John Q. Trojanowski

Personal ViewTracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers

In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimers disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.

Epitope mapping of LB509, a monoclonal antibody directed against human α-synuclein

Abstract α-Synuclein is a 140 amino acid protein that forms the major component of the abnormal filaments that make up the Lewy bodies and Lewy neurites of Parkinsons disease and dementia with Lewy bodies. It is also the major component of the filamentous glial cytoplasmic inclusions of multiple system atrophy. Here we have used recombinant α-synucleins and peptide competition to show that the monoclonal anti-α-synuclein antibody LB509 recognizes amino acids 115–122 of human α-synuclein. The antibody strongly labelled filaments extracted from multiple system atrophy brain, showing the presence of residues 115–122 of α-synuclein. LB509 failed to react with mouse, rat and zebra finch α-synuclein, because of amino acid differences with human α-synuclein. Since LB509 recognizes human but not rodent α-synuclein, it will be a useful reagent for the characterization of mouse lines transgenic for human α-synuclein.

CSF protein biomarkers predicting longitudinal reduction of CSF β-amyloid42 in cognitively healthy elders

β-amyloid (Aβ) plaque accumulation is a hallmark of Alzheimer’s disease (AD). It is believed to start many years prior to symptoms and is reflected by reduced cerebrospinal fluid (CSF) levels of the peptide Aβ1–42 (Aβ42). Here we tested the hypothesis that baseline levels of CSF proteins involved in microglia activity, synaptic function and Aβ metabolism predict the development of Aβ plaques, assessed by longitudinal CSF Aβ42 decrease in cognitively healthy people. Forty-six healthy people with three to four serial CSF samples were included (mean follow-up 3 years, range 2–4 years). There was an overall reduction in Aβ42 from a mean concentration of 211–195 pg ml−1 after 4 years. Linear mixed-effects models using longitudinal Aβ42 as the response variable, and baseline proteins as explanatory variables (n=69 proteins potentially relevant for Aβ metabolism, microglia or synaptic/neuronal function), identified 10 proteins with significant effects on longitudinal Aβ42. The most significant proteins were angiotensin-converting enzyme (ACE, P=0.009), Chromogranin A (CgA, P=0.009) and Axl receptor tyrosine kinase (AXL, P=0.009). Receiver-operating characteristic analysis identified 11 proteins with significant effects on longitudinal Aβ42 (largely overlapping with the proteins identified by linear mixed-effects models). Several proteins (including ACE, CgA and AXL) were associated with Aβ42 reduction only in subjects with normal baseline Aβ42, and not in subjects with reduced baseline Aβ42. We conclude that baseline CSF proteins related to Aβ metabolism, microglia activity or synapses predict longitudinal Aβ42 reduction in cognitively healthy elders. The finding that some proteins only predict Aβ42 reduction in subjects with normal baseline Aβ42 suggest that they predict future development of the brain Aβ pathology at the earliest stages of AD, prior to widespread development of Aβ plaques.

Tau and α-Synuclein in Neurodegenerative Diseases

The past 2 yr have been extremely prolific in the area of neurodegenerative research, particularly with regard to diseases involving the proteins tau and synuclein. Tau aggregation in the form of filaments has long been implicated in diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), as well as others. The recent discovery of tau gene mutations in patients afflicted by a heterogeneous disease entity termed fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has provided genetic corroboration for the importance of tau in disease and opens novel avenues of investigation into the nature of tau dysfunctions that lead to the demise of neurons. The discovery of mutations in α-synuclein in familial cases of Parkinson’s disease (PD) has led to the revelation that this protein likely plays a prominent role in the etiology of several sporadic neurodegenerative disorders including PD, dementia with Lewy body (DLB) and multiple system atrophy (MSA), collectively grouped as synucleinopathies. In common with the subset of neurodegenerative diseases known as tauopathies because they are characterized by prominent filamentous tau aggregates in neurons and glia, similar fibrillary inclusions also accumulate in the brains of patients with synucleinopathies, but these inclusions are comprised predominantly of α-synuclein aggregates. In this chapter, the current knowledge of synuclein and tau proteins and their possible aberrant, malevolent role(s) in the onset and/or progression of brain diseases is reviewed.