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1.  Cerebrospinal Fluid Biomarkers and Cerebral Atrophy in Distinct Clinical Variants of Probable Alzheimer’s Disease 
Neurobiology of aging  2015;36(8):2340-2347.
Different clinical variants of probable Alzheimer’s disease (AD) share underlying plaques and tangles but show distinct atrophy patterns. We included 52 posterior cortical atrophy (PCA), 29 logopenic variant primary progressive aphasia (lvPPA), 53 early-onset (EOAD) and 42 late-onset AD (LOAD) patients, selected for abnormal CSF-Aβ42, with CSF and MRI data available. Bootstrapping revealed no differences in the prevalence of abnormal CSF total-tau and phosphorylated-tau between probable AD variants (range total-tau: 84.9–92.3%, phosphorylated-tau: 79.2–93.1%, p>0.05). Voxel-wise linear regressions showed various relationships between lower CSF-Aβ42 and syndrome-specific atrophy, involving precuneus, posterior cingulate, and medial temporal lobe (MTL) in EOAD, occipital cortex and middle temporal gyrus in PCA; anterior cingulate, insular cortex and precentral gyrus (left>right) in lvPPA; and MTL, thalamus, and temporal pole in LOAD (all at p<0.001 uncorrected). In contrast, CSF-tau was not related to gray matter atrophy in any group. Our findings suggest that lower CSF-Aβ42 – and not increased total-tau and phosphorylated-tau – relates to reduced gray matter volumes, mostly in regions that are typically atrophied in distinct clinical variants of probable AD.
doi:10.1016/j.neurobiolaging.2015.04.011
PMCID: PMC4465267  PMID: 25990306
Alzheimer’s disease; cerebrospinal fluid; magnetic resonance imaging; amyloid; tau; atrophy
2.  Amyloid imaging, risk disclosure and Alzheimer’s disease: ethical and practical issues 
SUMMARY
PET ligands that bind with high specificity to amyloid plaques represent a major breakthrough in Alzheimer’s disease (AD) research. Amyloid neuroimaging is now approved by the US FDA to aid in the diagnosis of AD, and is being used to identify amyloid-positive but asymptomatic individuals for secondary AD prevention trials. The use of amyloid neuroimaging in preclinical populations raises important ethical and practical challenges, including determining appropriate uses of this technology, evaluating the potential benefits and harms of disclosing results, and communicating effectively about testing with patients and family members. Emerging policy issues also require consideration (e.g., legal safeguards for biomarker-positive individuals). Further research is needed to inform effective and ethical implementation and regulation of amyloid imaging.
doi:10.2217/nmt.13.25
PMCID: PMC4498486  PMID: 26167204
3.  Increased metabolic vulnerability in early-onset Alzheimer’s disease is not related to amyloid burden 
Brain  2010;133(2):512-528.
Patients with early age-of-onset Alzheimer’s disease show more rapid progression, more generalized cognitive deficits and greater cortical atrophy and hypometabolism compared to late-onset patients at a similar disease stage. The biological mechanisms that underlie these differences are not well understood. The purpose of this study was to examine in vivo whether metabolic differences between early-onset and late-onset Alzheimer’s disease are associated with differences in the distribution and burden of fibrillar amyloid-β. Patients meeting criteria for probable Alzheimer’s disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's; Disease and Related Disorders Association criteria) were divided based on estimated age at first symptom (less than or greater than 65 years) into early-onset (n = 21, mean age-at-onset 55.2 ± 5.9 years) and late-onset (n = 18, 72.0 ± 4.7 years) groups matched for disease duration and severity. Patients underwent positron emission tomography with the amyloid-β-ligand [11C]-labelled Pittsburgh compound-B and the glucose analogue [18F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 ± 6.4) was studied for comparison. [11C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [18F]-labelled fluorodeoxyglucose images were normalized to mean activity in the pons. Group differences in tracer uptake were assessed on a voxel-wise basis using statistical parametric mapping, and by comparing mean values in regions of interest. To account for brain atrophy, analyses were repeated after applying partial volume correction to positron emission tomography data. Compared to normal controls, both early-onset and late-onset Alzheimer’s disease patient groups showed increased [11C]-labelled Pittsburgh compound-B uptake throughout frontal, parietal and lateral temporal cortices and striatum on voxel-wise and region of interest comparisons (P < 0.05). However, there were no significant differences in regional or global [11C]-labelled Pittsburgh compound-B binding between early-onset and late-onset patients. In contrast, early-onset patients showed significantly lower glucose metabolism than late-onset patients in precuneus/posterior cingulate, lateral temporo–parietal and occipital corticies (voxel-wise and region of interest comparisons, P < 0.05). Similar results were found for [11C]-labelled Pittsburgh compound-B and [18F]-labelled fluorodeoxyglucose using atrophy-corrected data. Age-at-onset correlated positively with glucose metabolism in precuneus, lateral parietal and occipital regions of interest (controlling for age, education and Mini Mental State Exam, P < 0.05), while no correlations were found between age-at-onset and [11C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-β was associated with greater posterior cortical hypometabolism in early-onset Alzheimer’s disease. Our data are consistent with a model in which both early amyloid-β accumulation and increased vulnerability to amyloid-β pathology play critical roles in the pathogenesis of Alzheimer’s disease in young patients.
doi:10.1093/brain/awp326
PMCID: PMC2858015  PMID: 20080878
Alzheimer’s disease; age of onset; amyloid-β; [18F]-labelled fluorodeoxyglucose; [11C]-labelled Pittsburgh compound-B
4.  Frontotemporal Lobar Degeneration 
CNS drugs  2010;24(5):375-398.
Frontotemporal lobar degeneration (FTLD) is a clinically and pathologically heterogeneous syndrome, characterized by progressive decline in behaviour or language associated with degeneration of the frontal and anterior temporal lobes. While the seminal cases were described at the turn of the 20th century, FTLD has only recently been appreciated as a leading cause of dementia, particularly in patients presenting before the age of 65 years. Three distinct clinical variants of FTLD have been described: (i) behavioural-variant frontotemporal dementia, characterized by changes in behaviour and personality in association with frontal-predominant cortical degeneration; (ii) semantic dementia, a syndrome of progressive loss of knowledge about words and objects associated with anterior temporal neuronal loss; and (iii) progressive nonfluent aphasia, characterized by effortful language output, loss of grammar and motor speech deficits in the setting of left perisylvian cortical atrophy.
The majority of pathologies associated with FTLD clinical syndromes include either tau-positive (FTLD-TAU) or TAR DNA-binding protein 43 (TDP-43)-positive (FTLD-TDP) inclusion bodies. FTLD overlaps clinically and pathologically with the atypical parkinsonian disorders corticobasal degeneration and progressive supranuclear palsy, and with amyotrophic lateral sclerosis. The majority of familial FTLD cases are caused by mutations in the genes encoding microtubule-associated protein tau (leading to FTLD-TAU) or progranulin (leading to FTLD-TDP). The clinical and pathologic heterogeneity of FTLD poses a significant diagnostic challenge, and in vivo prediction of underlying histopathology can be significantly improved by supplementing the clinical evaluation with genetic tests and emerging biological markers. Current pharmacotherapy for FTLD focuses on manipulating serotonergic or dopaminergic neurotransmitter systems to ameliorate behavioural or motor symptoms. However, recent advances in FTLD genetics and molecular pathology make the prospect of biologically driven, disease-specific therapies for FTLD seem closer than ever.
doi:10.2165/11533100-000000000-00000
PMCID: PMC2916644  PMID: 20369906
5.  A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques 
Introduction
Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease.
Results
We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance.
Conclusions
TARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-015-0190-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s40478-015-0190-6
PMCID: PMC4382926  PMID: 25853458
Frontotemporal lobar degeneration; Frontotemporal dementia; Motor neuron disease; TDP-43; TARDBP; Postmortem
6.  Tau, Amyloid, and Hypometabolism in a Patient with Posterior Cortical Atrophy 
Annals of neurology  2014;77(2):338-342.
Determining the relative contribution of amyloid plaques and neurofibrillary tangles to brain dysfunction in Alzheimer disease is critical for therapeutic approaches, but until recently could only be assessed at autopsy. We report a patient with posterior cortical atrophy (visual variant of Alzheimer disease) who was studied using the novel tau tracer [18F]AV-1451 in conjunction with [11C]Pittsburgh compound B (PIB; amyloid) and [18F]fluorodeoxyglucose (FDG) positron emission tomography. Whereas [11C]PIB bound throughout association neocortex, [18F]AV-1451 was selectively retained in posterior brain regions that were affected clinically and showed markedly reduced [18F]FDG uptake. This provides preliminary in vivo evidence that tau is more closely linked to hypometabolism and symptomatology than amyloid.
doi:10.1002/ana.24321
PMCID: PMC4382124  PMID: 25448043
7.  Predicting amyloid status in corticobasal syndrome using modified clinical criteria, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography 
Introduction
Group comparisons demonstrate greater visuospatial and memory deficits and temporoparietal-predominant degeneration on neuroimaging in patients with corticobasal syndrome (CBS) found to have Alzheimer’s disease (AD) pathology versus those with underlying frontotemporal lobar degeneration (FTLD). The value of these features in predicting underlying AD pathology in individual patients is unknown. The goal of this study is to evaluate the utility of modified clinical criteria and visual interpretations of magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) for predicting amyloid deposition (as a surrogate of Alzheimer’s disease neuropathology) in patients presenting with CBS.
Methods
In total, 25 patients meeting CBS core criteria underwent amyloid (Pittsburgh compound B; PIB) PET scans. Clinical records, MRI, and FDG scans were reviewed blinded to PIB results. Modified clinical criteria were used to classify CBS patients as temporoparietal variant CBS (tpvCBS) or frontal variant CBS (fvCBS). MRI and FDG-PET were classified based on the predominant atrophy/hypometabolism pattern (frontal or temporoparietal).
Results
A total of 9 out of 13 patients classified as tpvCBS were PIB+, compared to 2out of 12 patients classified as fvCBS (P < 0.01, sensitivity 82%, specificity 71% for PIB+ status). Visual MRI reads had 73% sensitivity and 46% specificity for PIB+ status with moderate intra-rater reliability (Cohen’s kappa = 0.42). Visual FDG reads had higher sensitivity (91%) for PIB+ status with perfect intra-rater reliability (kappa = 1.00), though specificity was low (50%). PIB results were confirmed in all 8 patients with available histopathology (3 PIB+ with confirmed AD, 5 PIB- with FTLD).
Conclusions
Splitting CBS patients into frontal or temporoparietal clinical variants can help predict the likelihood of underlying AD, but criteria require further refinement. Temporoparietal-predominant neuroimaging patterns are sensitive but not specific for AD.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-014-0093-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-014-0093-y
PMCID: PMC4346122  PMID: 25733984
8.  Divergent CSF tau alterations in two common tauopathies: Alzheimer’s disease and Progressive Supranuclear Palsy 
Background
Elevated CSF tau is considered a biomarker of neuronal injury in newly developed Alzheimer’s disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of tau species in other primary tauopathies. We assessed CSF tau protein abnormalities in AD, a tauopathy with prominent Aβ pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterized by deposition of four microtubule binding repeat (4R) tau with minimal Aβ pathology.
Methods
26 normal control (NC), 37 AD, and 24 PSP patients participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aβ, total tau, and ptau181. Additional, novel ELISAs targeting different N-terminal and central tau epitopes were developed to examine CSF tau components and to investigate interactions between diagnostic group, demographics, and genetic variables.
Results
PSP had lower CSF N-terminal and C-terminal tau concentrations than NC and AD measured with both the novel tau ELISAs and the standard AlzBio3 tau and ptau assays. AD had higher total tau and ptau levels than NC and PSP. There was a gender by diagnosis interaction in both AD and PSP for most tau species, with lower concentrations for male compared to female patients.
Conclusions
CSF tau fragment concentrations are different in PSP compared with AD despite the presence of severe tau pathology and neuronal injury in both disorders. CSF tau concentration likely reflects multiple factors in addition to the degree of neuronal injury.
doi:10.1136/jnnp-2014-308004
PMCID: PMC4256124  PMID: 24899730
Alzheimer’s disease; Progressive supranuclear palsy; CSF; Tau
9.  Prodromal Posterior Cortical Atrophy: Clinical, Neuropsychological and Radiological Correlation 
Neurocase  2013;21(1):44-55.
We present longitudinal clinical, cognitive and neuroimaging data from a 63-year-old woman who enrolled in research as a normal control and evolved posterior cortical atrophy (PCA) over five year follow-up. At baseline she reported only subtle difficulty driving and performed normally on cognitive tests, but already demonstrated atrophy in left visual association cortex. With follow-up she developed insidiously progressive visuospatial and visuoperceptual deficits, correlating with progressive atrophy in bilateral visual areas. Amyloid PET was positive. This case tracks the evolution of PCA from the prodromal stage, and illustrates challenges to early diagnosis as well as the utility of imaging biomarkers.
doi:10.1080/13554794.2013.860176
PMCID: PMC4318700  PMID: 24308559
10.  Handedness and language learning disability differentially distribute in progressive aphasia variants 
Brain  2013;136(11):3461-3473.
Primary progressive aphasia is a neurodegenerative clinical syndrome that presents in adulthood with an isolated, progressive language disorder. Three main clinical/anatomical variants have been described, each associated with distinctive pathology. A high frequency of neurodevelopmental learning disability in primary progressive aphasia has been reported. Because the disorder is heterogeneous with different patterns of cognitive, anatomical and biological involvement, we sought to identify whether learning disability had a predilection for one or more of the primary progressive aphasia subtypes. We screened the University of California San Francisco Memory and Aging Center's primary progressive aphasia cohort (n = 198) for history of language-related learning disability as well as hand preference, which has associations with learning disability. The study included logopenic (n = 48), non-fluent (n = 54) and semantic (n = 96) variant primary progressive aphasias. We investigated whether the presence of learning disability or non-right-handedness was associated with differential effects on demographic, neuropsychological and neuroimaging features of primary progressive aphasia. We showed that a high frequency of learning disability was present only in the logopenic group (χ2 = 15.17, P < 0.001) and (χ2 = 11.51, P < 0.001) compared with semantic and non-fluent populations. In this group, learning disability was associated with earlier onset of disease, more isolated language symptoms, and more focal pattern of left posterior temporoparietal atrophy. Non-right-handedness was instead over-represented in the semantic group, at nearly twice the prevalence of the general population (χ2 = 6.34, P = 0.01). Within semantic variant primary progressive aphasia the right-handed and non-right-handed cohorts appeared homogeneous on imaging, cognitive profile, and structural analysis of brain symmetry. Lastly, the non-fluent group showed no increase in learning disability or non-right-handedness. Logopenic variant primary progressive aphasia and developmental dyslexia both manifest with phonological disturbances and posterior temporal involvement. Learning disability might confer vulnerability of this network to early-onset, focal Alzheimer’s pathology. Left-handedness has been described as a proxy for atypical brain hemispheric lateralization. As non-right-handedness was increased only in the semantic group, anomalous lateralization mechanisms might instead be related to frontotemporal lobar degeneration with abnormal TARDBP. Taken together, this study suggests that neurodevelopmental signatures impart differential trajectories towards neurodegenerative disease.
doi:10.1093/brain/awt242
PMCID: PMC3808687  PMID: 24056533
Alzheimer’s disease; frontotemporal dementia; dementia aphasia; case control study; risk factors in epidemiology
11.  Neurodegenerative disease phenotypes in carriers of MAPT p.A152T, a risk factor for frontotemporal dementia spectrum disorders and Alzheimer's disease 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31828cc357.
Recently, Coppola and colleagues demonstrated that a rare MAPT sequence variant, c.454G>A (p.A152T), significantly increases the risk of frontotemporal dementia (FTD) spectrum disorders and Alzheimer's disease (AD) in a screen of 15,369 subjects1. We describe clinical features of 9 patients with neurodegenerative disease (4 women) harboring p.A152T, aged 51 to 79 years at symptom onset. Seven developed FTD spectrum clinical syndromes, including progressive supranuclear palsy syndrome (PSP, n=2), behavioral variant FTD (bvFTD, n=1), nonfluent variant primary progressive aphasia (nfvPPA, n=2), and corticobasal syndrome (CBS, n=2); two patients were diagnosed with clinical AD. Thus, MAPT p.A152T is associated with a variety of FTD spectrum clinical presentations, although patients with clinical AD are also identified. These data warrant larger studies with clinicopathological correlation to elucidate the influence of this genetic variant on neurodegenerative disease.
doi:10.1097/WAD.0b013e31828cc357
PMCID: PMC3796183  PMID: 23518664
All Cognitive Disorders/Dementia; Alzheimer's disease; Frontotemporal Dementia; Corticobasal degeneration; Progressive Supranuclear Palsy
12.  Amyloid imaging in atypical dementia 
doi:10.1503/cmaj.131158
PMCID: PMC4049995  PMID: 24446462
13.  Seizures and Epileptiform Activity in the Early Stages of Alzheimer Disease 
JAMA neurology  2013;70(9):1158-1166.
IMPORTANCE
Epileptic activity associated with Alzheimer disease (AD) deserves increased attention because it has a harmful impact on these patients, can easily go unrecognized and untreated, and may reflect pathogenic processes that also contribute to other aspects of the illness. We report key features of AD-related seizures and epileptiform activity that are instructive for clinical practice and highlight similarities between AD and transgenic animal models of the disease.
OBJECTIVE
To describe common clinical characteristics and treatment outcomes of patients with amnestic mild cognitive impairment (aMCI) or early AD who also have epilepsy or subclinical epileptiform activity.
DESIGN
Retrospective observational study from 2007 to 2012.
SETTING
Memory and Aging Center, University of California, San Francisco.
PATIENTS
We studied 54 patients with a diagnosis of aMCI plus epilepsy (n = 12), AD plus epilepsy (n = 35), and AD plus subclinical epileptiform activity (n = 7).
MAIN OUTCOMES AND MEASURES
Clinical and demographic data, electroencephalogram (EEG) readings, and treatment responses to antiepileptic medications.
RESULTS
Patients with aMCI who had epilepsy presented with symptoms of cognitive decline 6.8 years earlier than patients with aMCI who did not have epilepsy (64.3 vs 71.1 years; P = .02). Patients with AD who had epilepsy presented with cognitive decline 5.5 years earlier than patients with AD who did not have epilepsy (64.8 vs 70.3 years; P = .001). Patients with AD who had subclinical epileptiform activity also had an early onset of cognitive decline (58.9 years). The timing of seizure onset in patients with aMCI and AD was nonuniform (P < .001), clustering near the onset of cognitive decline. Epilepsies were most often complex partial seizures (47%) and more than half were nonconvulsive (55%). Serial or extended EEG monitoring appeared to be more effective than routine EEG at detecting interictal and subclinical epileptiform activity. Epileptic foci were predominantly unilateral and temporal. Of the most commonly prescribed antiepileptics, treatment outcomes appeared to be better for lamotrigine and levetiracetam than for phenytoin.
CONCLUSIONS AND RELEVANCE
Common clinical features of patients with aMCI- or AD-associated epilepsy at our center included early age at onset of cognitive decline, early incidence of seizures in the disease course, unilateral temporal epileptic foci detected by serial/extended EEG, transient cognitive dysfunction, and good seizure control and tolerability with lamotrigine and levetiracetam. Careful identification and treatment of epilepsy in such patients may improve their clinical course.
doi:10.1001/jamaneurol.2013.136
PMCID: PMC4013391  PMID: 23835471
14.  Parallel ICA of FDG-PET and PiB-PET in three conditions with underlying Alzheimer's pathology 
NeuroImage : Clinical  2014;4:508-516.
The relationships between clinical phenotype, β-amyloid (Aβ) deposition and neurodegeneration in Alzheimer's disease (AD) are incompletely understood yet have important ramifications for future therapy. The goal of this study was to utilize multimodality positron emission tomography (PET) data from a clinically heterogeneous population of patients with probable AD in order to: (1) identify spatial patterns of Aβ deposition measured by (11C)-labeled Pittsburgh Compound B (PiB-PET) and glucose metabolism measured by FDG-PET that correlate with specific clinical presentation and (2) explore associations between spatial patterns of Aβ deposition and glucose metabolism across the AD population. We included all patients meeting the criteria for probable AD (NIA–AA) who had undergone MRI, PiB and FDG-PET at our center (N = 46, mean age 63.0 ± 7.7, Mini-Mental State Examination 22.0 ± 4.8). Patients were subclassified based on their cognitive profiles into an amnestic/dysexecutive group (AD-memory; n = 27), a language-predominant group (AD-language; n = 10) and a visuospatial-predominant group (AD-visuospatial; n = 9). All patients were required to have evidence of amyloid deposition on PiB-PET. To capture the spatial distribution of Aβ deposition and glucose metabolism, we employed parallel independent component analysis (pICA), a method that enables joint analyses of multimodal imaging data. The relationships between PET components and clinical group were examined using a Receiver Operator Characteristic approach, including age, gender, education and apolipoprotein E ε4 allele carrier status as covariates. Results of the first set of analyses independently examining the relationship between components from each modality and clinical group showed three significant components for FDG: a left inferior frontal and temporoparietal component associated with AD-language (area under the curve [AUC] 0.82, p = 0.011), and two components associated with AD-visuospatial (bilateral occipito-parieto-temporal [AUC 0.85, p = 0.009] and right posterior cingulate cortex [PCC]/precuneus and right lateral parietal [AUC 0.69, p = 0.045]). The AD-memory associated component included predominantly bilateral inferior frontal, cuneus and inferior temporal, and right inferior parietal hypometabolism but did not reach significance (AUC 0.65, p = 0.062). None of the PiB components correlated with clinical group. Joint analysis of PiB and FDG with pICA revealed a correlated component pair, in which increased frontal and decreased PCC/precuneus PiB correlated with decreased FDG in the frontal, occipital and temporal regions (partial r = 0.75, p < 0.0001). Using multivariate data analysis, this study reinforced the notion that clinical phenotype in AD is tightly linked to patterns of glucose hypometabolism but not amyloid deposition. These findings are strikingly similar to those of univariate paradigms and provide additional support in favor of specific involvement of the language network, higher-order visual network, and default mode network in clinical variants of AD. The inverse relationship between Aβ deposition and glucose metabolism in partially overlapping brain regions suggests that Aβ may exert both local and remote effects on brain metabolism. Applying multivariate approaches such as pICA to multimodal imaging data is a promising approach for unraveling the complex relationships between different elements of AD pathophysiology.
Highlights
•Multivariate approaches may be best suited to study links between biomarkers.•This is the first effort to apply pICA to FDG and PiB data in three groups with AD.•Hypometabolism was focal but amyloid binding was similar across conditions.•Results provide support for involvement of functional networks in variants of AD.•Aβ may exert both local and remote effects on brain metabolism.
doi:10.1016/j.nicl.2014.03.005
PMCID: PMC3984448  PMID: 24818077
Multivariate data analysis; Parallel ICA; Alzheimer's disease; Amyloid imaging; PiB-PET; FDG-PET; Functional connectivity; Networks; AD or AD-memory, Alzheimer's disease; AUC, area under the curve; AD-language or LPA, logopenic variant primary progressive aphasia; PCA or AD-visuospatial, posterior cortical atrophy; PCC, posterior cingulate cortex; PPC, posterior parietal cortex
15.  Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients 
Background
ApoE4 has been associated with an increased risk of Alzheimer’s disease (AD), amyloid deposition and hypometabolism. ApoE4 is less prevalent in non-amnestic AD variants suggesting a direct effect on the clinical phenotype. However, the impact of ApoE4 on amyloid burden and glucose metabolism across different clinical AD syndromes is not well understood. We aimed to assess the relationship between amyloid deposition, glucose metabolism and ApoE4 genotype in a clinically heterogeneous population of AD patients.
Methods
Fifty-two patients with probable AD (NIA-AA) underwent [11C]Pittsburgh compound B (PIB) and [18F]fluorodeoxyglucose (FDG) PET scans. All patients had positive PIB-PET scans. 23 were ApoE4+ (14 heterozygous, 9 homozygous) and 29 were ApoE4−. Groups consisted of language-variant AD, visual-variant AD, and AD patients with amnestic and dysexecutive deficits. 52 healthy controls were included for comparison. FDG and PIB uptake was compared between groups on a voxel-wise basis and in regions-of-interest.
Results
Whilst PIB patterns were diffuse in both patient groups, ApoE4− patients showed higher PIB uptake than ApoE4+ patients across the cortex. Higher PIB uptake in ApoE4− patients was particularly significant in right lateral frontotemporal regions. In contrast, similar patterns of hypometabolism relative to controls were found in both patient groups, mainly involving lateral temporoparietal cortex, precuneus, posterior cingulate cortex, and middle frontal gyrus. Comparing patient groups, ApoE4+ subjects showed greater hypometabolism in bilateral medial temporal and right lateral temporal regions, and ApoE4− patients showed greater hypometabolism in cortical areas including supplementary motor cortex and superior frontal gyrus.
Conclusions
ApoE4+ AD patients showed lower global amyloid burden and greater medial temporal hypometabolism compared to matched ApoE4− patients. These findings suggest that ApoE4 may increase susceptibility to molecular pathology and modulate the anatomic pattern of neurodegeneration in AD.
doi:10.1136/jnnp-2013-305858
PMCID: PMC3946299  PMID: 23965289
Alzheimer’s disease; PET; amyloid; glucose metabolism; apolipoprotein E
16.  Diverging patterns of amyloid deposition and hypometabolism in clinical variants of probable Alzheimer’s disease 
Brain  2013;136(3):844-858.
The factors driving clinical heterogeneity in Alzheimer’s disease are not well understood. This study assessed the relationship between amyloid deposition, glucose metabolism and clinical phenotype in Alzheimer’s disease, and investigated how these relate to the involvement of functional networks. The study included 17 patients with early-onset Alzheimer’s disease (age at onset <65 years), 12 patients with logopenic variant primary progressive aphasia and 13 patients with posterior cortical atrophy [whole Alzheimer’s disease group: age = 61.5 years (standard deviation 6.5 years), 55% male]. Thirty healthy control subjects [age = 70.8 (3.3) years, 47% male] were also included. Subjects underwent positron emission tomography with 11C-labelled Pittsburgh compound B and 18F-labelled fluorodeoxyglucose. All patients met National Institute on Ageing–Alzheimer’s Association criteria for probable Alzheimer’s disease and showed evidence of amyloid deposition on 11C-labelled Pittsburgh compound B positron emission tomography. We hypothesized that hypometabolism patterns would differ across variants, reflecting involvement of specific functional networks, whereas amyloid patterns would be diffuse and similar across variants. We tested these hypotheses using three complimentary approaches: (i) mass-univariate voxel-wise group comparison of 18F-labelled fluorodeoxyglucose and 11C-labelled Pittsburgh compound B; (ii) generation of covariance maps across all subjects with Alzheimer’s disease from seed regions of interest specifically atrophied in each variant, and comparison of these maps to functional network templates; and (iii) extraction of 11C-labelled Pittsburgh compound B and 18F-labelled fluorodeoxyglucose values from functional network templates. Alzheimer’s disease clinical groups showed syndrome-specific 18F-labelled fluorodeoxyglucose patterns, with greater parieto-occipital involvement in posterior cortical atrophy, and asymmetric involvement of left temporoparietal regions in logopenic variant primary progressive aphasia. In contrast, all Alzheimer’s disease variants showed diffuse patterns of 11C-labelled Pittsburgh compound B binding, with posterior cortical atrophy additionally showing elevated uptake in occipital cortex compared with early-onset Alzheimer’s disease. The seed region of interest covariance analysis revealed distinct 18F-labelled fluorodeoxyglucose correlation patterns that greatly overlapped with the right executive-control network for the early-onset Alzheimer’s disease region of interest, the left language network for the logopenic variant primary progressive aphasia region of interest, and the higher visual network for the posterior cortical atrophy region of interest. In contrast, 11C-labelled Pittsburgh compound B covariance maps for each region of interest were diffuse. Finally, 18F-labelled fluorodeoxyglucose was similarly reduced in all Alzheimer’s disease variants in the dorsal and left ventral default mode network, whereas significant differences were found in the right ventral default mode, right executive-control (both lower in early-onset Alzheimer’s disease and posterior cortical atrophy than logopenic variant primary progressive aphasia) and higher-order visual network (lower in posterior cortical atrophy than in early-onset Alzheimer’s disease and logopenic variant primary progressive aphasia), with a trend towards lower 18F-labelled fluorodeoxyglucose also found in the left language network in logopenic variant primary progressive aphasia. There were no differences in 11C-labelled Pittsburgh compound B binding between syndromes in any of the networks. Our data suggest that Alzheimer’s disease syndromes are associated with degeneration of specific functional networks, and that fibrillar amyloid-β deposition explains at most a small amount of the clinico-anatomic heterogeneity in Alzheimer’s disease.
doi:10.1093/brain/aws327
PMCID: PMC3580269  PMID: 23358601
Alzheimer’s disease; posterior cortical atrophy; logopenic variant of PPA; positron emission tomography (PET); functional networks
17.  Imaging markers for Alzheimer disease 
Neurology  2013;81(5):487-500.
Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, 18F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured (“metric”: visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR−), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR− between 0.25 and 0.08, whereas prognostic LR+ and LR− were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR− from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR−. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR−. Within markers, the largest proportion of diagnostic LR+ and LR− variability was within 18F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.
doi:10.1212/WNL.0b013e31829d86e8
PMCID: PMC3776529  PMID: 23897875
18.  Alzheimer’s disease neurodegenerative biomarkers are associated with decreased cognitive function but not beta-amyloid in cognitively normal older individuals 
Beta amyloid (Aβ)-plaque deposition and neurodegeneration within temporoparietal and hippocampal regions may indicate increased risk of Alzheimer’s disease (AD). This study examined relationships between AD biomarkers of Aβ and neurodegeneration as well as cognitive performance in cognitively normal older individuals. Aβ burden was quantified in 72 normal older human subjects from the Berkeley Aging Cohort (BAC) using [11C] Pittsburgh compound B (PIB) PET. In the same individuals, we measured hippocampal volume, as well as glucose metabolism and cortical thickness, which were extracted from a template of cortical AD-affected regions. The three functional and structural biomarkers were merged into a highly AD-sensitive multi-modality biomarker reflecting neural integrity. In the normal older individuals, there was no association between Aβ burden and either the single-modality or the multi-modality neurodegenerative biomarkers. While lower neural integrity within the AD-affected regions and a control area (the visual cortex) was related to lower scores on memory and executive function tests, the same association was not found with PIB retention. The relationship between cognition and the multi-modality AD biomarker was stronger in individuals with the highest PIB uptake. The findings indicate that neurodegeneration occurs within AD regions irrespective of Aβ deposition and accounts for worse cognition in cognitively normal older people. The impact of neural integrity on cognitive functions is enhanced in the presence of high Aβ burden for regions that are vulnerable to AD pathology.
doi:10.1523/JNEUROSCI.4409-12.2013
PMCID: PMC3687777  PMID: 23536070
19.  Association of Lifetime Cognitive Engagement and Low β-Amyloid Deposition 
Archives of neurology  2012;69(5):623-629.
Objective
To assess the association between lifestyle practices (cognitive and physical activity) and β-amyloid deposition, measured with positron emission tomography using carbon 11–labeled Pittsburgh Compound B ([11C]PiB), in healthy older individuals.
Design
Cross-sectional clinical study.
Setting
Berkeley, California.
Participants
Volunteer sample of 65 healthy older individuals (mean age, 76.1 years), 10 patients with Alzheimer disease (AD) (mean age, 74.8 years), and 11 young controls (mean age, 24.5 years) were studied from October 31, 2005, to February 22, 2011.
Main Outcome Measures
Cortical [11C]PiB average (frontal, parietal, lateral temporal, and cingulate regions) and retrospective, self-report scales assessing participation in cognitive activities (eg, reading, writing, and playing games) and physical exercise.
Results
Greater participation in cognitively stimulating activities across the lifespan, but particularly in early and middle life, was associated with reduced [11C]PiB uptake (P <.001, accounting for age, sex, and years of education). Older participants in the highest cognitive activity tertile had [11C]PiB uptake comparable to young controls, whereas those in the lowest cognitive activity tertile had [11C]PiB uptake comparable to patients with AD. Although greater cognitive activity was associated with greater physical exercise, exercise was not associated with [11C]PiB uptake.
Conclusions
Individuals with greater early- and middle-life cognitive activity had lower [11C]PiB uptake. The tendency to participate in cognitively stimulating activities is likely related to engagement in a variety of lifestyle practices that have been implicated in other studies showing reduced risk of AD-related pathology. We report a direct association between cognitive activity and [11C]PiB uptake, suggesting that lifestyle factors found in individuals with high cognitive engagement may prevent or slow deposition of β-amyloid, perhaps influencing the onset and progression of AD.
doi:10.1001/archneurol.2011.2748
PMCID: PMC3747737  PMID: 22271235
20.  Posterior Cortical Atrophy 
Lancet neurology  2012;11(2):170-178.
Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterized by a progressive decline in visuospatial, visuoperceptual, literacy and praxic skills. The progressive neurodegeneration affecting parietal, occipital and occipito-temporal cortices which underlies PCA is attributable to Alzheimer's disease (AD) in the majority of patients. However, alternative underlying aetiologies including Dementia with Lewy Bodies (DLB), corticobasal degeneration (CBD) and prion disease have also been identified, and not all PCA patients have atrophy on clinical imaging. This heterogeneity has led to diagnostic and terminological inconsistencies, caused difficulty comparing studies from different centres, and limited the generalizability of clinical trials and investigations of factors driving phenotypic variability. Significant challenges remain in identifying the factors associated with both the selective vulnerability of posterior cortical regions and the young age of onset seen in PCA. Greater awareness of the syndrome and agreement over the correspondence between syndrome-and disease-level classifications are required in order to improve diagnostic accuracy, research study design and clinical management.
doi:10.1016/S1474-4422(11)70289-7
PMCID: PMC3740271  PMID: 22265212
21.  White Matter atrophy in Alzheimer Disease variants 
Background
In comparison to late-onset Alzheimer’s disease (LO-AD, onset > 65), early age-of-onset Alzheimer’s disease (EO-AD, onset<65 years) more often presents with language, visuospatial and/or executive impairment, often occurring earlier than a progressive memory deficit. The logopenic variant of primary progressive aphasia (lv-PPA) and the posterior cortical atrophy (PCA) have recently been described as possible atypical variants of EO-AD. Lv-PPA is characterized by isolated language deficit, while PCA is characterized by predominant visuospatial deficits. Severe hemispheric grey matter (GM) atrophy associated with EO-AD, lv-PPA and PCA has been described, but regional patterns of white matter (WM) damage are still poorly understood.
Methods
Using structural MRI and voxel-based morphometry, we investigated WM damage in 16 EO-AD, 13 PCA, 10 lv-PPA, and 14 LO-AD patients at presentation, and 72 age-matched controls.
Results
In EO-AD, PCA and lv-PPA patients, WM atrophy was centered on lateral temporal and parietal regions, including cingulum and posterior corpus callosum. Compared to controls, lv-PPA patients showed a more severe left parietal damage, and PCA showed a more severe occipital atrophy. Moreover, EO-AD had greater cingulum atrophy compared with LO-AD. LO-AD showed WM damage in medial temporal regions and less extensive hemispheric involvement.
Conclusions
Patterns of WM damage in EO-AD, lv-PPA and PCA are consistent with the clinical syndromes and GM atrophy patterns. WM injury in AD atypical variants may contribute to symptoms and disease pathogenesis.
doi:10.1016/j.jalz.2012.04.010
PMCID: PMC3717610  PMID: 23021625
Alzheimer’s disease; white matter damage; cerebral network; age of onset; VBM
22.  ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease 
Neurocase  2012;19(3):295-301.
Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is characterized by neuronal cytoplasmic inclusions containing TDP-43. Apolipoprotein E4 (apoE4), derived from the apoE ε4 allele, enhances brain atrophy in FTLD through unknown mechanisms. Here, we studied two siblings with C9ORF72-linked familial FTLD-MND, an apoE ε4 homozygote and an apoE ε3 homozygote. The apoE ε4 homozygote had more cognitive-behavioral symptoms, fronto-insulo-temporal atrophy, and apoE fragments and aggregates in the anterior cingulate cortex. ApoE formed complexes with TDP-43 that were more abundant in the apoE ε4 homozygote. Although differences seen in a sibling pair could arise due to chance, these findings raise the possibility that apoE4 exacerbates brain pathology in FTLD through formation of neurotoxic apoE fragments and interactions with TDP-43.
doi:10.1080/13554794.2012.667124
PMCID: PMC3655113  PMID: 22512241
Apolipoprotein E; TDP-43; Frontotemporal dementia; Motor neuron disease; Neuropathology
23.  Cognition, glucose metabolism and amyloid burden in Alzheimer’s disease 
Neurobiology of aging  2010;33(2):215-225.
We investigated relationships between glucose metabolism, amyloid load and measures of cognitive and functional impairment in Alzheimer’s disease (AD). Patients meeting criteria for probable AD underwent [11C]PIB and [18F]FDG PET imaging and were assessed on a set of clinical measures. PIB Distribution volume ratios and FDG scans were spatially normalized and average PIB counts from regions-of-interest (ROI) were used to compute a measure of global PIB uptake. Separate voxel-wise regressions explored local and global relationships between metabolism, amyloid burden and clinical measures. Regressions reflected cognitive domains assessed by individual measures, with visuospatial tests associated with more posterior metabolism, and language tests associated with metabolism in the left hemisphere. Correlating regional FDG uptake with these measures confirmed these findings. In contrast, no correlations were found between either voxel-wise or regional PIB uptake and any of the clinical measures. Finally, there were no associations between regional PIB and FDG uptake. We conclude that regional and global amyloid burden does not correlate with clinical status or glucose metabolism in AD.
doi:10.1016/j.neurobiolaging.2010.03.011
PMCID: PMC2920373  PMID: 20417582
amyloid plaques; amyloidosis; Alzheimer’s disease; glucose metabolism; Pittsburgh compound-B; Fluorodeoxyglucose; dementia severity; cognition
24.  Not quite PIB-positive, not quite PIB-negative: slight PIB elevations in elderly normal control subjects are biologically relevant. 
NeuroImage  2011;59(2):1152-1160.
Researchers employing Pittsburgh Compound B positron emission tomography (PIB-PET) imaging have consistently indentified old normal control (oNC) subjects with elevated tracer uptake, suggesting the presence of beta-amyloid deposition in these individuals. However, a consensus regarding the level at which PIB reveals a biologically meaningful signal does not exist (ie. an appropriate cutoff value for PIB positivity remains unclear). In this exploratory study, we sought to investigate the range of PIB distribution volume ratio (DVR) values present in our oNC cohort (N=75, age range=58-97). oNC subjects were classified based on global PIB index values (average DVR across prefrontal, parietal, lateral temporal and cingulate cortices) by employing two approaches: (1) an iterative outlier approach that revealed a cutoff value of 1.16 (IO-cutoff) and (2) an approach using data from a sample of young normal control subjects (N=11, age range=20-30) that yielded a cutoff value of 1.08 (yNC-cutoff). oNC subjects falling above the IO-cutoff had values similar to AD subjects (“PIB+”, 15%). Subjects falling between the 2 cutoffs were considered to have ambiguous PIB status (“Ambig”, 20%) and the remaining oNC were considered “PIB-“ (65%). Additional measures capturing focal DVR magnitude and extent of elevated DVR values were consistent with the classification scheme using PIB index values, and revealed evidence for elevated DVR values in a subset of PIB- oNC subjects. Furthermore, there were a greater proportion of ambiguously elevated values compared to low values, and these elevated values were present in regions known to show amyloid deposition. The analyses presented in this study, in conjunction with recently published pathological data, suggest a biological relevance of slight PIB elevations in aging.
doi:10.1016/j.neuroimage.2011.07.098
PMCID: PMC3230690  PMID: 21884802
PIB-PET imaging; aging; Alzheimer's disease (AD); beta-amyloid; PIB-positivity; preclinical AD
25.  Using Pittsburgh Compound B for In Vivo PET Imaging of Fibrillar Amyloid-Beta 
The development of Aβ-PET imaging agents has allowed for detection of fibrillar Aβ deposition in vivo and marks a major advancement in understanding the role of Aβ in Alzheimer’s disease (AD). Imaging Aβ thus has many potential clinical benefits: early or perhaps preclinical detection of disease and accurately distinguishing AD from dementias of other non-Aβ causes in patients presenting with mild or atypical symptoms or confounding comorbidities (in which the distinction is difficult to make clinically). From a research perspective, imaging Aβ allows us to study relationships between amyloid pathology and changes in cognition, brain structure, and function across the continuum from normal aging to mild cognitive impairment (MCI) to AD; and to monitor the effectiveness of anti-Aβ drugs and relate them to neurodegeneration and clinical symptoms. Here, we will discuss the application of one of the most broadly studied and widely used Aβ imaging agents, Pittsburgh Compound-B (PiB).
doi:10.1016/B978-0-12-394816-8.00002-7
PMCID: PMC3542972  PMID: 22840744

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