LTNS Brief︱Imaging Strengthens Knowledge of Alzheimer disease

Fig. 1 Proposed relationships between pathological protein accumulation, neurodegeneration and drivers of the Alzheimer disease process. 

Alzheimer disease (AD) is a progressive neurodegenerative disorder clinically characterized by failure to form new memory in its early stage, suggesting dysfunction the medial temporal lobe (MTL) episodic memory system [1]. With disease progressing, AD is stage ageing, AD presents feature of dementia associated with widespread amyloid-β (Aβ) plaques and tau aggregates as neurofibrillary tangles [2].

Recently multimodal imaging technologies have been flourished, and transformed research on human ageing and dementia, these technologies provide researchers opportunities to investigate complex interrelated mechanisms of AD [3-4].

Using positron emission tomography (PET) Aβ and tau aggregate can be visualized, the downstream consequence of neurodegeneration can be also examined with structural MRI, functional MRI and glucose metabolism PET [3-4]. Thus, imaging can potentially explain the evolution of AD from normal ageing to dementia.

However, there remains a major unresolved question — whether aggregation of tau in the MTL is the first stage in AD or a fairly benign phenomenon. Despite a strong link between Aβ and tau, the relationship between Aβ and neurodegeneration is weak; rather, it is tau that is associated with brain atrophy and hypometabolism, which, in turn, are related to cognition (Table 1)  [5-6].

Although supportive evidence  for an interaction between Aβ and tau results in neurodegeneration that leads to dementia, the unknown nature of this interaction, the strikingly different patterns of brain Aβ and tau deposition and the appearance of neurodegeneration in the absence of Aβ and tau are challenges to this model that ultimately must be explained (Talbe 1)  [7].

In this Review, William Jagust have unified the sometimes conflicting and confusing data relating protein deposition in AD [6-9].  Most of the conflicting data do not seem to contradict an underlying sequential model for AD , but they indicate the likely importance of additional non-amyloid or tau-related disease pathways. Molecular mechanisms are either poorly understood or entirely missing (Fig.1).

Although these crucial data will probably will appear over the next few years, the lack of large longitudinal data sets limits causal inferences [10]. Associational studies aslo show that unmeasured variables could play important or causal roles in driving the pathological processes [11].  Most models of complex diseases, including model of AD pathogenesis are probably incorrect, so it is uncertain provides reasonable therapeutic targets [12-13].

Given the most invinctive test of causal association requires experimental intervention, researchers should develop a beautiful experiment to remove one or more of inciting protein, neurodegeneration and cognitive decline can be ameliorated. This experiment would be a positive clinical trial to discuss an promising Aβ or tau-modifying therapy for AD patents.

William Jagust MD

Endowed Chair in Geriatric Medicine

Professor, Public Health and Neuroscience,University of

California, Berkeley, CA, USA.

Email: [e-mail]

To see more: https://jagustlab.neuro.berkeley.edu/

Lab Research

The Jagust Lab is engaged in the study of brain aging and dementia. We use the techniques of positron emission tomography (PET), structural magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), neuropsychology, and cognitive neuroscience to understand the anatomic, biochemical, and neurochemical bases of changes in behavior with age and dementia.

At LBNL, neuroscientists, radiochemists, physicists, engineers, and computer scientists work together to develop and refine imaging techniques. The imaging facility at LBNL includes a PET, SPECT and 1.5T MRI. 

 Lab memebers  Credit: the Jagust Lab

Key References

[1] Nelson, P. T. et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J. Neuropathol. Exp. Neurol. 71, 362–381 (2012).

[2] Hyman, B. T. et al. National Institute on Aging- Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 8, 1–13 (2012).

[3] Sabri, O. et al. Florbetaben PET imaging to detect amyloid β plaques in Alzheimer’s disease: phase 3 study. Alzheimers Dement. 11, 964–974 (2015).

[4] Schonhaut, D. R. et al. 18 F- flortaucipir tau positron emission tomography distinguishes established  progressive supranuclear palsy from controls and Parkinson disease: a multicenter study. Ann. Neurol. 82, 622–634 (2017).

[5] Ewers, M. et al. CSF biomarker and PIB- PET-derivedβ- amyloid signature predicts metabolic, gray matter, and cognitive changes in nondemented subjects. Cereb. Cortex 22, 1993–2004 (2012).

[6] Dore, V. et al. Cross- sectional and longitudinal analysis of the relationship between Aβ deposition, cortical thickness, and memory in cognitively unimpaired individuals and in Alzheimer disease. JAMA Neurol.70, 903–911 (2013)

[7] Tosun, D. et al. Association between tau deposition and antecedent amyloid- β accumulation rates in normal and early symptomatic individuals. Brain 140, 1499–1512 (2017).

[8] Villemagne, V. L. et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 12, 357–367 (2013).

[9] William Jagust. Imaging the evolution and pathophysiology of Alzheimer disease. Nat. Rev. Neurosci. DOI: https://doi.org/10.1038/s41583-018-0067-3 (2018) .

[10] Becker, J. A. et al. Amyloid- β associated cortical thinning in clinically normal elderly. Ann. Neurol. 69, 1032–1042 (2011).

[11] Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018).

[12] Jack, C. R. Jr. et al. Brain β- amyloid load approaches a plateau. Neurology 80, 890–896 (2013).

[13] Duyckaerts, C. et al. PART is part of Alzheimer disease. Acta Neuropathol. 129, 749–756 (2015).

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