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.
amyloid plaques; amyloidosis; Alzheimer’s disease; glucose metabolism; Pittsburgh compound-B; Fluorodeoxyglucose; dementia severity; cognition
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.
PIB-PET imaging; aging; Alzheimer's disease (AD); beta-amyloid; PIB-positivity; preclinical AD
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).
The role of biomarkers in predicting pathological findings in the frontotemporal dementia (FTD) clinical spectrum disorders is still being explored. We present comprehensive, prospective longitudinal data for a 66 year old, right-handed female who met current criteria for the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA). She first presented with a 3-year history of progressive speech and language impairment mainly characterized by severe apraxia of speech. Neuropsychological and general motor functions remained relatively spared throughout the clinical course. Voxel-based morphometry (VBM) showed selective cortical atrophy of the left posterior inferior frontal gyrus (IFG) and underlying insula that worsened over time, extending along the left premotor strip. Five years after her first evaluation, she developed mild memory impairment and underwent PET-FDG and PiB scans that showed left frontal hypometabolism and cortical amyloidosis. Three years later (11 years from first symptom), post-mortem histopathological evaluation revealed Pick’s disease, with severe degeneration of left IFG, mid-insula, and precentral gyrus. Alzheimer’s disease (AD) (CERAD frequent / Braak Stage V) was also detected. This patient demonstrates that biomarkers indicating brain amyloidosis should not be considered conclusive evidence that AD pathology accounts for a typical FTD clinical/anatomical syndrome.
Nonfluent primary progressive aphasia; PPA; apraxia of speech; Voxel-based morphometry; PiB-PET; Pick’s disease; Alzheimer disease; Frontotemporal dementia
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.
Although beta-amyloid (Aβ) deposition is a characteristic feature of Alzheimer's disease (AD), this pathology is commonly found in elderly normal controls (NC). The pattern of Aβ deposition as detected with Pittsburgh compound-B positron emission tomography (PIB-PET) imaging shows substantial spatial overlap with the default mode network (DMN), a group of brain regions that typically deactivates during externally driven cognitive tasks. In this study, we show that DMN functional connectivity (FC) during rest is altered with increasing levels of PIB uptake in NC. Specifically, FC decreases were identified in regions implicated in episodic memory (EM) processing (posteromedial cortex, ventral medial prefrontal cortex, and angular gyrus), whereas connectivity increases were detected in dorsal and anterior medial prefrontal and lateral temporal cortices. This pattern of decreases is consistent with previous studies that suggest heightened vulnerability of EM-related brain regions in AD, whereas the observed increases in FC may reflect a compensatory response.
aging; beta-amyloid; PIB-PET; resting state fMRI
To characterize cognitive and behavioral features, physical findings and brain atrophy patterns in pathology-proven corticobasal degeneration (CBD) and corticobasal syndrome (CBS) with known histopathology.
We reviewed clinical and MRI data in all patients evaluated at our center with either an autopsy diagnosis of CBD (n=18) or clinical CBS at first presentation with known histopathology (n=40). Atrophy patterns were compared using voxel-based morphometry.
CBD was associated with four clinical syndromes: progressive nonfluent aphasia (5), behavioral variant frontotemporal dementia (5), executive-motor (7), and posterior cortical atrophy (1). Behavioral or cognitive problems were the initial symptoms in 15/18 patients; less than half exhibited early motor findings. Compared to controls, CBD patients showed atrophy in dorsal prefrontal and peri-rolandic cortex, striatum and brainstem (p<0.001 uncorrected). The most common pathologic substrates for clinical CBS were CBD (35%), Alzheimer’s disease (AD, 23%), progressive supranuclear palsy (13%), and frontotemporal lobar degeneration (FTLD) with TDP inclusions (13%). CBS was associated with perirolandic atrophy irrespective of underlying pathology. In CBS due to FTLD (tau or TDP), atrophy extended into prefrontal cortex, striatum and brainstem, while in CBS due to AD, atrophy extended into temporoparietal cortex and precuneus (p<0.001 uncorrected).
Frontal lobe involvement is characteristic of CBD, and in many patients frontal, not parietal or basal ganglia symptoms, dominate early-stage disease. CBS is driven by medial peri-rolandic dysfunction, but this anatomy is not specific to one single underlying histopathology. Antemortem prediction of CBD will remain challenging until clinical features of CBD are redefined, and sensitive, specific biomarkers are identified.
In the past decade, positron emission tomography (PET) with carbon-11-labeled Pittsburgh Compound B (PIB) has revolutionized the neuroimaging of aging and dementia by enabling in vivo detection of amyloid plaques, a core pathologic feature of Alzheimer's disease (AD). Studies suggest that PIB-PET is sensitive for AD pathology, can distinguish AD from non-AD dementia (for example, frontotemporal lobar degeneration), and can help determine whether mild cognitive impairment is due to AD. Although the short half-life of the carbon-11 radiolabel has thus far limited the use of PIB to research, a second generation of tracers labeled with fluorine-18 has made it possible for amyloid PET to enter the clinical era. In the present review, we summarize the literature on amyloid imaging in a range of neurodegenerative conditions. We focus on potential clinical applications of amyloid PET and its role in the differential diagnosis of dementia. We suggest that amyloid imaging will be particularly useful in the evaluation of mildly affected, clinically atypical or early age-at-onset patients, and illustrate this with case vignettes from our practice. We emphasize that amyloid imaging should supplement (not replace) a detailed clinical evaluation. We caution against screening asymptomatic individuals, and discuss the limited positive predictive value in older populations. Finally, we review limitations and unresolved questions related to this exciting new technique.
The availability of new PET ligands offers the potential to measure fibrillar β-amyloid in the brain. Nevertheless, physiological information in the form of perfusion or metabolism may still be useful in differentiating causes of dementia during life. In this study we investigated whether early 11C-PIB PET frames (perfusion, pPIB) can provide information equivalent to blood flow and metabolism by assessing the similarity of pPIB and 18F-FDG PET images first in a test cohort with various clinical diagnoses (N=10) and then validating the results on a cohort of Alzheimer’s disease (AD, N=42, age 66.6±10.6, MMSE 22.2±6.0) and frontotemporal lobar degeneration (FTLD, N=31, age 63.9±7.1, MMSE 23.8±6.7) patients.
To identify the 11C-PIB frames best representing perfusion, an iterative algorithm was run on the test cohort. This included: (1) generating normalized (cerebellar reference) perfusion pPIB images across variable frame ranges, and (2) calculating Pearson’s R values of the sum of these pPIB frames with the sum of all 18F-FDG frames (cerebellar normalized) for all brain tissue voxels. Once this perfusion frame range was determined on the test cohort, it was then validated on an extended cohort and the power of pPIB in differential diagnosis was compared to 18F-FDG by performing a logistic regression of ROI tracer measure (pPIB or 18F-FDG) versus diagnosis.
A seven-minute window, corresponding to minutes 1–8 (frame 5–15) produced the highest voxel-wise correlation between 18F-FDG and pPIB (R=0.78±0.05). This pPIB frame range was further validated on the extended AD and FTLD cohort across 12 ROIs (R=0.91±0.09). A logistic model using pPIB was able to classify 90.5% of the AD and 83.9% of the FTLD patients correctly. Using 18F-FDG, 88.1% of AD and 83.9% of FTLD patients were classified correctly. The temporal pole and the temporal neocortex were significant discriminators (p<0.05) in both models, whereas in the model with pPIB the frontal region was also significant.
The high correlation between pPIB and 18F-FDG measures and their comparable performance in differential diagnosis is promising in providing functional information using 11C-PIB PET data. This could be a useful approach, obviating the need for 18F-FDG scans when longer-lived amyloid imaging agents become available
Pittsburgh compound-B (11C-PIB); perfusion; 18F-Fluorodeoxyglucose (18F-FDG); Aβ-amyloid plaques; cerebral glucose metabolism
Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer’s disease cause atrophy within two major networks, an anterior ‘Salience Network’ (atrophied in behavioural variant frontotemporal dementia) and a posterior ‘Default Mode Network’ (atrophied in Alzheimer’s disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer’s disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer’s disease) and the Default Mode Network (disrupted in Alzheimer’s disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer’s disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer’s disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic connectivity enhancement within the reciprocal network. In behavioural variant frontotemporal dementia, clinical severity correlated with loss of right frontoinsular Salience Network connectivity and with biparietal Default Mode Network connectivity enhancement. Based on these results, we explored whether a combined index of Salience Network and Default Mode Network connectivity might discriminate between the three groups. Linear discriminant analysis achieved 92% clinical classification accuracy, including 100% separation of behavioural variant frontotemporal dementia and Alzheimer’s disease. Patients whose clinical diagnoses were supported by molecular imaging, genetics, or pathology showed 100% separation using this method, including four diagnostically equivocal ‘test’ patients not used to train the algorithm. Overall, the findings suggest that behavioural variant frontotemporal dementia and Alzheimer’s disease lead to divergent network connectivity patterns, consistent with known reciprocal network interactions and the strength and deficit profiles of the two disorders. Further developed, intrinsic connectivity network signatures may provide simple, inexpensive, and non-invasive biomarkers for dementia differential diagnosis and disease monitoring.
functional magnetic resonance imaging; frontotemporal dementia; Alzheimer’s disease; functional connectivity; biomarker
Sporadic corticobasal syndrome (CBS) has been associated with diverse pathological substrates, but frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) has only been linked to CBS among progranulin mutation carriers. We report the clinical, neuropsychological, imaging, genetic, and neuropathological features of GS, a patient with sporadic corticobasal syndrome. Genetic testing revealed no mutations in the microtubule associated protein tau (MAPT) or progranulin (PGRN) genes, but GS proved homozygous for the T allele of the rs5848 PGRN variant. Autopsy showed ubiquitin and TDP-43 pathology most similar to a pattern previously associated with PGRN mutation carriers. These findings confirm that FTLD-TDP should be included in the pathological differential diagnosis for sporadic CBS.
corticobasal degeneration; TDP-43; frontotemporal lobar degeneration; progranulin
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.
Alzheimer’s disease; age of onset; amyloid-β; [18F]-labelled fluorodeoxyglucose; [11C]-labelled Pittsburgh compound-B
Seizures are relatively common in Alzheimer disease (AD) and other neurodegenerative disorders. To our knowledge, however, there have been no reports of seizures associated with corticobasal degeneration (CBD). We describe a patient with brain biopsy features suggestive of CBD whose course was complicated by complex partial seizures with secondary generalization. Thus, the occurrence of seizures in a patient with dementia should not exclude the diagnosis of CBD.
Some patients meeting behavioral variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy, and have thus been referred to as bvFTD “phenocopies” or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have found no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, we describe two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions.
Three hundred and eighty-four patients with FTD clinical spectrum and Alzheimer’s disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns assessed using voxel-based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls.
Both patients were age 48 at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over seven years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over two years, her neuropsychological and functional scores as well as brain atrophy remained stable.
C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.
C9ORF72; C9FTD/ALS; frontotemporal dementia; genetics; dementia
Dementia with Lewy bodies (DLB) is a neurodegenerative condition that results in loss of mesopontine cholinergic neurons and sympathetic deinnervation. While acetylcholinesterase inhibitors (ChE-Is) have been shown to improve cognitive and behavioral deficits in DLB, these patients may be more susceptible to bradyarrhythmetic side effects from this class of drugs due to the autonomic insufficiency associated with the disease. We present a patient who experienced a dose-dependent, symptomatic sinus bradyarrhythmia with donepezil doses at and greater than 5 mg. Due to underlying autonomic dysfunction, patients with DLB may be at increased risk of bradyarrhythmia resulting from treatment with ChE-Is.