Belen Pascual

Brain Glucose Metabolism in Vascular White Matter Disease With Dementia. Differentiation From Alzheimer Disease

Background and Purpose— The boundary between vascular dementia and Alzheimer disease (AD) continues to be unclear. Some posit that gradually progressive vascular dementia, as with small vessel disease, is simply vascular disease plus AD. Because AD presents a characteristic pattern on fluorodeoxyglucose positron emission tomography, we sought to determine whether the fluorodeoxyglucose pattern of vascular dementia resembled more AD or the pattern in nondemented patients with severe microvascular brain disease. Methods— Vascular disease patients were selected on the basis of confluent white matter lesions on both hemispheres. Among them, with a similar degree of vascular disease on MRI, neuropsychological testing separated groups with dementia and without dementia. Patients with AD and healthy controls were also studied. The 4 groups, with 12 subjects each, were matched by age, gender, and educational level. Fluorodeoxyglucose distribution was analyzed using both voxel-based and volume of interest methods. Results— The AD group had the characteristic pattern of bilaterally decreased metabolism in parieto-temporal association cortex and precuneus. By contrast, patients with vascular disease and dementia had a similar anatomic pattern to that of the vascular patients without dementia, but with greater metabolic abnormalities, particularly in the frontal lobes and deep nuclei. Conclusions— The anatomy of metabolic abnormalities in vascular disease with dementia suggests that, at least in some cases, dementia with vascular disease may be independent of AD. The metabolic abnormality involves the thalamus, caudate, and frontal lobe, a pattern concordant with the neuropsychological findings of impaired executive function characteristic of vascular dementia.

New scoring methodology improves the sensitivity of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) in clinical trials

IntroductionAs currently used, the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) has low sensitivity for measuring Alzheimer’s disease progression in clinical trials. A major reason behind the low sensitivity is its sub-optimal scoring methodology, which can be improved to obtain better sensitivity.MethodsUsing item response theory, we developed a new scoring methodology (ADAS-CogIRT) for the ADAS-Cog, which addresses several major limitations of the current scoring methodology. The sensitivity of the ADAS-CogIRT methodology was evaluated using clinical trial simulations as well as a negative clinical trial, which had shown an evidence of a treatment effect.ResultsThe ADAS-Cog was found to measure impairment in three cognitive domains of memory, language, and praxis. The ADAS-CogIRT methodology required significantly fewer patients and shorter trial durations as compared to the current scoring methodology when both were evaluated in simulated clinical trials. When validated on data from a real clinical trial, the ADAS-CogIRT methodology had higher sensitivity than the current scoring methodology in detecting the treatment effect.ConclusionsThe proposed scoring methodology significantly improves the sensitivity of the ADAS-Cog in measuring progression of cognitive impairment in clinical trials focused in the mild-to-moderate Alzheimer’s disease stage. This provides a boost to the efficiency of clinical trials requiring fewer patients and shorter durations for investigating disease-modifying treatments.

Tau, amyloid, and hypometabolism in the logopenic variant of primary progressive aphasia

A 57-year-old right-handed woman had an 8-year history of progressive word retrieval and repetition deficits, consistent with the logopenic variant of Alzheimer disease.1 She was studied using the novel hyperphosphorylated-tau tracer 18F-AV-1451,2 in conjunction with metabolic (18F-fluorodeoxyglucose [FDG]) and β-amyloid (18F-florbetapir) PET (figure). Areas with high tau, such as the left inferior parietal lobule, had decreased metabolism. By contrast, some areas with high amyloid, such as striated cortex, had normal metabolism. This case illustrates tau sparing of primary cortex and provides preliminary in vivo evidence that regional tau is more closely linked to hypometabolism than amyloid density.

Ventricular Wall Granulations and Draining of Cerebrospinal Fluid in Chronic Giant Hydrocephalus

BACKGROUND In rare cases, adults with normal or almost normal cognition may have giant brain ventricles surrounded by a sliver of brain. Because the usual flow of cerebrospinal fluid (CSF) is interrupted in these individuals, they may develop alternative CSF pathways to preserve brain function. OBJECTIVE To describe novel morphologic autopsy findings in a patient with chronic giant hydrocephalus that suggest the existence of alternative CSF draining pathways. DESIGN Case report. SETTING Autopsy study. PATIENT A 48-year-old man with chronic compensated hydrocephalus associated with a Dandy-Walker malformation. MAIN OUTCOME MEASURE Autopsy findings. RESULTS We observed microscopic structures on the ventricular wall that may facilitate CSF resorption. Their histologic appearance, reminiscent of pacchionian granulations, showed the opposite relation in regard to CSF/blood compartments: whereas the core of a pacchionian granulation contains CSF and the granulation is bathed in blood of the venous sinus, the core of the ventricular granulation in our patient contained venules, with the granulation bathed in ventricular CSF. CONCLUSIONS These previously unreported (to our knowledge) ventricular wall granulations may facilitate draining of CSF into the venous system when CSF outflow from the ventricular system is occluded. The presence of these ventricular structures illustrates biologic adaptation to anomalous conditions and successful compensation.

Genetic and degenerative disorders primarily causing dementia

Neuroimaging comprises a powerful set of instruments to diagnose the different causes of dementia, clarify their neurobiology, and monitor their treatment. Magnetic resonance imaging (MRI) depicts volume changes with neurodegeneration and inflammation, as well as abnormalities in functional and structural connectivity. MRI arterial spin labeling allows for the quantification of regional cerebral blood flow, characteristically altered in Alzheimers disease, diffuse Lewy-body disease, and the frontotemporal dementias. Positron emission tomography allows for the determination of regional metabolism, with similar abnormalities as flow, and for the measurement of β-amyloid and abnormal tau deposition in the brain, as well as regional inflammation. These instruments allow for the quantification in vivo of most of the pathologic features observed in disorders causing dementia. Importantly, they allow for the longitudinal study of these abnormalities, having revealed, for instance, that the deposition of β-amyloid in the brain can antecede by decades the onset of dementia. Thus, a therapeutic window has been opened and the efficacy of immunotherapies directed at removing β-amyloid from the brain of asymptomatic individuals is currently being tested. Tau and inflammation imaging, still in their infancy, combined with genomics, should provide powerful insights into these disorders and facilitate their treatment.

Head-to-head comparison of 11C-PBR28 and 18F-GE180 for the quantification of TSPO in the human brain

18F-GE180 is a third-generation PET tracer for quantifying the translocator protein (TSPO), a biomarker for inflammation. The aim of this study was to perform a head-to-head comparison of 18F-GE180 and the well-established TSPO tracer 11C-PBR28 by scanning with both tracers during the same day in the same subjects. Methods: Five subjects underwent a 90-min PET scan with 11C-PBR28 in the morning and 18F-GE180 in the afternoon. A metabolite-corrected arterial input function was obtained in each subject for both tracers, and the brain uptake was quantified with a 2-tissue-compartment model. Results: The rate of metabolism of 18F-GE180 in arterial blood was slower than that of 11C-PBR28 (the percentages of nonmetabolized parent in plasma at 90 min were 74.9% ± 4.15% [mean ± SD] and 11.2% ± 1.90%, respectively). The plasma free fractions were similar for both tracers: 3.5% ± 1.1% for 18F-GE180 and 4.1% ± 1.1% for 11C-PBR28. The average total volume of distribution (VT) of 18F-GE180 was about 20 times smaller than that of 11C-PBR28 (0.15 ± 0.03 mL/cm3 for 18F-GE180 and 3.27 ± 0.66 mL/cm3 for 11C-PBR28). 18F-GE180 was characterized by poor transfer from the vascular compartment to the brain (its plasma-to-tissue rate constant [K1] was about 10 times smaller than that of 11C-PBR28). Moreover, kinetic modeling was more difficult with 18F-GE180, as its VT values were identified with a lower precision than those of 11C-PBR28 and outlying values were more frequent. Conclusion: The VT of 18F-GE180 was about 20 times smaller than that of 11C-PBR28 because of low penetration into the brain from the vascular compartment. In addition, kinetic modeling of 18F-GE180 was more challenging than that of 11C-PBR28. Therefore, compared with 11C-PBR28, 18F-GE180 had unfavorable characteristics for TSPO imaging of the brain.

OLDER HEALTHY PEOPLE HAVE INCREASED VASCULAR PERMEABILITY IN REGIONS SHOWING ‘OFF-TARGET’ [18F]AV-1451 UPTAKE

tical analysis. Results: In preclinical AD stage 1, significantly increased DBSI cellularity fraction was observed on the right side of the cerebral peduncle (Fig. 1A) and the right side of the anterior limb of internal capsule (Fig. 1B), suggesting the presence of neuroinflammation. CSF level of YKL-40, correlated with the DBSI total WM neuroinflammation index (r1⁄40.69, p<0.005) (Fig. 2). This finding is consist with DBSI being a noninvasive measure of WM neuroinflammation. Conclusions: In this study, DBSI detected the early presence of WM neuroinflammation in preclinical AD stage 1, and positively correlated with the CSF levels of YKL-40, a marker of gliosis/neuroinflammation. DBSI holds great promise as a potential novel, noninvasive and non-radioactive means to quantify neuroinflammation and study its role in AD pathogenesis and progression.

Hypothalamic relapse of a cardiac large B-cell lymphoma presenting with memory loss, confabulation, alexia–agraphia, apathy, hypersomnia, appetite disturbances and diabetes insipidus

A 37-year-old Hispanic man with a right atrial intracardiac mass diagnosed as diffuse large B-cell lymphoma (DLBCL) was successfully treated with surgery and chemotherapy. During 4 years, several total-body positron emission tomography and MRI scans showed no extracardiac lymphoma. On year 5 after the cardiac surgery, patient presented with sleepiness, hyperphagia, memory loss, confabulation, dementia and diabetes insipidus. Brain MRI showed a single hypothalamic recurrence of the original lymphoma that responded to high-dose methotrexate treatment. Correction of diabetes insipidus improved alertness but amnesia and cognitive deficits persisted, including incapacity to read and write. This case illustrates two unusual locations of DLBCL: primary cardiac lymphoma and hypothalamus. We emphasise the importance of third ventricle tumours as causing amnesia, confabulation, behavioural changes, alexia–agraphia, endocrine disorders and alterations of the circadian rhythm of wakefulness–sleep secondary to lesions of specific hypothalamic nuclei and disruption of hypothalamic–thalamic circuits.

NEUROINFLAMMATION AND 18F-AV-1451 PET FINDINGS IN SEMANTIC DEMENTIA

memory. Finally, we performed gray matter masking and partial volume correction to examine group differences in mGluR5 binding when accounting for gray matter volume loss. Results:AD participants (73.165.1 years, CDR1⁄40.5-1.0) ranged from amnestic Mild Cognitive Impairment (n1⁄48) to mild dementia (n1⁄48). CN participants (71.568.4 years) were free of clinical disease (CDR1⁄40) (Table 1). AD participants – compared to CN participants – demonstrated significant reductions inmGluR5 binding (F(1,31)1⁄47.4, p1⁄40.011). Post hoc analyses revealed that mGluR5 binding in the hippocampus (p1⁄40.003), but not association cortex (p1⁄40.093) was reduced in AD (Table 2). Hippocampal reductions persisted after graymattermasking (p1⁄40.011) and partial volume correction (p1⁄40.050) (Table 3). Exploratory analyses revealed reductions in entorhinal cortex, and parahippocampal gyrus (Table 2, 3). Reduced hippocampal mGluR5 binding was associated with more severe disease (r 1⁄4 -0.534, p1⁄40.002) and lower episodic memory scores (r 1⁄4 0.398, p1⁄40.027) in the overall sample. Conclusions: [F]FPEB-PET revealed reductions in hippocampal mGluR5 binding in the early stages of AD. Further study is needed to refine the pattern ofmGluR5 reductions and the associations with cognitive and functional impairment. Quantification of mGluR5 binding in AD may expand our understanding of AD pathogenesis as well as the development of novel treatments and biomarkers.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials

Background Combining optimized cognitive (Alzheimers Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimers disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimers disease. Method Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimers clinical trials that combines cognitive and atrophy markers. Results Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimers disease for clinical trials. Conclusion The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimers disease.BACKGROUND Combining optimized cognitive (Alzheimers Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimers disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimers disease. METHOD Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimers clinical trials that combines cognitive and atrophy markers. RESULTS Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimers disease for clinical trials. CONCLUSION The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimers disease.