We evaluated positron emission tomography (PET)-based classification of neurodegenerative pathology in mild cognitive impairment (MCI).
A cross-sectional and prospective evaluation of a cohort of 27 MCI subjects drawn from a university-based Cognitive Disorders clinic. We compared expert clinical consensus classification of MCI at entry, and possible dementia at follow-up, with molecular imaging-based classification employing [11C]DTBZ-PET measurement of striatal dopamine terminal integrity and [11C]PiB-PET measurement of cerebral amyloid burden.
Eleven subjects were initially classified clinically as amnestic MCI, 7 as multidomain MCI, and 9 as nonamnestic MCI. At mean follow-up of 3 years, 18 subjects converted to dementia. PET imaging evidence of significant cerebral amyloid deposition and/or nigrostriatal denervation were strong predictors of conversion to dementia. There was only moderate concordance between expert clinical classifications and PET-based classifications of dementia subtypes.
Combined PET molecular imaging of cerebral amyloid burden and striatal dopamine terminal integrity may be useful identifying subjects at high risk for progression to dementia and in defining neurochemically differentiated subsets of MCI subjects.
Dementia; Alzheimer disease; Lewy Body dementia; Frontotemporal dementia
Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) population, we examined (1) cross-sectional relationships between amyloid deposition, hypometabolism, and cognition, and (2) associations between amyloid and hypometabolism measurements and longitudinal cognitive measurements.
We examined associations between mean cortical florbetapir uptake, mean 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) within a set of predefined regions, and Alzhiemer’s Disease Assessment Scale (ADAS-cog) performance in 426 ADNI participants (126 normal, 162 early mild cognitive impairment [EMCI], 85 late MCI [LMCI], 53 Alzheimer disease [AD] patients). For a subset of these (76 normal, 81 LMCI) we determined whether florbetapir and FDG-PET were associated with retrospective decline in longitudinal ADAS-cog measurements.
Twenty-nine percent of normal subjects, 43% of EMCI patients, 62% of LMCI patients, and 77% of AD patients were categorized as florbetapir positive. Florbetapir was negatively associated with concurrent FDG and ADAS-cog in both MCI groups. In longitudinal analyses, florbetapir-positive subjects in both normal and LMCI groups had greater ongoing ADAS-cog decline than those who were florbetapir negative. However, in normal subjects, florbetapir positivity was associated with greater ADAS-cog decline than FDG, whereas in LMCI, FDG positivity was associated with greater decline than florbetapir.
Although both hypometabolism and β-amyloid (Aβ) deposition are detectable in normal subjects and all diagnostic groups, Aβ showed greater associations with cognitive decline in normal participants. In view of the minimal cognitive deterioration overall in this group, this suggests that amyloid deposition has an early and subclinical impact on cognition that precedes metabolic changes. At moderate and later stages of disease (LMCI/AD), hypometabolism becomes more pronounced and more closely linked to ongoing cognitive decline.
The aim of our study was to examine the relationship between corticostriatal Aβ-amyloid deposition and cognitive dysfunction in a cohort of patients with Parkinson disease (PD) at risk for dementia.
This was a cross-sectional study of 40 patients with PD with mild cognitive impairment (MCI) or other known dementia risk factors. Subjects underwent dynamic Aβ-amyloid and vesicular monoamine transporter 2 PET imaging using [11C] Pittsburgh compound B (PiB) and [11C]dihydrotetrabenazine (DTBZ), respectively, and neuropsychological assessment. PiB and DTBZ PET data were analyzed using the Logan graphical method to determine cerebral PiB deposition relative to the cerebellar hemispheres and striatal DTBZ binding relative to occipital neocortex. Component z scores were calculated for individual cognitive domains (memory, visuospatial processing, working memory/attention, and executive function) and combined linearly for global estimation of cognition. Correlation of cognitive function and cortical PiB binding was investigated.
Elevated cerebral PiB binding at levels seen in patients with AD was infrequent (6 of 40 subjects). Mean cortical PiB binding in the entire cohort was 1.16 ± 0.16 (distribution volume ratio; range 0.96–1.78). A significant correlation was noted between cortical PiB binding and global composite cognitive function (r = −0.55, p < 0.005) as well as the Wechsler Adult Intelligence Scale score (r = −0.54, p = 0.0004).
Elevated cerebral Aβ-amyloid deposition at levels seen in Alzheimer disease is uncommon in subjects with PD at risk for dementia. In our sample, the prevalence of markedly elevated PiB binding was significantly lower than that found in prior studies of cognitively normal elderly individuals. Neocortical PiB binding correlated robustly with measures of cognitive impairment in our cohort.
Oxytocin, classically involved in social and reproductive activities, is increasingly recognized as an antinociceptive and anxiolytic agent, effects which may be mediated via oxytocin’s interactions with the dopamine system. Thus, genetic variation within the oxytocin gene (OXT) is likely to explain variability in dopamine-related stress responses. As such, we examined how OXT variation is associated with stress-induced dopaminergic neurotransmission in a healthy human sample.
Fifty-five young healthy volunteers were scanned using [11C] raclopride positron emission tomography while they underwent a standardized physical and emotional stressor that consisted of moderate levels of experimental sustained deep muscle pain, and a baseline, control state. Four haplotype tagging single nucleotide polymorphisms located in regions near OXT were genotyped. Measures of pain, affect, anxiety, well-being and interpersonal attachment were also assessed.
Female rs4813625 C allele carriers demonstrated greater stress-induced dopamine release, measured as reductions in receptor availability from baseline to the pain-stress condition relative to female GG homozygotes. No significant differences were detected among males. We also observed that female rs4813625 C allele carriers exhibited higher attachment anxiety, higher trait anxiety and lower emotional well-being scores. In addition, greater stress-induced dopamine release was associated with lower emotional well-being scores in female rs4813625 C allele carriers.
Our results suggest that variability within the oxytocin gene appear to explain interindividual differences in dopaminergic responses to stress, which are shown to be associated with anxiety traits, including those linked to attachment style, as well as emotional well-being in women.
oxytocin; genetics; dopamine; positron emission tomography; humans; sex differences
Parkinson's disease (PD) is a multisystem neurodegenerative disorder. Heterogeneous clinical features may reflect heterogeneous changes in different brain regions. In contrast to the pronounced nigrostriatal denervation characteristic of PD, cholinergic changes are less marked. We investigated cholinergic innervation activity in PD subjects relative to normal subjects. Nondemented PD subjects (n=101, age 65.3±7.2 years) and normal subjects (n=29, age 66.8±10.9 years) underwent clinical assessment and [11C]methyl-4-piperidinyl propionate acetylcholinesterase and [11C]dihydrotetrabenazine monoaminergic positron emission tomography (PET) imaging. Cholinergic projection changes were heterogeneous for 65 out of 101 PD subjects who had neocortical and thalamic acetylcholinesterase activity within the normal range. The remainder had combined neocortical and thalamic (13/101), isolated neocortical (18/101), or isolated thalamic (5/101) acetylcholinesterase activity below the normal range. The low neocortical acetylcholinesterase activity subgroup had significantly lower global cognitive performance compared with the normal range subgroup (F=7.64, P=0.0069) with an independent effect for nigrostriatal denervation (F=7.60, P=0.0074). The low thalamic acetylcholinesterase activity subgroup did not differ from the normal thalamic acetylcholinesterase activity subgroup in cognitive performance or motor impairments except for a history of falls (P=0.0023). Cholinergic denervation is heterogeneous with reduced neocortical and/or thalamic acetylcholinesterase activity in 36% of nondemented PD subjects with corresponding clinical phenotypic variation. Results also show independent cognitive effects for both cholinergic and dopaminergic system changes in nondemented PD subjects.
acetylcholinesterase; cognitive impairment; dopamine; motor; Parkinson's disease; PET
Rapid eye movement sleep behavior disorder (RBD) is common in Parkinson disease (PD), but its relationship to the varied neurotransmitter deficits of PD and prognostic significance remain incompletely understood. RBD and cholinergic system degeneration are identified independently as risk factors for cognitive impairment in PD. We aimed to assess the association between cholinergic denervation and symptoms of RBD in PD patients without dementia.
Eighty subjects with PD without dementia (age, 64.6 ± 7.0 years; range, 50–82 years; 60 males, 20 females; mean Montreal Cognitive Assessment Test [MoCA] score, 26.2 ± 2.1; range 21–30) underwent clinical assessment, neuropsychological testing, and [11C]methylpiperidyl propionate acetylcholinesterase and [11C]dihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 positron emission tomography (PET) imaging. 11C3-Amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) serotonin transporter PET imaging was performed in a subset of 35 subjects. The presence of RBD symptoms was determined using the Mayo Sleep Questionnaire.
Twenty-seven of 80 subjects (33.8%) indicated a history of RBD symptoms. Subjects with and without RBD symptoms showed no significant differences in age, motor disease duration, MoCA, Unified Parkinson Disease Rating Scale motor scores, or striatal DTBZ binding. Subjects with RBD symptoms, in comparison to those without, exhibited decreased neocortical, limbic cortical, and thalamic cholinergic innervation (0.0213 ± 0.0018 vs 0.0236 ± 0.0022, t = 4.55, p < 0.0001; 0.0388 ± 0.0029 vs 0.0423 ± 0.0058, t = 2.85, p = 0.0056; 0.0388 ± 0.0025 vs 0.0427 ± 0.0042, t = 4.49, p < 0.0001, respectively). Brainstem and striatal DASB binding showed no significant differences between groups.
The presence of RBD symptoms in PD is associated with relative neocortical, limbic cortical, and thalamic cholinergic denervation although not with differential serotoninergic or nigrostriatal dopaminergic denervation. The presence of RBD symptoms may signal cholinergic system degeneration.
Prior studies suggest that serotoninergic neurotransmission reduces β-amyloid (Aβ) production.
To determine whether serotoninergic system degeneration in Parkinson disease promotes Aβ deposition, using in vivo positron emission tomographic probes of serotonin system integrity and Aβ deposition.
Design, Setting, and Patients
Cross-sectional study of 13 subjects with Parkinson disease from the movement disorders clinics at the University of Michigan Health System and Veterans Affairs Ann Arbor Healthcare System, with positron emission tomography using the serotonin transporter ligand carbon 11 ([11C])–labeled 3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile (DASB) and the Aβ ligand [11C]Pittsburgh compound B.
Inverse correlations were found between DASB and Pittsburgh compound B distribution volume ratios in the neocortex (ρ=−0.577; P=.04) and striatum (ρ=−0.780; P=.002).
Serotoninergic system degeneration in Parkinson disease may promote the development of cerebral amyloidopathy.
There are two major sources of cholinergic projections in the brain. The nucleus basalis of Meynert provides the principal cholinergic input of the cortical mantle and the pedunculopontine nucleus-laterodorsal tegmental complex (PPN-LDTC; hereafter referred to as PPN) provides the major cholinergic input to the thalamus. Cortical cholinergic denervation has previously been shown to be part of Alzheimer and parkinsonian dementia but there is less information about subcortical thalamic cholinergic denervation. We investigated thalamic cholinergic afferent integrity by measuring PPN-Thalamic (PPN-Thal) acetylcholinesterase (AChE) activity via PET imaging in Alzheimer (AD), Parkinson disease without dementia (PD), Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB).
AD (n=13; mean age 75.4±5.5), PD (n=11; age 71.4±6.4), PDD (n=6; age 70.8±4.7), DLB (n=6; age 68.0±8.6) and normal controls (NC; n=14; age 69.0±7.5) subjects underwent AChE [11C]-methyl-4-piperidinyl propionate (PMP) PET imaging. PPN-Thal PET data were analyzed using the Nagatsuka method.
There were no significant differences in mean age between the groups (F=1.86, p=0.134). Kruskal-Wallis testing demonstrated a significant group effect for PPN-Thal AChE hydrolysis rates (F=9.62, P<0.0001). Compared to NC, reduced thalamic k3 hydrolysis rate was noted in subjects with PDD (−19.8%; AChE k3 hydrolysis rates 0.1072±0.0143 min−1), DLB (−17.4%; 0.1103±0.0112 min−1) and PD (−12.8%; 0.1165±0.0114 min−1). Each of these 3 subgroups were statistically different from AD subjects (−0.7%; 0.1326±0.0095 min−1) who showed relatively spared thalamic k3 hydrolysis rates which were comparable to NC (0.1336±0.0142 min−1).
Thalamic cholinergic denervation is present in PD, PDD, and DLB but not in AD. Neurodegenerative involvement of thalamic cholinergic afferent projections may contribute to disease-specific motor and cognitive abnormalities.
Acetylcholine; [11C] PMP PET; Alzheimer disease; Parkinson disease; PPN; Parkinson disease with dementia
Objective: Our goal was to evaluate the association of APOE with amyloid deposition, cerebrospinal fluid levels (CSF) of Aβ, tau, and p-tau, brain atrophy, cognition and cognitive complaints in E-MCI patients and cognitively healthy older adults (HC) in the ADNI-2 cohort.
Methods: Two-hundred and nine E-MCI and 123 HC participants from the ADNI-2 cohort were included. We evaluated the impact of diagnostic status (E-MCI vs. HC) and APOE ε4 status (ε4 positive vs. ε4 negative) on cortical amyloid deposition (AV-45/Florbetapir SUVR PET scans), brain atrophy (structural MRI scans processed using voxel-based morphometry and Freesurfer version 5.1), CSF levels of Aβ, tau, and p-tau, and cognitive performance and complaints.
Results: E-MCI participants showed significantly impaired cognition, higher levels of cognitive complaints, greater levels of tau and p-tau, and subcortical and cortical atrophy relative to HC participants (p < 0.05). Cortical amyloid deposition and CSF levels of Aβ were significantly associated with APOE ε4 status but not E-MCI diagnosis, with ε4 positive participants showing more amyloid deposition and lower levels of CSF Aβ than ε4 negative participants. Other effects of APOE ε4 status on cognition and CSF tau levels were also observed.
APOE ε4 status is associated with amyloid accumulation and lower CSF Aβ, as well as increased CSF tau levels in early prodromal stages of AD (E-MCI) and HC. Alternatively, neurodegeneration, cognitive impairment, and increased complaints are primarily associated with a diagnosis of E-MCI. These findings underscore the importance of considering APOE genotype when evaluating biomarkers in early stages of disease.
apolipoprotein E (APOE); early mild cognitive impairment (E-MCI); Florbetapir/AV-45/Amyvid; positron emission tomography (PET); magnetic resonance imaging (MRI); cerebrospinal fluid (CSF); Alzheimer's disease neuroimaging initiative (ADNI)
Leucoaraiosis is associated with motor symptoms in otherwise normal older adults. Comorbid leucoaraiosis is predicted to contribute also to motor features in Parkinson’s disease but previous studies of white matter changes in Parkinson’s disease show variable results. No prior studies have compared directly the effects of both leucoaraiosis and the degree of nigrostriatal dopaminergic denervation on motor features. We investigated the effect of leucoaraiosis severity on motor impairment independent of the degree of nigrostriatal dopaminergic denervation in Parkinson’s disease. Seventy-three subjects with Parkinson’s disease (Hoehn and Yahr stages 1–3) underwent brain magnetic resonance and [11C]dihydrotetrabenazine vesicular monoamine transporter type 2 positron emission tomography imaging. Automated assessment of supratentorial fluid-attenuated inversion recovery magnetic resonance hyperintense white matter voxels was performed using cerebellar white matter as the intensity reference. White matter signal hyperintensity burden was log-transformed and normalized for brain volume. Unified Parkinson’s Disease Rating Scale total and subscore ratings were assessed to determine motor impairment. Subjects receiving dopaminergic medications were examined in the clinically defined ‘OFF’ state. Multivariate regression analysis with measures of white matter signal hyperintensity burden and nigrostriatal denervation as independent variables demonstrated a significant overall model for total motor Unified Parkinson's Disease Rating Scale scores (F = 11.4, P < 0.0001) with significant regression effects for both white matter signal hyperintensity burden (t = 2.0, β = 0.22, P = 0.045) and striatal monoaminergic binding (t = −3.5, β = −0.38, P = 0.0008). Axial motor impairment demonstrated a robust association with white matter signal hyperintensity burden (t = 4.0, β = 0.43, P = 0.0001) compared with striatal monoaminergic binding (t = −2.1, β = 0.22, P = 0.043). White matter signal hyperintensity burden regression effects for bradykinesia had borderline significance. No significant white matter signal hyperintensity burden effects were found for rigidity or tremor subscores. White matter signal hyperintensity burden was significantly higher in the subgroup with postural instability and gait difficulties compared with the tremor-predominant subgroup despite no significant differences in age or duration of disease. These findings indicate that increased white matter signal hyperintensity burden is associated with worse motor performance independent of the degree of nigrostriatal dopaminergic denervation in Parkinson’s disease. Comorbid white matter disease is a greater determinant of axial motor impairment than nigrostriatal dopaminergic denervation.
dopamine; motor; Parkinson’s disease; leucoaraiosis; magnetic resonance imaging; white matter hyperintensities
Sleep dysfunction and excessive daytime sleepiness are common in Parkinson disease (PD). Several studies suggest that PD patients exhibit high prevalence of sleep-disordered breathing (SDB). PD has a complex profile of neurochemical deficits in which abnormalities of different neurotransmitter systems may play significant and differing roles in the development of non-motor features. In the present study, we investigated whether SDB in PD is related to serotoninergic neuron degeneration. We used a cross-sectional design to assess the correlation between SDB and measures of caudal brainstem serotonin neuron integrity. Fifty one PD participants with mean disease duration of 6.0 (SD 3.7) years and mean age of 63.9 (SD 6.2) years were studied. We measured caudal brainstem serotoninergic innervation with [11C]DASB positron emission tomography (PET) imaging and striatal dopaminergic innervation with [11C]DTBZ PET imaging. SDB was assessed with polysomnography (PSG) and sleepiness with multiple sleep latency tests. Greater than half of participants exhibited PSG evidence of significant SDB; 12 participants had normal PSGs, 6 had mild SDB, 20 had moderate SDB, and 13 had severe SDB. We found no association between severity of SDB and caudal brainstem serotoninergic innervation in PD participants. Striatal dopaminergic denervation did not correlate with severity of SDB. We did find significant correlations between measures of motor function impairment and sleep quantity and quality in PD. Neither serotoninergic nor dopaminergic neuron degeneration is likely to play a major role in SDB observed in PD patients.
The Functional Activities Questionnaire (FAQ) and Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog) are frequently-used indices of cognitive decline in Alzheimer’s disease (AD). The goal of this study was to compare FDG-PET and clinical measurements in a large sample of elderly subjects with memory disturbance. We examined relationships between glucose metabolism in FDG-PET regions of interest (FDG-ROIs), and ADAS-cog and FAQ scores in AD and mild cognitive impairment (MCI) patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Low glucose metabolism at baseline predicted subsequent ADAS-cog and FAQ decline. In addition, longitudinal glucose metabolism decline was associated with concurrent ADAS-cog and FAQ decline. Additionally, a power analysis revealed that FDG-ROI values have greater statistical power than ADAS-cog to detect attenuation of cognitive decline in AD and MCI patients. Glucose metabolism is a sensitive measure of change in cognition and functional ability in AD and MCI, and has value in predicting future cognitive decline.
FDG-PET; Alzheimer’s disease; Mild Cognitive Impairment
We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of aβ-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score ≥ 18) underwent a conventional clinical evaluation followed by 11C-dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine transporters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical aβ-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer’s disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer’s disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer’s disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in ∼35% of subjects (Cohen’s κ = 0.39). Discordant classifications were least frequent in clinical consensus Alzheimer’s disease (17%), followed by dementia with Lewy bodies (29%) and were most common in frontotemporal dementia (64%). Accurate clinical classification of mild neurodegenerative dementia is challenging. Though additional post-mortem correlations are required, positron emission tomography imaging likely distinguishes subgroups corresponding to neurochemically defined pathologies. Use of these positron emission tomography imaging methods may augment clinical classifications and allow selection of more uniform subject groups in disease-modifying therapeutic trials and other prospective research involving subjects in the early stages of dementia.
Alzheimer’s disease; Lewy body dementia; frontotemporal dementia; amyloid; dopamine; diagnosis
This article introduces a hypometabolic convergence index (HCI) for the assessment of Alzheimer’s disease (AD), compares it to other biological, cognitive and clinical measures, and demonstrate its promise to predict clinical decline in mild cognitive impairment (MCI) patients using data from the AD Neuroimaging Initiative (ADNI). The HCI is intended to reflect in a single measurement the extent to which the pattern and magnitude of cerebral hypometabolism in an individual’s fluorodeoxyglucose positron emission tomography (FDG PET) image corresponds to that in probable AD patients, and is generated using a fully automated voxel-based image analysis algorithm. HCIs, magnetic resonance imaging (MRI) hippocampal volume measurements, cerebrospinal fluid (CSF) assays, memory test scores, and clinical ratings were compared in 47 probable AD patients, 21 MCI patients who converted to probable AD within the next 18 months, 76 MCI patients who did not, and 47 normal controls (NCs) in terms of their ability to characterize clinical disease severity and predict conversion rates from MCI to probable AD. HCIs were significantly different in the probable AD, MCI converter, MCI stable and NC groups (p = 9e-17) and correlated with clinical disease severity. Using retrospectively characterized threshold criteria, MCI patients with either higher HCI’s or smaller hippocampal volumes had the highest hazard ratios (HRs) for 18-month progression to probable AD (7.38 and 6.34, respectively), and those with both had an even higher HR (36.72). In conclusion, the HCI, alone or in combination with certain other biomarker measurements, have the potential to help characterize AD and predict subsequent rates of clinical decline. More generally, our conversion index strategy could be applied to a range of imaging modalities and voxel-based image-analysis algorithms.
hypometabolic convergence index; Alzheimer’s disease; FDG; PET; MCI; hippocampal volume
Amyloid imaging with [11C]Pittsburgh Compound-B (PiB) provides in vivo data on plaque deposition in those with, or at risk for, Alzheimer’s disease (AD). We performed a gene-based association analysis of 15 quality-controlled amyloid-pathway associated candidate genes in 103 Alzheimer’s Disease Neuroimaging Initiative participants. The mean normalized PiB uptake value across four brain regions known to have amyloid deposition in AD was used as a quantitative phenotype. The minor allele of an intronic SNP within DHCR24 was identified and associated with a lower average PiB uptake. Further investigation at whole-brain voxel-wise level indicated that non-carriers of the minor allele had higher PiB uptake in frontal regions compared to carriers. DHCR24 has been previously shown to confer resistance against beta-amyloid and oxidative stress-induced apoptosis, thus our findings support a neuroprotective role. Pathway-based genetic analysis of targeted molecular imaging phenotypes appears promising to help elucidate disease pathophysiology and identify potential therapeutic targets.
Alzheimer’s disease; ADNI; Pathway-based gene analysis; PiB-PET; Endophenotype; Voxel-based analysis
To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).
Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.
Academic medical centers
45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)
Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.
Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.
We compared the frequency of rhinorrhea between 34 Parkinson disease (PD) subjects and 15 normal controls (NC), and explored relationships between rhinorrhea and clinical functions, and degree of nigrostriatal dopaminergic denervation using 11C-dihydrotetrabenazine (DTBZ) brain positron emission tomography (PET) imaging. 68% (23/34) of PD subjects reported rhinorrhea of any cause compared to 27% (4/15) of NC (χ2=7.07, p=0.008). Rhinorrhea frequency remained higher in the PD group after excluding possible rhinitic etiologies: 35% (12/34) PD versus 7% (1/15) of NC (χ2=4.38, p=0.04). There were no differences in demographics, nigrostriatal dopaminergic denervation, and clinical motor or non-motor variables between PD subjects with and without rhinorrhea, except that more PD subjects with rhinorrhea complained of lightheadedness (52% vs. 9%, χ2=5.85, p=0.02). Rhinorrhea is a common non-dopaminergic feature of PD, unrelated to olfactory or motor deficits. Further investigations are needed to determine if rhinorrhea correlates with sympathetic denervation or other autonomic symptoms in PD.
Parkinson disease; rhinorrhea; PET; olfaction; dopamine transporter
Fluorodeoxyglucose positron emission tomography (FDG-PET) studies report characteristic patterns of cerebral hypometabolism in probable Alzheimer's disease (pAD) and amnestic mild cognitive impairment (aMCI). This study aims to characterize the consistency of regional hypometabolism in pAD and aMCI patients enrolled in the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM) and bootstrap resampling, and to compare bootstrap based reliability index to the commonly used type-I error approach with or without correction for multiple comparisons. Batched SPM5 was run for each of 1,000 bootstrap iterations to compare FDG-PET images from 74 pAD and 142 aMCI patients, respectively, to 82 normal controls. Maps of the hypometabolic voxels detected for at least a specific percentage of times over the 1000 runs were examined and compared to an overlap of the hypometabolic maps obtained from 3 randomly partitioned independent sub-datasets. The results from the bootstrap derived reliability of regional hypometabolism in the overall data set were similar to that observed in each of the three non-overlapping sub-sets using family-wise error. Strong but non-linear association was found between the bootstrap based reliability index and the type-I error. For threshold p=0.0005, pAD was associated with extensive hypometabolic voxels in the posterior cingulate/precuneus and parietotemporal regions with reliability between 90% and 100%. Bootstrap analysis provides an alternative to the parametric family-wise error approach used to examine consistency of hypometabolic brain voxels in pAD and aMCI patients. These results provide a foundation for the use of bootstrap analysis characterize statistical ROIs or search regions in both cross-sectional and longitudinal FDG PET studies. This approach offers promise in the early detection and tracking of AD, the evaluation of AD-modifying treatments, and other biologically or clinical important measurements using brain images and voxel-based data analysis techniques.
Alzheimer's Disease; MCI; FDG PET; Reproducibility of Results; Reliability; Bootstrap Resampling; Familywise Error; SPM
Amyloid imaging with [11 C]Pittsburgh Compound-B (PiB) provides in vivo data on plaque deposition in those with, or at risk for, Alzheimer’s disease (AD). We performed a gene-based association analysis of 15 quality-controlled amyloid-pathway associated candidate genes in 103 Alzheimer’s Disease Neuroimaging Initiative participants. The mean normalized PiB uptake value across four brain regions known to have amyloid deposition in AD was used as a quantitative phenotype. The minor allele of an intronic SNP within DHCR24 was identified and associated with a lower average PiB uptake. Further investigation at whole-brain voxel-wise level indicated that non-carriers of the minor allele had higher PiB uptake in frontal regions compared to carriers. DHCR24 has been previously shown to confer resistance against beta-amyloid and oxidative stress-induced apoptosis, thus our findings support a neuroprotective role. Pathway-based genetic analysis of targeted molecular imaging phenotypes appears promising to help elucidate disease pathophysiology and identify potential therapeutic targets.
Alzheimer’s disease; ADNI; Pathway-based gene analysis; PiB-PET; Endophenotype; Voxel-based analysis
To compare assessment of regional cerebral metabolic changes with DTBZ-PET measurement of regional cerebral blood flow (K1) and FDG-PET measurement of regional cerebral glucose uptake (CMRglc) in a clinically representative sample of mild dementia and mild cognitive impairment (MCI) subjects. We hypothesized that DTBZ-PET K1 and FDG-PET CMRglc provide equivalent information.
Design, Setting, Participants
DTBZ-PET K1 measurement of regional cerebral blood flow and FDG-PET CMRglc measurement of regional cerebral glucose uptake was performed in 50 subjects with either mild dementia (MMSE ≥ 18) or MCI drawn from a university based Cognitive Disorders Clinic. Results were compared with 80 normal control subjects.
Main Outcome Measures
DTBZ-PET regional K1 measurements and FDG-PET CMRglc measurements were compared with standard correlation analysis. The overall patterns of DTBZ-PET K1 deficits and FDG-PET CMRglc deficits were assessed with stereotaxic surface projections (SSP) of parametric images.
DTBZ-PET regional K1 measurements and FDG-PET CMRglc measurements were highly correlated, both within and between subjects. SSP maps of deficits in DTBZ-PET regional K1 measurements and FDG-PET CMRglcs were markedly similar. DTBZ-PET K1 SSP maps exhibited a mild decrease in sensitivity relative to FDG-PET CMRglc maps.
DTBZ-PET K1 and FDG-PET CMRglc provide comparable information in assessment of regional cerebral metabolic deficits in mild dementia and MCI. K1 measures can assess regional cerebral metabolism deficits accurately in mild dementia and MCI. K1 assessments of regional cerebral metabolic deficits can be combined with tracer binding results to improve of utility of PET imaging in mild dementia and MCI.
Alzheimer's disease (AD) is characterized by specific and progressive reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), some of which may precede the onset of symptoms. In this report, we describe twelve-month CMRgl declines in 69 probable AD patients, 154 amnestic mild cognitive impairment (MCI) patients, and 79 cognitively normal controls (NCs) from the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM). We introduce the use of an empirically predefined statistical region-of-interest (sROI) to characterize CMRgl declines with optimal power and freedom from multiple comparisons, and we estimate the number of patients needed to characterize AD-slowing treatment effects in multi-center randomized clinical trials (RCTs). The AD and MCI groups each had significant twelve-month CMRgl declines bilaterally in posterior cingulate, medial and lateral parietal, medial and lateral temporal, frontal and occipital cortex, which were significantly greater than those in the NC group and correlated with measures of clinical decline. Using sROIs defined based on training sets of baseline and follow-up images to assess CMRgl declines in independent test sets from each patient group, we estimate the need for 66 AD patients or 217 MCI patients per treatment group to detect a 25% AD-slowing treatment effect in a twelve-month, multi-center RCT with 80% power and two-tailed alpha=0.05, roughly one-tenth the number of the patients needed to study MCI patients using clinical endpoints. Our findings support the use of FDG PET, brain-mapping algorithms and empirically pre-defined sROIs in RCTs of AD-slowing treatments.
This is a progress report of the Alzheimer's Disease Neuroimaging Initiative (ADNI) PET Core.
The Core has supervised the acquisition, quality control, and analysis of longitudinal [18F]fluorodeoxyglucose PET (FDG-PET) data in approximately half of the ADNI cohort. In an “add on” study, approximately 100 subjects also underwent scanning with [11C]PIB-PET for amyloid imaging. The Core developed quality control procedures and standardized image acquisition by developing an imaging protocol that has been widely adopted in academic and pharmaceutical industry studies. Data processing provides users with scans that have identical orientation and resolution characteristics despite acquisition on multiple scanner models. The Core labs have used a number of different approaches to characterize differences between subject groups (AD, MCI, controls), to examine longitudinal change over time in glucose metabolism and amyloid deposition, and to assess the use of FDG-PET as a potential outcome measure in clinical trials.
ADNI data indicate that FDG-PET increases statistical power over traditional cognitive measures, might aid subject selection, and could substantially reduce the sample size in a clinical trial. PIB-PET data showed expected group differences, and identified subjects with significant annual increases in amyloid load across the subject groups. The next activities of the PET core in ADNI will entail developing standardized protocols for amyloid imaging using the [18F]-labeled amyloid imaging agent AV45, which can be delivered to virtually all ADNI sites.
ADNI has demonstrated the feasibility and utility of multicenter PET studies and is helping to clarify the role of biomarkers in the study of aging and dementia.
PET; fluorodeoxyglucose; amyloid imaging; biomarkers
Cerebrospinal fluid (CSF) measures of Ab and tau, Pittsburgh Compound B (PIB) imaging and hippocampal atrophy are promising Alzheimer’s disease biomarkers yet the associations between them are not known. We applied a validated, automated hippocampal labeling method and 3D radial distance mapping to the 1.5T structural magnetic resonance imaging (MRI) data of 388 ADNI subjects with baseline CSF Ab42, total tau (t-tau) and phosphorylated tau (p-tau181) and 98 subjects with positron emission tomography (PET) imaging using PIB. We used linear regression to investigate associations between hippocampal atrophy and average cortical, parietal and precuneal PIB standardized uptake value ratio (SUVR) and CSF Ab42, t-tau, p-tau181, t-tau/Ab42 and p-tau181/Ab42. All CSF measures showed significant associations with hippocampal volume and radial distance in the pooled sample. Strongest correlations were seen for p-tau181, followed by p-tau181/Ab42 ratio, t-tau/Ab42 ratio, t-tau and Ab42. p-tau181 showed stronger correlation in ApoE4 carriers, while t-tau showed stronger correlation in ApoE4 noncarriers. Of the 3 PIB measures the precuneal SUVR showed strongest associations with hippocampal atrophy.
Alzheimer’s disease; MRI; Magnetic resonance imaging; Imaging; PIB; Amyloid imaging; Abeta; tau; Hippocampus; Atrophy; Biomarkers; ADNI