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Objective:We examined the utility of distinguishing between patients with frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD) using quantitative cerebral blood flow (CBF) imaging with arterial spin labeled (ASL) perfusion MRI. Methods:Forty-two patients with FTLD and 18 patients with AD, defined by autopsy or CSFderived biomarkers for AD, and 23 matched controls were imaged with a continuous ASL method to quantify CBF maps covering the entire brain. Results:Patients with FTLD and AD showed distinct patterns of hypoperfusion and hyperperfusion. Compared with controls, patients with FTLD showed significant hypoperfusion in regions of the frontal lobe bilaterally, and hyperperfusion in posterior cingulate and medial parietal/precuneus regions. Compared with controls, patients with AD showed significant hypoperfusion in the medial parietal/precuneus and lateral parietal cortex, and hyperperfusion in regions of the frontal lobe. Direct comparison of patient groups showed significant inferior, medial, and dorsolateral frontal hypoperfusion in FTLD, and significant hypoperfusion in bilateral lateral temporal-parietal and medial parietal/precuneus regions in AD.Conclusions: Doubly dissociated areas of hypoperfusion in FTLD and AD are consistent with areas of significant histopathologic burden in these groups. ASL is a potentially useful biomarker for distinguishing patients with these neurodegenerative diseases. Neurology ® 2010;75:881-888 GLOSSARY A␤42 ϭ ␤-amyloid 1-42 ; AD ϭ Alzheimer disease; ASL ϭ arterial spin labeling; bvFTD ϭ behavioral-variant frontotemporal dementia; cASL ϭ continuous arterial spin labeling; CBS ϭ corticobasal syndrome; CBF ϭ cerebral blood flow; dACC ϭ dorsal anterior cingulate cortex; dlPFC ϭ dorsolateral prefrontal cortex; FDR ϭ false detection rate; FTLD ϭ frontotemporal lobar degeneration; GM ϭ gray matter; iFC ϭ inferior frontal cortex; MCI ϭ mild cognitive impairment; MNI ϭ Montreal Neurological Institute; mTC ϭ middle temporal cortex; OFC ϭ orbital frontal cortex; PC ϭ parietal cortex; PCA ϭ principal component analysis; PCC ϭ posterior cingulate cortex; PPA ϭ primary progressive aphasia; PRC ϭ precuneus; PVE ϭ partial volume effect; t-tau ϭ total tau; TE ϭ echo time; TI ϭ inversion time; TR ϭ repetition time; WM ϭ white matter.Frontotemporal lobar degeneration (FTLD) is the most common cause of progressive cognitive decline in young-onset dementia. Because Alzheimer disease (AD) accounts for 30% of cases presenting with a clinical diagnosis of primary progressive aphasia (PPA) or behavioral-variant frontotemporal dementia (bvFTD), 1,2 it is important to distinguish between FTLD and AD so that appropriate treatments can be initiated. This distinction is difficult on clinical grounds alone, because AD can mimic PPA and bvFTD, 1,2 and FTLD can present with a memory disorder.

A monoclonal antibody (AP422) specific for phospboserine 422 in microtubnle-associated protein tau has been produced. It strongly labels paired helical f'dament (PHF) tan from Alzheimer's disease brain in a pbosphorylation-dependent manner. By contrast, AP422 only labels a small fraction of fetal tau and a very small fraction of tan from adult brain. The amount of tau phospborylated at Ser-422 in normal brain is minor relative to that phosphorylated at sites recognized by other pbosphorylation-dependent anti-tau antibodies of known epitope. It follows that AP422 is the most specific anti-tau antibody available for detecting the neurofibrillary lesions of Alzheimer's disease. We also show that Ser-422 in tau is a good in vitro substrate for mitogen-activated protein kinase, but not for glycogen synthase kinase-3 or neuronal cdc2-1ike kinase.

The increasing prevalence of Alzheimer’s disease and the devastating consequences of late-life dementia motivates the drive to develop diagnostic biomarkers to reliably identify the pathology associated with this disorder. Strategies to accomplish this include the detection of altered levels of tau and amyloid in cerebrospinal fluid, the use of structural MRI to identify disease-specific patterns of regional atrophy and MRI T₁ρ to detect disease-related macromolecular protein aggregation, and the direct imaging of amyloid deposits using positron emission tomography and single photon emission computerized tomography. Success will facilitate the ability to reliably diagnose Alzheimer’s disease while the symptoms of brain failure are mild and may provide objective measures of disease-modifying treatment efficacy.

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