molecular basis of the non-specific retention of amyloid tracers in white matter.

[F-18]AV-1451 PET IN NON-DEMENTED ADULTS WITH DOWN SYNDROME IS RELATED TO BOTH AMYLOID AND COGNITION

Background:Aging and neurodegeneration, including Alzheimer’s disease (AD), may involve many metabolism-associated processes, which in combination may render the brain more vulnerable to AD pathology. Our preliminary studies demonstrate that a decline in glucose metabolism, and especially its non-oxidative part (aerobic glycolysis or AG, a marker of metabolic functions involved in synaptic plasticity), in the aging brain is greatest in regions known to accumulate the most amyloid plaques in symptomatic AD, such as the precuneus. These data suggest substantial loss in metabolic brain reserve supporting synaptic plasticity and neuroprotection, and as a result, development of selective vulnerability to processes leading to AD pathology and cognitive decline. In this study, we evaluated AG and other metabolic and perfusion positron emission tomography (PET) measures in autosomal dominant AD (ADAD). Methods:Positron emission tomography (PET) using inhalation of O-CO and O-O2, and injection of O-water, and F-fluorodeoxyglucose (FDG) was performed in 13 mutation carriers (MC) (mean age 39611 yr, 11 cognitively normal) and 20 non-carriers (NC) (mean age 4267 yr) from families with known ADAD. AG, cerebral metabolic rate of glucose (CMRGlu) and oxygen (CMRO2), and cerebral blood flow (CBF) were calculated for the precuneus region defined using FreeSurfer software. All participants underwent amyloid Pittsburg Compound B (PIB) PET scan and 30 individuals had CSF Ab42 measured (INNOTEST) within 7 weeks of AG PET. Association between AG and AD biomarkers was evaluated with linear regression models, adjusted for age and gender. Results: AG and CMRGlu (but not CMRO2 or CBF) declined substantially with parental estimated year of onset in mutation carriers compared to non-carriers (F1,281⁄48.341, p1⁄40.007 for AG; and F1,281⁄46.504, p1⁄40.017 for CMRGlu; adjusted for gender). We demonstrated a significant difference between MC and NC in the relationship between AG and CSF Ab42 (F1,241⁄44.514, p1⁄40.044) and PIB binding (F1,271⁄45.110, p1⁄40.032): in MC, AG was positively correlated with CSF Ab42 and negatively to PIB deposition. Similar correlations were observed for CMRGlu, but not for CMRO2 or CBF. Conclusions: Our findings suggest that individuals with ADADmay undergo premature metabolic brain aging, which manifests as AG decline associated with CSF Ab42 decrease and brain amyloid plaque accumulation.