Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers. A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimer's disease.

Progranulin (GRN) mutations are associated with different clinical phenotypes, including Frontotemporal Lobar Degeneration (FTLD), Corticobasal Degeneration and Alzheimer's disease (AD). In addition, the range of age at onset is very wide and patients presenting initial symptoms around eighty years have been described. Previous studies demonstrated that progranulin plasma levels determination may be a reliable method to identify GRN deletion carriers. We thus evaluated progranulin plasma levels in all patients followed at our Alzheimer's Centre whose plasma was available (n=176) and found four patients displaying low values. Three of them carried the CACT deletion in exon 7 and their clinical diagnosis was behavioral variant Frontotemporal Dementia. We also identified a patient carrying a previously reported CAGT deletion in exon 5. Here, we report on this case. The onset of symptoms was at 77 years and the initial diagnosis was of amnestic Mild Cognitive Impairment (aMCI), which converted to AD six months later. In the following years, the patient also developed behavioral disturbances, gait apraxia and parkinsonian symptoms. At present, she is 84 years old and is still followed-up periodically. This case confirms progranulin plasma levels as a reliable biomarker to identify GRN deletion carriers and discriminate between FTLD and other dementias which may mimic it. We thus encourage the inclusion of this non-invasive and easy test in clinical practice.

J Neurol Sci. 2009 Dec 15;287(1-2):291-3

Disease tracking markers for Alzheimer's disease at the prodromal (MCI) stage

Older persons with Mild Cognitive Impairment (MCI) feature neurobiological Alzheimer's Disease (AD) in 50% to 70% of the cases and develop dementia within the next 5 to 7 years. Current evidence suggests that biochemical, neuroimaging, electrophysiological, and neuropsychological markers can track the disease over time since the MCI stage (also called prodromal AD). The amount of evidence supporting their validity is of variable strength. The Brescia Group performed this interesting review categorizing evidence of validity into three classes: Class A, availability of multiple serial studies; Class B a single serial study or multiple cross sectional studies of patients with increasing disease severity from MCI to probable AD; and class C, multiple cross sectional studies of patients in the dementia stage, not including the MCI stage. Several Class A studies suggest that episodic memory and semantic fluency are the most reliable neuropsychological markers of progression. Hippocampal atrophy, ventricular volume and whole brain atrophy are structural MRI markers with class A evidence. Resting-state fMRI and connectivity, and diffusion MR markers in the medial temporal white matter (parahippocampus and posterior cingulum) and hippocampus are promising but require further validation. Change in amyloid load in MCI patients warrant further investigations, e.g. over longer period of time, to assess its value as marker of disease progression. Several spectral markers of resting state EEG rhythms that might reflect neurodegenerative processes in the prodromal stage of AD (EEG power density, functional coupling, spectral coherence, and synchronization) suffer from lack of appropriately designed studies. Although serial studies on late event-related potentials (ERPs) in healthy elders or MCI patients are inconclusive, others tracking disease progression and effects of cholinesterase inhibiting drugs in AD, and cross-sectional including MCI or predicting development of AD offer preliminary evidence of validity as a marker of disease progression from the MCI stage. CSF Markers, such as Aβ 1-42, t-tau and p-tau are valuable markers which support the clinical diagnosis of Alzheimer's disease. However, these markers are not sensitive to disease progression and cannot be used to monitor the severity of Alzheimer's disease. For Isoprostane F2 some evidence exists that its increase correlates with the progression and the severity of AD.

Journal of Alzheimer's disease : JAD.(2011) :26 Suppl 3 DOI: 10.3233/JAD-2011-0043

Biomarkers in AlzSWAN

The increasing age of populations in the developed world is associated with a dramatic rise in dementia-related disorders such as Alzheimer disease (AD). As current state-of-the-art diagnostics for these disorders are invasive (lumbar puncture), expensive (MRI and PET amyloid imaging) and time-consuming (comprehensive examination at specialist clinics), they have limited utility as high-throughput, or front-line, screening tools. Avalible online

In Big Picture, Familial AD’s Biomarker Data Resemble LOAD

Researchers with eyes peeled toward prodromal Alzheimer’s disease probably see this diagram in their sleep—the one where the field’s five most validated markers trace their poignant path from normal cognition to fully developed AD. Two research groups proposed this theoretical model some years ago (see Perrin et al., 2009; Jack et al., 2010). But is it true? At least in its broad strokes, the answer seems to be yes, according to early data pouring in from biomarker studies in autosomal-dominant AD. By and large, brain amyloid, brain metabolism, atrophy, and functional connectivity data from independent analyses of theDominantly Inherited Alzheimer Network (DIAN) and the Alzheimer’s Prevention Initiative (API) jibe with each other and confirm the sequence of preclinical biomarker changes proposed for late-onset AD. This article highlights DIAN and API neuroimaging results reported 14-19 July 2012 at the Alzheimer’s Association International Conference (AAIC) in Vancouver, Canada.

CSF Markers: Goodbye, Research Use Only; Hello, Clinical

This is Part 1 of a two-part series. See also Part 2.
What a difference a year can make. At the 2011 Alzheimer’s Association International Conference in Paris, France, leading scientists in the CSF Alzheimer’s biomarker field met to tackle the vexing problem of measurement variability with the available commercial assays. Alas, back then a listener could be forgiven for thinking of the Tower of Babel, as groups presented their own stance and talked past each other as much as finding common ground.