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1.  A Hand-Held Beta Imaging Probe for FDG 
Annals of nuclear medicine  2012;27(3):203-208.
Objectives
Advances in radiopharmaceuticals and clinical understanding have escalated the use of intraoperative gamma probes in surgery. However, most probes on the market are non-imaging gamma probes that suffer from the lack of ancillary information of the surveyed tissue area. We have developed a novel, hand-held digital Imaging Beta Probe™ (IBP™) to be used in surgery in conjunction with beta-emitting radiopharmaceuticals such as 18FDG, 131I and 32P for real-time imaging of a surveyed area with higher spatial resolution and sensitivity and greater convenience than existing instruments.
Methods
We describe the design and validation of a hand-held beta probe intended to be used as a visual mapping device to locate and confirm excision of 18FDG-avid primary tumors and metastases in an animal model.
Results
We have demonstrated a device which can generate beta images from 18FDG avid lesions in an animal model.
Conclusions
It is feasible to image beta irradiation in animal models of cancer given 18FDG. This technology may be applied to clinical mapping of tumors and/or their metastases in the operating room. Visual image depiction of malignancy may aid the surgeon in localization and excision of lesions of interest.
doi:10.1007/s12149-012-0672-6
PMCID: PMC3622128  PMID: 23229110
18FDG; PET; 131I; Imaging; Beta Probe
2.  Brain Injury Biomarkers Are Not Dependent on β-amyloid in Normal Elderly 
Annals of neurology  2013;73(4):472-480.
Background
The new criteria for preclinical Alzheimer’s Disease (AD) proposed 3 stages: abnormal levels of β-amyloid (stage 1); stage 1 plus evidence of brain injury (stage 2); and stage 2 plus subtle cognitive changes (stage 3). However, a large group of subjects with normal β-amyloid biomarkers have evidence of brain injury; we labeled them as “suspected non-Alzheimer pathway” (sNAP) group. The characteristics of the sNAP group are poorly understood.
Methods
Using the preclinical AD classification, 430 cognitively normal subjects from the Mayo Clinic Study of Aging who underwent brain MR, 18fluorodeoxyglucose (FDG) and Pittsburgh compound B (PiB) positron emission tomography (PET) were evaluated with FDG PET regional volumetrics, MR regional brain volumetrics, white matter hyperintensity (WMH) volume and number of infarcts. We examined cross-sectional associations across AD preclinical stages, those with all biomarkers normal, and the sNAP group.
Results
The sNAP group had a lower proportion (14%) with APOE ε4 genotype than the preclinical AD stages 2 + 3. The sNAP group did not show any group differences compared to stages 2 + 3 of the preclinical AD group on measures of FDG PET regional hypometabolism, MR regional brain volume loss, cerebrovascular imaging lesions, vascular risk factors, imaging changes associated with α-synucleinopathy or physical findings of parkinsonism.
Conclusions
Cognitively normal persons with brain injury biomarker abnormalities, with or without abnormal levels of β-amyloid, were indistinguishable on a variety of imaging markers, clinical features and risk factors. The initial appearance of brain injury biomarkers that occurs in cognitively normal persons with preclinical AD may not depend on β-amyloidosis.
doi:10.1002/ana.23816
PMCID: PMC3660408  PMID: 23424032
Alzheimer’s disease; PET imaging; MR imaging; Epidemiology
3.  Multimodal Nanoprobes to target cerebrovascular amyloid in Alzheimer’s disease brain 
Biomaterials  2013;35(6):1967-1976.
Cerebral amyloid angiopathy (CAA) results from the accumulation of Aβ proteins primarily within the media and adventitia of small arteries and capillaries of the cortex and leptomeninges. CAA affects a majority of Alzheimer’s disease (AD) patients and is associated with a rapid decline in cognitive reserve. Unfortunately, there is no pre-mortem diagnosis available for CAA. Furthermore, treatment options are few and relatively ineffective. To combat this issue, we have designed nanovehicles (nanoparticles-IgG4.1) capable of targeting cerebrovascular amyloid (CVA) and serving as early diagnostic and therapeutic agents. These nanovehicles were loaded with Gadolinium (Gd) based (Magnevist®) magnetic resonance imaging contrast agents or single photon emission computed tomography (SPECT) agents, such as 125I. In addition, the nanovehicles carry either anti-inflammatory and anti-amyloidogenic agents such as curcumin or immunosuppressants such as dexamethasone, which were previously shown to reduce cerebrovascular inflammation. Owing to the anti-amyloid antibody (IgG4.1) grafted on the surface, the nanovehicles are capable of specifically targeting CVA deposits. The nanovehicles effectively marginate from the blood flow to the vascular wall as determined by using quartz crystal microbalance with dissipation monitoring (QCM-D) technology. They demonstrate excellent distribution to the brain vasculature and target CVA, thus providing MRI and SPECT contrast specific to the CVA in the brain. In addition, they also display the potential to carry therapeutic agents to reduce cerebrovascular inflammation associated with CAA, which is believed to trigger hemorrhage in CAA patients.
doi:10.1016/j.biomaterials.2013.10.075
PMCID: PMC3970424  PMID: 24331706
Cerebrovascular amyloid (CVA); Brain targeting; Alzheimer’s disease (AD); Nanovehicles; Magnetic resonance imaging (MRI); Single photon emission computed; tomography (SPECT)
4.  Brain β-amyloid load approaches a plateau 
Neurology  2013;80(10):890-896.
Objective:
To model the temporal trajectory of β-amyloid accumulation using serial amyloid PET imaging.
Methods:
Participants, aged 70–92 years, were enrolled in either the Mayo Clinic Study of Aging (n = 246) or the Mayo Alzheimer's Disease Research Center (n = 14). All underwent 2 or more serial amyloid PET examinations. There were 205 participants classified as cognitively normal and 55 as cognitively impaired (47 mild cognitive impairment and 8 Alzheimer dementia). We measured baseline amyloid PET-relative standardized uptake values (SUVR) and, for each participant, estimated a slope representing their annual amyloid accumulation rate. We then fit regression models to predict the rate of amyloid accumulation given baseline amyloid SUVR, and evaluated age, sex, clinical group, and APOE as covariates. Finally, we integrated the amyloid accumulation rate vs baseline amyloid PET SUVR association to an amyloid PET SUVR vs time association.
Results:
Rates of amyloid accumulation were low at low baseline SUVR. Rates increased to a maximum at baseline SUVR around 2.0, above which rates declined—reaching zero at baseline SUVR above 2.7. The rate of amyloid accumulation as a function of baseline SUVR had an inverted U shape. Integration produced a sigmoid curve relating amyloid PET SUVR to time. The average estimated time required to travel from an SUVR of 1.5–2.5 is approximately 15 years.
Conclusion:
This roughly 15-year interval where the slope of the amyloid SUVR vs time curve is greatest and roughly linear represents a large therapeutic window for secondary preventive interventions.
doi:10.1212/WNL.0b013e3182840bbe
PMCID: PMC3653215  PMID: 23446680
5.  USING FLUORODEOXYTHYMIDINE TO MONITOR ANTI-EGFR INHIBITOR THERAPY IN SQUAMOUS CELL CARCINOMA XENOGRAFTS 
Head & neck  2008;30(6):790-799.
Background
3′-18F-fluoro-3′-deoxy-fluorothymidine (18F-FLT), a nucleoside analog, could monitor effects of molecularly targeted therapeutics on tumor proliferation.
Methods
We tested whether 18F-FLT positron emission tomography (PET) uptake changes are associated with antitumor effects of erlotinib in A431 xenografts or cetuximab in SCC1 xenografts.
Results
Compared with pretreatment FLT PET scans, 3 days of erlotinib in A431 reduced the standardized uptake value (SUV) by 18%, whereas placebo increased SUV by 1% (p = .005). One week of cetuximab in SCC1 reduced SUV by 62%, whereas placebo reduced SUV by 16% (p = .005). FLT uptake suppression following anti–epidermal growth factor receptor (EGFR) treatment was associated with reduced tumor thymidine kinase-1 (TK1) activity. In vitro TK1 knockdown studies confirmed the importance of TK1 activity on intracellular FLT accumulation suppression.
Conclusions
18F-FLT PET imaging detects tumor responses to EGFR-inhibitors within days of starting therapy. This technique may identify patients likely to benefit from EGFR-inhibitors early in their treatment course.
doi:10.1002/hed.20770
PMCID: PMC3942889  PMID: 18286491
fluorodeoxythymidine (FLT); anti-EGFR inhibitor therapy; squamous cell carcinoma xenografts; cetuximab; erlotinib
6.  Elevated occipital β-amyloid deposition is associated with widespread cognitive impairment in logopenic progressive aphasia 
Background
Most subjects with logopenic primary progressive aphasia (lvPPA) have beta-amyloid (Aβ) deposition on Pittsburgh Compound B PET (PiB-PET), usually affecting prefrontal and temporoparietal cortices, with less occipital involvement.
Objectives
To assess clinical and imaging features in lvPPA subjects with unusual topographic patterns of Aβ deposition with highest uptake in occipital lobe.
Methods
Thirty-three lvPPA subjects with Aβ deposition on PiB-PET were included in this case-control study. Line-plots of regional PiB uptake were created, including frontal, temporal, parietal and occipital regions, for each subject. Subjects in which the line sloped downwards in occipital lobe (lvPPA-low), representing low uptake, were separated from those where the line sloped upwards in occipital lobe (lvPPA-high), representing unusually high occipital uptake compared to other regions. Clinical variables, atrophy on MRI, hypometabolism on F18-fluorodeoxyglucose PET, and presence and distribution of microbleeds and white matter hyperintensities (WMH) were assessed.
Results
Seventeen subjects (52%) were classified as lvPPA-high. Mean occipital PiB uptake in lvPPA-high was higher than all other regions, and higher than all regions in lvPPA-low. The lvPPA-high subjects performed more poorly on cognitive testing, including executive and visuospatial testing, but the two groups did not differ in aphasia severity. Proportion of microbleeds and WMH was higher in lvPPA-high than lvPPA-low. Parietal hypometabolism was greater in lvPPA-high than lvPPA-low.
Conclusions
Unusually high occipital Aβ deposition is associated with widespread cognitive impairment and different imaging findings in lvPPA. These findings help explain clinical heterogeneity in lvPPA, and suggest that Aβ influences severity of overall cognitive impairment but not aphasia.
doi:10.1136/jnnp-2013-305628
PMCID: PMC3920541  PMID: 23946416
7.  Selective Worsening of Brain Injury Biomarker Abnormalities in Cognitively Normal Elderly with β-amyloidosis 
JAMA neurology  2013;70(8):10.1001/jamaneurol.2013.182.
Importance
The appearance of β-amyloidosis and brain injury biomarkers in cognitively normal (CN) persons is thought to define risk for the future development of cognitive impairment due to Alzheimer’s disease (AD), but their interaction is poorly understood.
Objective
To test the hypothesis that the joint presence of β-amyloidosis and brain injury biomarkers would lead to more rapid neurodegeneration.
Design
Longitudinal Cohort Study
Setting
Population-based Mayo Clinic Study of Aging.
Participants
191 CN persons (median age 77, range 71–93) in the Mayo Clinic Study of Aging who underwent MR, FDG PET and PiB PET imaging at least twice 15 months apart. Subjects were grouped according to the recommendations of the NIA-AA Preclinical AD criteria, based on the presence of β-amyloidosis, defined as a PiB PET SUVr >1.5, alone (Stage 1) or with brain injury (stage 2+3), defined as hippocampal atrophy or FDG hypometabolism. We also studied a group of MCI (n=17) and dementia (n=9) patients from the Mayo Clinic Study of Aging or the Mayo Alzheimer Center with similar follow-up times who had had comparable imaging and who all had PiB PET SUVr >1.5.
Main Outcome Measures
Rate of change of cortical volume on volumetric MR scans and rate of change of glucose metabolism on FDG PET scans.
Results
There were 25 CN subjects with both high PiB retention and low hippocampal volume or FDG hypometabolism at baseline (Preclinical AD stages 2+3). On follow-up scans, the Preclinical AD stages 2+3 subjects had greater loss of medial temporal lobe volume and greater glucose hypometabolism in the medial temporal lobe compared to other CN groups. The changes were similar to the cognitively impaired participants. Extra-temporal regions did not show similar changes.
Conclusions
Higher rates of medial temporal neurodegeneration occurred in CN individuals who, on their initial scans, had abnormal levels of both β-amyloid and brain injury biomarkers.
doi:10.1001/jamaneurol.2013.182
PMCID: PMC3884555  PMID: 23797806
Alzheimer’s disease; PET imaging; MR imaging; Epidemiology
8.  The role of LAT1 in 18F-DOPA uptake in malignant gliomas 
Journal of neuro-oncology  2012;111(1):11-18.
Positron emission tomography (PET) imaging with the amino acid tracer 6-18F-fluoro-l-3,4-dihydroxy-phenylalanine (18F-DOPA) may provide better spatial and functional information in human gliomas than CT or MRI alone. The l-type amino acid transporter 1 (LAT1) is responsible for membrane transport of large neutral amino acids in normal cells. This study assessed the relationship between LAT1 expression and 18F-DOPA uptake in human astrocytomas. Endogenous LAT1 expression was measured in established glioblastoma (GBM) cell lines and primary GBM xenografts using Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Uptake of 18F-DOPA was approximated in vitro using 3H-l-DOPA as an analog. Uptake of 3H-l-DOPA was assessed in cells expressing LAT1 shRNA or LAT1 siRNA and compared to non-targeted (NT) control shRNA or siRNA sequences, respectively. To demonstrate the clinical relevance of these findings, LAT1 immunofluorescence staining was compared with corresponding regions of 18F-DOPA PET uptake in patients with newly diagnosed astrocytomas. LAT1 mRNA and protein expression varies in GBM, and the extent of 3H-l-DOPA uptake was positively correlated with endogenous LAT1 expression. Stable shRNA-mediated LAT1 knockdown in T98 and GBM28 reduced 3H-l-DOPA uptake relative to NT shRNA by 57 (P < 0.0001) and 52 % (P < 0.001), respectively. Transient siRNA-mediated LAT1 knockdown in T98 reduced 3H-l-DOPA uptake relative to NT siRNA up to 68 % (P < 0.01). In clinical samples, LAT1 expression positively correlated with 18F-DOPA PET uptake (P = 0.04). Expression of LAT1 is strongly associated with 3H-l-DOPA uptake in vitro and 18F-DOPA uptake in patient biopsy samples. These results define LAT1 as a key determinant of 18F-DOPA accumulation in GBM.
doi:10.1007/s11060-012-0986-1
PMCID: PMC3907171  PMID: 23086431
18F-DOPA PET/CT; Glioma; Glioblastoma; Amino acid transport
9.  Micro-computed tomography and nuclear magnetic resonance imaging for noninvasive, live-mouse cholangiography 
The cholangiopathies are a diverse group of biliary tract disorders, many of which lack effective treatment. Murine models are an important tool for studying their pathogenesis, but existing noninvasive methods for assessing biliary disease in vivo are not optimal. Here we report our experience with using micro-computed tomography (microCT) and nuclear magnetic resonance (MR) imaging to develop a technique for live-mouse cholangiography. Using mdr2 knockout (mdr2KO, a model for primary sclerosing cholangitis (PSC)), bile duct-ligated (BDL), and normal mice, we performed in vivo: (1) microCT on a Siemens Inveon PET/CT scanner and (2) MR on a Bruker Avance 16.4 T spectrometer, using Turbo Rapid Acquisition with Relaxation Enhancement, IntraGate Fast Low Angle Shot, and Half-Fourier Acquisition Single-shot Turbo Spin Echo methods. Anesthesia was with 1.5–2.5% isoflurane. Scans were performed with and without contrast agents (iodipamide meglumine (microCT), gadoxetate disodium (MR)). Dissection and liver histology were performed for validation. With microCT, only the gallbladder and extrahepatic bile ducts were visualized despite attempts to optimize timing, route, and dose of contrast. With MR, the gallbladder, extra-, and intrahepatic bile ducts were well-visualized in mdr2KO mice; the cholangiographic appearance was similar to that of PSC (eg, multifocal strictures) and could be improved with contrast administration. In BDL mice, MR revealed cholangiographically distinct progressive dilation of the biliary tree without ductal irregularity. In normal mice, MR allowed visualization of the gallbladder and extrahepatic ducts, but only marginal visualization of the diminutive intrahepatic ducts. One mouse died during microCT and MR imaging, respectively. Both microCT and MR scans could be obtained in ≤ 20min. We, therefore, demonstrate that MR cholangiography can be a useful tool for longitudinal studies of the biliary tree in live mice, whereas microCT yields suboptimal duct visualization despite requiring contrast administration. These findings support further development and application of MR cholangiography to the study of mouse models of PSC and other cholangiopathies.
doi:10.1038/labinvest.2013.52
PMCID: PMC3875307  PMID: 23588707
animal models; biliary tract diseases; live-animal imaging; magnetic resonance cholangiopancreatography; primary sclerosing cholangitis; strictures
10.  Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity 
Neurology  2013;81(20):1732-1740.
Objective:
To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity.
Methods:
Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n = 207). Twelve subjects with Alzheimer disease dementia were included for comparison.
Results:
Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline.
Conclusions:
The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both “amyloid-first” and “neurodegeneration-first” biomarker profile pathways to preclinical AD exist.
doi:10.1212/01.wnl.0000435556.21319.e4
PMCID: PMC3821718  PMID: 24132377
11.  Effect of Lifestyle Activities on AD Biomarkers and Cognition 
Annals of neurology  2012;72(5):730-738.
Objectives
To investigate the effect of intellectual and physical activity on biomarkers of Alzheimer’s disease (AD) pathophysiology and cognition in a non-demented elderly population. The biomarkers evaluated were brain Aβ-amyloid load via PIB-PET, neuronal dysfunction via FDG-PET and neurodegeneration via Structural-MRI.
Methods
We studied 515 non-demented (428 cognitively normal and 87 MCI) participants in the population based Mayo Clinic Study of Aging who completed a 3T MRI, PET scans, APOE genotype, had lifestyle activity measures and cognition data available. The imaging measures computed were global PiB-PET uptake; global FDG-PET and MRI based hippocampal volume. We consolidated activity variables into lifetime intellectual, current intellectual and current physical activities. We used a global cognitive Z-score as a measure of cognition. We applied two independent methods – partial correlation analysis adjusted for age and gender and path analysis using structural equations to evaluate the associations between lifestyle activities, imaging biomarkers and global cognition.
Results
None of the lifestyle variables correlated with the biomarkers and the path associations between lifestyle variables and biomarkers were not significant (p>0.05). On the other hand, all the biomarkers were correlated with global cognitive Z-score (p<0.05) and the path associations between (lifetime and current) intellectual activities and global Z-score were significant (p<0.01).
Interpretation
Intellectual and physical activity lifestyle factors were not associated with AD biomarkers but intellectual lifestyle factors explained variability in the cognitive performance in this non-demented population. This study provides evidence that lifestyle activities may delay the onset of dementia but do not significantly influence the expression of AD pathophysiology.
doi:10.1002/ana.23665
PMCID: PMC3539211  PMID: 23280791
Alzheimer’s disease; Imaging biomarkers; Lifestyle Activities
12.  Indicators of amyloid burden in a population-based study of cognitively normal elderly 
Neurology  2012;79(15):1570-1577.
Objectives:
Secondary prevention trials in subjects with preclinical Alzheimer disease may require documentation of brain amyloidosis. The identification of inexpensive and noninvasive screening variables that can identify individuals who have significant amyloid accumulation would reduce screening costs.
Methods:
A total of 483 cognitively normal (CN) individuals, aged 70–92 years, from the population-based Mayo Clinic Study of Aging, underwent Pittsburgh compound B (PiB)–PET imaging. Logistic regression determined whether age, sex, APOE genotype, family history, or cognitive performance was associated with odds of a PiB retention ratio >1.4 and >1.5. Area under the receiver operating characteristic curve (AUROC) evaluated the discrimination between PiB-positive and -negative subjects. For each characteristic, we determined the number needed to screen in each age group (70–79 and 80–89) to identify 100 participants with PiB >1.4 or >1.5.
Results:
A total of 211 (44%) individuals had PiB >1.4 and 151 (31%) >1.5. In univariate and multivariate models, discrimination was modest (AUROC ∼0.6–0.7). Multivariately, age and APOE best predicted odds of PiB >1.4 and >1.5. Subjective memory complaints were similar to cognitive test performance in predicting PiB >1.5. Indicators of PiB positivity varied with age. Screening APOE ε4 carriers alone reduced the number needed to screen to enroll 100 subjects with PIB >1.5 by 48% in persons aged 70–79 and 33% in those aged 80–89.
Conclusions:
Age and APOE genotype are useful predictors of the likelihood of significant amyloid accumulation, but discrimination is modest. Nonetheless, these results suggest that inexpensive and noninvasive measures could significantly reduce the number of CN individuals needed to screen to enroll a given number of amyloid-positive subjects.
doi:10.1212/WNL.0b013e31826e2696
PMCID: PMC3475629  PMID: 22972644
13.  Multimodality Imaging Characteristics of Dementia with Lewy Bodies 
Neurobiology of Aging  2011;33(9):2091-2105.
Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD). Our objective was to determine whether the 11C–Pittsburgh Compound-B (PiB) retention and regional hypometabolism on PET and regional cortical atrophy on MRI are complementary in characterizing patients with DLB and differentiating them from AD. We studied age, gender and education matched patients with a clinical diagnosis of DLB (n=21), AD (n=21), and cognitively normal subjects (n=42). Hippocampal atrophy, global cortical PiB retention and occipital lobe metabolism in combination distinguished DLB from AD better than any of the measurements alone (area under the receiver operating characteristic=0.98).Five of the DLB and AD patients who underwent autopsy were distinguished through multimodality imaging. These data demonstrate that MRI and PiB PET contribute to characterizing the distinct pathological mechanisms in patients with AD compared to DLB. Occipital and posterior parietotemporal lobe hypometabolism is a distinguishing feature of DLB and this regional hypometabolic pattern is independent of the amyloid pathology.
doi:10.1016/j.neurobiolaging.2011.09.024
PMCID: PMC3288845  PMID: 22018896
Dementia with Lewy bodies; MRI; PET; FDG; PiB; Alzheimer's disease
14.  Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies 
Brain  2012;135(8):2470-2477.
Acetylcholinesterase inhibitors are commonly used to treat patients with dementia with Lewy bodies. Hippocampal atrophy on magnetic resonance imaging and amyloid-β load on positron emission tomography are associated with the Alzheimer’s disease-related pathology in patients with dementia with Lewy bodies. To date, few studies have investigated imaging markers that predict treatment response in patients with dementia with Lewy bodies. Our objective was to determine whether imaging markers of Alzheimer’s disease-related pathology such as hippocampal volume, brain amyloid-β load on 11C Pittsburgh compound B positron emission tomography predict treatment response to acetylcholinesterase inhibitors in patients with dementia with Lewy bodies. We performed a retrospective analysis on consecutive treatment-naive patients with dementia with Lewy bodies (n = 54) from the Mayo Clinic Alzheimer’s Disease Research Centre who subsequently received acetylcholinesterase inhibitors and underwent magnetic resonance imaging with hippocampal volumetry. Baseline and follow-up assessments were obtained with the Mattis Dementia Rating Scale. Subjects were divided into three groups (reliable improvement, stable or reliable decline) using Dementia Rating Scale reliable change indices determined previously. Associations between hippocampal volumes and treatment response were tested with analysis of covariance adjusting for baseline Dementia Rating Scale, age, gender, magnetic resonance field strength and Dementia Rating Scale interval. Seven subjects underwent 11C Pittsburgh compound B imaging within 12 weeks of magnetic resonance imaging. Global cortical 11C Pittsburgh compound B retention (scaled to cerebellar retention) was calculated in these patients. Using a conservative psychometric method of assessing treatment response, there were 12 patients with reliable decline, 29 stable cases and 13 patients with reliable improvement. The improvers had significantly larger hippocampi than those that declined (P = 0.02) and the stable (P = 0.04) group. An exploratory analysis demonstrated larger grey matter volumes in the temporal and parietal lobes in improvers compared with those who declined (P < 0.05). The two patients who had a positive 11C Pittsburgh compound B positron emission tomography scan declined and those who had a negative 11C Pittsburgh compound B positron emission tomography scan improved or were stable after treatment. Patients with dementia with Lewy bodies who do not have the imaging features of coexistent Alzheimer’s disease-related pathology are more likely to cognitively improve with acetylcholinesterase inhibitor treatment.
doi:10.1093/brain/aws173
PMCID: PMC3407425  PMID: 22810436
dementia with Lewy bodies; acetylcholinesterase inhibitors; MRI; PiB; PET; amyloid
15.  Antemortem amyloid imaging and β-amyloid pathology in a case with dementia with Lewy Bodies 
Neurobiology of Aging  2010;33(5):878-885.
The association between antemortem [11C]-Pittsburgh Compound B (PiB) retention and β-amyloid (Aβ) load, Lewy body (LB) and neurofibrillary tangle (NFT) densities were investigated in a pathologically confirmed case of dementia with LB (DLB). 76-year-old man presenting with a clinical diagnosis of DLB had undergone PiB–positron emission tomography (PET), 18F FDG-PET and MRI 18 months before death. The pathologic diagnosis was DLB neocortical-type with low-likelihood of Alzheimer's disease by NIA-Reagan criteria. Sections from regions of interest (ROI) on post-mortem examination were studied. A significant correlation was found between cortical Aβ density and PiB retention in the 17 corresponding ROIs (r=0.899; p<0.0001). Bielschowsky silver stain revealed mostly sparse neocortical neuritic plaques; whereas diffuse plaques were frequent. There was no correlation between LB density and PiB retention (r=0.13; p=0.66); nor between NFT density and PiB retention (r=−0.36; p=0.17). The ROI-based analysis of imaging and histopathological data confirms that PiB uptake on PET is a specific marker for Aβ density, but cannot differentiate neuritic from diffuse amyloid plaques in this case with DLB.
doi:10.1016/j.neurobiolaging.2010.08.007
PMCID: PMC3026854  PMID: 20961664
Dementia with Lewy bodies; amyloid imaging; PET; pathology; amyloid
16.  FDG PET and MRI in Logopenic Primary Progressive Aphasia versus Dementia of the Alzheimer’s Type 
PLoS ONE  2013;8(4):e62471.
Objectives
The logopenic variant of primary progressive aphasia is an atypical clinical variant of Alzheimer’s disease which is typically characterized by left temporoparietal atrophy on magnetic resonance imaging and hypometabolism on F-18 fluorodeoxyglucose positron emission tomography. We aimed to characterize and compare patterns of atrophy and hypometabolism in logopenic primary progressive aphasia, and determine which brain regions and imaging modality best differentiates logopenic primary progressive aphasia from typical dementia of the Alzheimer’s type.
Methods
A total of 27 logopenic primary progressive aphasia subjects underwent fluorodeoxyglucose positron emission tomography and volumetric magnetic resonance imaging. These subjects were matched to 27 controls and 27 subjects with dementia of the Alzheimer’s type. Patterns of atrophy and hypometabolism were assessed at the voxel and region-level using Statistical Parametric Mapping. Penalized logistic regression analysis was used to determine what combinations of regions best discriminate between groups.
Results
Atrophy and hypometabolism was observed in lateral temporoparietal and medial parietal lobes, left greater than right, and left frontal lobe in the logopenic group. The logopenic group showed greater left inferior, middle and superior lateral temporal atrophy (inferior p = 0.02; middle p = 0.007, superior p = 0.002) and hypometabolism (inferior p = 0.006, middle p = 0.002, superior p = 0.001), and less right medial temporal atrophy (p = 0.02) and hypometabolism (p<0.001), and right posterior cingulate hypometabolism (p<0.001) than dementia of the Alzheimer’s type. An age-adjusted penalized logistic model incorporating atrophy and hypometabolism achieved excellent discrimination (area under the receiver operator characteristic curve = 0.89) between logopenic and dementia of the Alzheimer’s type subjects, with optimal discrimination achieved using right medial temporal and posterior cingulate hypometabolism, left inferior, middle and superior temporal hypometabolism, and left superior temporal volume.
Conclusions
Patterns of atrophy and hypometabolism both differ between logopenic primary progressive aphasia and dementia of the Alzheimer’s type and both modalities provide excellent discrimination between groups.
doi:10.1371/journal.pone.0062471
PMCID: PMC3633885  PMID: 23626825
17.  Characterization of a Family With c9FTD/ALS Associated With the GGGGCC Repeat Expansion in C9ORF72 
Archives of neurology  2012;69(9):1164-1169.
Background
The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the pathogenic mechanism underlying many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychological, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism and ALS spectrum.
Objective
To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72
Design
Clinical series.
Setting
Tertiary care academic medical center.
Patients
The members of the family affected by the mutation with features of FTD and/or ALS.
Main Outcome Measures
Clinical, neuropsychological, and neuroimaging assessments.
Results
All three examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and one had ALS. MRI showed symmetric bilateral frontal, temporal, insular and cingulate atrophy.
Conclusions
This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the clinico-neuroimaging-neuropathologic correlations.
doi:10.1001/archneurol.2012.772
PMCID: PMC3625860  PMID: 22637471
18.  Shapes of the Trajectories of Five Major Biomarkers of Alzheimer’s Disease 
Archives of neurology  2012;69(7):856-867.
Objective
To characterize the shape of the trajectories of Alzheimer’s Disease (AD) biomarkers as a function of MMSE.
Design
Longitudinal registries from the Mayo Clinic and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Patients
Two different samples (n=343 and n=598) were created that spanned the cognitive spectrum from normal to AD dementia. Subgroup analyses were performed in members of both cohorts (n=243 and n=328) who were amyloid positive at baseline.
Main Outcome Measures
The shape of biomarker trajectories as a function of MMSE, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebro spinal fluid (CSF) Aβ42 and tau; amyloid and fluoro deoxyglucose position emission tomography (PET) imaging, and structural magnetic resonance imaging (MRI).
Results
Baseline biomarker values generally worsened (i.e., non-zero slope) with lower baseline MMSE. Baseline hippocampal volume, amyloid PET and FDG PET values plateaued (i.e., non-linear slope) with lower MMSE in one or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE. Non-constant within-subject rates (deceleration) of biomarker change were found in only one model.
Conclusions
Biomarker trajectory shapes by MMSE were complex and were affected by interactions with age and APOE status. Non-linearity was found in several baseline effects models. Non-constant within-subject rates of biomarker change were found in only one model, likely due to limited within-subject longitudinal follow up. Creating reliable models that describe the full trajectories of AD biomarkers will require significant additional longitudinal data in individual participants.
doi:10.1001/archneurol.2011.3405
PMCID: PMC3595157  PMID: 22409939
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; cerebro spinal fluid; amyloid PET imaging; FDG PET imaging
19.  An Operational Approach to NIA-AA Criteria for Preclinical Alzheimer’s Disease 
Annals of neurology  2012;71(6):765-775.
Objective
A workgroup commissioned by the Alzheimer’s Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer’s disease (AD). We performed a preliminary assessment of these guidelines.
Methods
We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis and 18fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cut-points. A group of 450 cognitively normal (CN) subjects from a population based sample was used to develop cognitive cut-points and to assess population frequencies of the different preclinical AD stages using different cut-point criteria.
Results
The new criteria subdivide the preclinical phase of AD into stages 1–3. To classify our CN subjects, two additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected Non-AD Pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cut-points corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0; 16% stage 1; 12 % stage 2; 3% stage 3; and 23% SNAP.
Interpretation
This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1–3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving just 3% unclassified. Future longitudinal validation of the criteria will be important.
doi:10.1002/ana.22628
PMCID: PMC3586223  PMID: 22488240
20.  Does amyloid deposition produce a specific atrophic signature in cognitively normal subjects?☆ 
NeuroImage : Clinical  2013;2:249-257.
The objective of our study was to evaluate whether cognitively normal (CN) elderly participants showing elevated cortical beta-amyloid (Aβ) deposition have a consistent neuroanatomical signature of brain atrophy that may characterize preclinical Alzheimer's disease (AD). 115 CN participants who were Aβ-positive (CN +) by amyloid PET imaging; 115 CN participants who were Aβ-negative (CN −); and 88 Aβ-positive mild cognitive impairment or AD participants (MCI/AD +) were identified. Cortical thickness (FreeSurfer) and gray matter volume (SPM5) were measured for 28 regions-of-interest (ROIs) across the brain and compared across groups. ROIs that best discriminated CN − from CN + differed for FreeSurfer cortical thickness and SPM5 gray matter volume. Group-wise discrimination was poor with a high degree of uncertainty in terms of the rank ordering of ROIs. In contrast, both techniques showed strong and consistent findings comparing MCI/AD + to both CN − and CN + groups, with entorhinal cortex, middle and inferior temporal lobe, inferior parietal lobe, and hippocampus providing the best discrimination for both techniques. Concordance across techniques was higher for the CN − and CN + versus MCI/AD + comparisons, compared to the CN − versus CN + comparison. The weak and inconsistent nature of the findings across technique in this study cast doubt on the existence of a reliable neuroanatomical signature of preclinical AD in elderly PiB-positive CN participants.
Highlights
► We measured atrophy in cognitively normal subjects with amyloid deposition (CN +). ► Findings in CN + subjects were weak and disconcordant across Freesurfer and SPM5. ► Concordance across techniques was higher when assessing Alzheimer disease subjects. ► Evidence for a neuroanatomical signature of preclinical AD in CN + subjects is weak.
doi:10.1016/j.nicl.2013.01.006
PMCID: PMC3778266  PMID: 24179779
Amyloid; Preclinical; Alzheimer's disease; Freesurfer; Voxel-based morphometry; Cognitively normal
21.  Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech 
Brain  2012;135(5):1522-1536.
Apraxia of speech is a disorder of speech motor planning and/or programming that is distinguishable from aphasia and dysarthria. It most commonly results from vascular insults but can occur in degenerative diseases where it has typically been subsumed under aphasia, or it occurs in the context of more widespread neurodegeneration. The aim of this study was to determine whether apraxia of speech can present as an isolated sign of neurodegenerative disease. Between July 2010 and July 2011, 37 subjects with a neurodegenerative speech and language disorder were prospectively recruited and underwent detailed speech and language, neurological, neuropsychological and neuroimaging testing. The neuroimaging battery included 3.0 tesla volumetric head magnetic resonance imaging, [18F]-fluorodeoxyglucose and [11C] Pittsburg compound B positron emission tomography scanning. Twelve subjects were identified as having apraxia of speech without any signs of aphasia based on a comprehensive battery of language tests; hence, none met criteria for primary progressive aphasia. These subjects with primary progressive apraxia of speech included eight females and four males, with a mean age of onset of 73 years (range: 49–82). There were no specific additional shared patterns of neurological or neuropsychological impairment in the subjects with primary progressive apraxia of speech, but there was individual variability. Some subjects, for example, had mild features of behavioural change, executive dysfunction, limb apraxia or Parkinsonism. Voxel-based morphometry of grey matter revealed focal atrophy of superior lateral premotor cortex and supplementary motor area. Voxel-based morphometry of white matter showed volume loss in these same regions but with extension of loss involving the inferior premotor cortex and body of the corpus callosum. These same areas of white matter loss were observed with diffusion tensor imaging analysis, which also demonstrated reduced fractional anisotropy and increased mean diffusivity of the superior longitudinal fasciculus, particularly the premotor components. Statistical parametric mapping of the [18F]-fluorodeoxyglucose positron emission tomography scans revealed focal hypometabolism of superior lateral premotor cortex and supplementary motor area, although there was some variability across subjects noted with CortexID analysis. [11C]-Pittsburg compound B positron emission tomography binding was increased in only one of the 12 subjects, although it was unclear whether the increase was actually related to the primary progressive apraxia of speech. A syndrome characterized by progressive pure apraxia of speech clearly exists, with a neuroanatomic correlate of superior lateral premotor and supplementary motor atrophy, making this syndrome distinct from primary progressive aphasia.
doi:10.1093/brain/aws032
PMCID: PMC3338923  PMID: 22382356
primary progressive apraxia of speech; apraxia of speech; primary progressive aphasia; voxel-based morphometry; diffusion tensor imaging; fluorodeoxyglucose; Pittsburg compound B; supplementary motor area
22.  Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 
Brain  2012;135(3):765-783.
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.
doi:10.1093/brain/aws004
PMCID: PMC3286335  PMID: 22366793
frontotemporal dementia; amyotrophic lateral sclerosis; motor neuron disease; TDP-43; neurogenetics; chromosome 9
24.  A Carrier for Non-Covalent Delivery of Functional Beta-Galactosidase and Antibodies against Amyloid Plaques and IgM to the Brain 
PLoS ONE  2011;6(12):e28881.
Background
Therapeutic intervention of numerous brain-associated disorders currently remains unrealized due to serious limitations imposed by the blood-brain-barrier (BBB). The BBB generally allows transport of small molecules, typically <600 daltons with high octanol/water partition coefficients, but denies passage to most larger molecules. However, some receptors present on the BBB allow passage of cognate proteins to the brain. Utilizing such receptor-ligand systems, several investigators have developed methods for delivering proteins to the brain, a critical requirement of which involves covalent linking of the target protein to a carrier entity. Such covalent modifications involve extensive preparative and post-preparative chemistry that poses daunting limitations in the context of delivery to any organ. Here, we report creation of a 36-amino acid peptide transporter, which can transport a protein to the brain after routine intravenous injection of the transporter-protein mixture. No covalent linkage of the protein with the transporter is necessary.
Approach
A peptide transporter comprising sixteen lysine residues and 20 amino acids corresponding to the LDLR-binding domain of apolipoprotein E (ApoE) was synthesized. Transport of beta-galactosidase, IgG, IgM, and antibodies against amyloid plques to the brain upon iv injection of the protein-transporter mixture was evaluated through staining for enzyme activity or micro single photon emission tomography (micro-SPECT) or immunostaining. Effect of the transporter on the integrity of the BBB was also investigated.
Principal Findings
The transporter enabled delivery to the mouse brain of functional beta-galactosidase, human IgG and IgM, and two antibodies that labeled brain-associated amyloid beta plaques in a mouse model of Alzheimer's disease.
Significance
The results suggest the transporter is able to transport most or all proteins to the brain without the need for chemically linking the transporter to a protein. Thus, the approach offers an avenue for rapid clinical evaluation of numerous candidate drugs against neurological diseases including cancer. (299 words).
doi:10.1371/journal.pone.0028881
PMCID: PMC3244419  PMID: 22216132
25.  Autoimmune Dementia: Clinical Course and Predictors of Immunotherapy Response 
Mayo Clinic Proceedings  2010;85(10):881-897.
OBJECTIVE: To define the diagnostic characteristics and predictors of treatment response in patients with suspected autoimmune dementia.
PATIENTS AND METHODS: Between January 1, 2002, and January 1, 2009, 72 consecutive patients received immunotherapy for suspected autoimmune dementia. Their baseline clinical, radiologic, and serologic characteristics were reviewed and compared between patients who were responsive to immunotherapy and those who were not. Patients were classified as responders if the treating physician had reported improvement after immunotherapy (documented in 80% by the Kokmen Short Test of Mental Status, neuropsychological testing, or both).
RESULTS: Initial immunotherapeutic regimens included methylprednisolone in 56 patients (78%), prednisone in 12 patients (17%), dexamethasone in 2 patients (3%), intravenous immune globulin in 1 patient (1%), and plasma exchange in 1 patient (1%). Forty-six patients (64%) improved, most in the first week of treatment. Thirty-five percent of these immunotherapy responders were initially diagnosed as having a neurodegenerative or prion disorder. Pretreatment and posttreatment neuropsychological score comparisons revealed improvement in almost all cognitive domains, most notably learning and memory. Radiologic or electroencephalographic improvements were reported in 22 (56%) of 39 patients. Immunotherapy responsiveness was predicted by a subacute onset (P<.001), fluctuating course (P<.001), tremor (P=.007), shorter delay to treatment (P=.005), seropositivity for a cation channel complex autoantibody (P=.01; neuronal voltage-gated potassium channel more than calcium channel or neuronal acetylcholine receptor), and elevated cerebrospinal fluid protein (>100 mg/dL) or pleocytosis (P=.02). Of 26 immunotherapy-responsive patients followed up for more than 1 year, 20 (77%) relapsed after discontinuing immunotherapy.
CONCLUSION: Identification of clinical and serologic clues to an autoimmune dementia allows early initiation of immunotherapy, and maintenance if needed, thus favoring an optimal outcome.
Identification of clinical and serologic clues to an autoimmune dementia allows early initiation of immunotherapy, and maintenance if needed, thus favoring an optimal outcome.
doi:10.4065/mcp.2010.0326
PMCID: PMC2947960  PMID: 20884824

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