Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD

OBJECTIVE:

To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD).

METHODS:

Patients meeting clinical criteria for AD (n = 62) and FTLD (n = 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n = 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls.

RESULTS:

PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB (κ = 0.96) than FDG (κ = 0.72), as was agreement between visual and quantitative classification (PiB κ = 0.88-0.92; FDG κ = 0.64-0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n = 12 patients) and 87% for FDG (n = 10).

CONCLUSIONS:

PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology.

 Neurology. 2011 Dec 6;77(23):2034-42

Age and diagnostic performance of Alzheimer disease CSF biomarkers

OBJECTIVES:

Core CSF changes in Alzheimer disease (AD) are decreased amyloid β(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly.

METHODS:

We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis.

RESULTS:

The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages.

CONCLUSION:

Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

Revised Criteria for Mild Cognitive Impairment May Compromise the Diagnosis of Alzheimer Disease Dementia.

OBJECTIVE:

To evaluate the potential impact of revised criteria for mild cognitive impairment (MCI), developed by a work group sponsored by the National Institute on Aging and the Alzheimer's Association, on the diagnosis of very mild and mild Alzheimer disease (AD) dementia.

DESIGN:

Retrospective review of ratings of functional impairment across diagnostic categories.

SETTING:

Alzheimer's Disease Centers and the National Alzheimer's Coordinating Center.

PARTICIPANTS:

Individuals (N = 17 535) with normal cognition, MCI, or AD dementia.

MAIN OUTCOME MEASURES:

The functional ratings of individuals with normal cognition, MCI, or AD dementia who were evaluated at Alzheimer's Disease Centers and submitted to the National Alzheimer's Coordinating Center were assessed in accordance with the definition of "functional independence" allowed by the revised criteria. Pairwise demographic differences between the 3 diagnostic groups were tested using t tests for continuous variables and χ(2) for categorical variables.

RESULTS:

Almost all (99.8%) individuals currently diagnosed with very mild AD dementia and the large majority (92.7%) of those diagnosed with mild AD dementia could be reclassified as having MCI with the revised criteria, based on their level of impairment in the Clinical Dementia Rating domains for performance of instrumental activities of daily living in the community and at home. Large percentages of these individuals with AD dementia also meet the revised "functional independence" criterion for MCI as measured by the Functional Assessment Questionnaire.

CONCLUSIONS:

The categorical distinction between MCI and milder stages of AD dementia has been compromised by the revised criteria. The resulting diagnostic overlap supports the premise that "MCI due to AD" represents the earliest symptomatic stage of AD.

Arch Neurol. 2012 Feb 6. [Epub ahead of print]

Wanted: Better Brain-Process Biomarkers for Drug Trials

Eight years ago, Peter Lansbury decided to become a drug developer. He was a neurology professor at Harvard Medical School with a background in chemistry, and had been doing well-regarded research on the origins of neurodegenerative diseases. Now he had an idea for a blockbuster treatment: a drug that would boost the brain’s ability to dispose of the harmful protein aggregates that seem to cause many of these diseases.
Lansbury and two investors founded a company, Link Medicine, and began screening libraries of chemical compounds for those that would increase autophagy, a natural process that clears away unwanted protein aggregates. Eventually they had a lead autophagy-boosting compound, LNK-754, that worked well in mouse models and appeared safe in human volunteers. In principle, LNK-754 could be useful in treating a number of illnesses including Parkinson’s, Alzheimer’s, and Huntington’s diseases. All that remained, it seemed, was for a large pharmaceutical company to buy the marketing rights and fund the large-scale clinical trials needed to prove LNK-754’s efficacy in humans.
But that hasn’t happened. “It used to be that if you had a drug whose mechanism makes sense, a drug that works in animals and is safe in people, you could immediately go and do a large clinical trial. But for drugs against neurodegenerative diseases, those days are gone,” says Lansbury.
The problem is that for these diseases, the standard measures needed in a conclusive clinical trial—such as cognitive test scores, for Alzheimer’s patients—are expected to show clear evidence of a treatment effect only very gradually, and only in a population of at least hundreds of patients, even for a drug that works. For a would-be disease-modifying drug, that typically means a trial of at least 18 months, costing on the order of $100 million. At the same time, pharmaceutical companies are all too aware that potential neurodegenerative disease treatments have almost always failed in clinical trials, in recent years. “The big pharma companies have become very risk averse,” Lansbury says. “The big issue now is not really the lack of drug strategies, it’s the inability to assess those strategies in short, economical trials.”

Alzheimer's Disease and Non-Demented High Pathology Control Nonagenarians: Comparing and Contrasting the Biochemistry of Cognitively Successful Aging

Amyloid plaques stained by the Campbell-Switzer technique.

The histological fields are representative of the amyloid plaque burden shown in 40 µm coronal sections of the frontal lobe.

The amyloid cascade hypothesis provides an economical mechanistic explanation for Alzheimer's disease (AD) dementia and correlated neuropathology. However, some nonagenarian individuals (high pathology controls, HPC) remain cognitively intact while enduring high amyloid plaque loads for decades. If amyloid accumulation is the prime instigator of neurotoxicity and dementia, specific protective mechanisms must enable these HPC to evade cognitive decline. We evaluated the neuropathological and biochemical differences existing between non-demented (ND)-HPC and an age-matched cohort with AD dementia. The ND-HPC selected for our study were clinically assessed as ND and possessed high amyloid plaque burdens. ELISA and Western blot analyses were used to quantify a group of proteins related to APP/Aβ/tau metabolism and other neurotrophic and inflammation-related molecules that have been found to be altered in neurodegenerative disorders and are pivotal to brain homeostasis and mental health. The molecules assumed to be critical in AD dementia, such as soluble or insoluble Aβ40, Aβ42 and tau were quantified by ELISA. Interestingly, only Aβ42 demonstrated a significant increase in ND-HPC when compared to the AD group. The vascular amyloid load which was not used in the selection of cases, was on the average almost 2-fold greater in AD than the ND-HPC, suggesting that a higher degree of microvascular dysfunction and perfusion compromise was present in the demented cohort. Neurofibrillary tangles were less frequent in the frontal cortices of ND-HPC. Biochemical findings included elevated vascular endothelial growth factor, apolipoprotein E and the neuroprotective factor S100B in ND-HPC, while anti-angiogenic pigment epithelium derived factor levels were lower. The lack of clear Aβ-related pathological/biochemical demarcation between AD and ND-HPC suggests that in addition to amyloid plaques other factors, such as neurofibrillary tangle density and vascular integrity, must play important roles in cognitive failure (Full text).

Neuropathologic Correlates of Hippocampal Atrophy in the Elderly: A Clinical, Pathologic, Postmortem MRI Study

The volume of the hippocampus measured with structural magnetic resonance imaging (MRI) is increasingly used as a biomarker for Alzheimer's disease (AD). However, the neuropathologic basis of structural MRI changes in the hippocampus in the elderly has not been directly assessed. Postmortem MRI of the aging human brain, combined with histopathology, could be an important tool to address this issue. Therefore, this study combined postmortem MRI and histopathology in 100 elderly subjects from the Rush Memory and Aging Project and the Religious Orders Study. 

A typical three-dimensional region of interest created by manually outlining the hippocampal formation in consecutive T₂-weighted sagittal images of a human cerebral hemisphere.

Shape analysis of (A) hippocampi affected by Alzheimer's disease (AD) and not hippocampal sclerosis (HS) compared to controls, (B) hippocampi most severely affected by AD compared to controls, and (C) hippocampi affected by HS with or without AD compared to controls.The top row of images contains the superior view of the hippocampus, while the bottom row contains the inferior view. Within each comparison, the left side shows a map of the difference in distance between points on the surface mesh of the first group versus the corresponding points on the surface mesh of the second group, projected along a unit vector that is normal to the surface. Thus, red shading shows areas of inward deformation of the first group relative to the second group, and green shading shows areas of outward deformation. The right side of each comparison shows significance maps with color indicating P-value. The significance maps show regions where points on the surface mesh of the first group are significantly displaced from the corresponding points on the surface mesh of the second group in any direction.

First, to validate the information contained in postmortem MRI data, we tested the hypothesis that postmortem hippocampal volume is smaller in subjects with clinically diagnosed Alzheimer's disease compared to subjects with mild or no cognitive impairment, as observed in antemortem imaging studies. Subsequently, the relations of postmortem hippocampal volume to AD pathology, Lewy bodies, amyloid angiopathy, gross infarcts, microscopic infarcts, and hippocampal sclerosis were examined. It was demonstrated that hippocampal volume was smaller in persons with a clinical diagnosis of AD compared to those with no cognitive impairment (P = 2.6×10⁻⁷) or mild cognitive impairment (P = 9.6×10⁻⁷). Additionally, hippocampal volume was related to multiple cognitive abilities assessed proximate to death, with its strongest association with episodic memory. Among all pathologies investigated, the most significant factors related to lower hippocampal volume were shown to be AD pathology (P = 0.0018) and hippocampal sclerosis (P = 4.2×10⁻⁷). Shape analysis allowed for visualization of the hippocampal regions most associated with volume loss for each of these two pathologies. Overall, this investigation confirmed the relation of hippocampal volume measured postmortem to clinical diagnosis of AD and measures of cognition, and concluded that both AD pathology and hippocampal sclerosis affect hippocampal volume in old age, though the impacts of each pathology on the shape of the hippocampus may differ.

Reference: Dawe RJ, Bennett DA, Schneider JA, Arfanakis K, 2011 Neuropathologic Correlates of Hippocampal Atrophy in the Elderly: A Clinical, Pathologic, Postmortem MRI Study. PLoS ONE 6(10): e26286. doi:10.1371/journal.pone.0026286 Free full text

Cerebrospinal Fluid Levels of sAPPα and sAPPβ in Lewy Body and Alzheimer's Disease: Clinical and Neurochemical Correlates

AbstractWe measured cerebrospinal fluid (CSF) levels of the soluble isoforms of amyloid precursor protein (APP; sAPPα sAPPβ) and other CSF biomarkers in 107 patients with Alzheimer's disease (AD), dementia with Lewy body dementia (DLB), Parkinson's disease dementia (PDD), and normal controls (NC) using commercial kits. DLB and PDD were combined in a Lewy body dementia group (LBD). No differences were observed in sAPPα and sAPPβ levels between the groups. Significant correlations were observed between sAPPα and sAPPβ and between sAPPβ and Mini-Mental State Examination scores in the total group analysis as well as when LBD and AD groups were analyzed separately. sAPPα and sAPPβ levels correlated with Aβ38, Aβ40, Aβ42, and Tau in the LBD group. In AD, sAPPα correlated with p-Tau and sAPPβ with Aβ40. The differential association between sAPPα and sAPPβ with Aβ and Tau species between LBD and AD groups suggests a possible relationship with the underlying pathologies in LBD and AD.

Full text