Objective

Abnormal immune responses and inflammatory mechanisms have been implicated in the pathogenesis of certain neurodegenerative diseases. Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by focal atrophy of the frontal and temporal lobes. Evidence supports the presence of inflammation in FTD; however, the relationship between inflammation and FTD pathogenesis is poorly understood.

In response to brain inflammation, microglia are activated and over-express the peripheral benzodiazepine receptor (PBR). In normal conditions, PBR is expressed in low numbers. Measuring PBR density can identify areas of brain inflammation, because activated microglial cells in these areas express more PBR than microglial cells in resting conditions. Positron emission tomography (PET) imaging can quantify PBR density in vivo using radioligands that bind to PBR sites. One PBR-specific radioligand, [11C]1-(2-chlorophenyl-N-methylpropyl)-3-isoquinoline carboxamide (PK11195), has been used to identify areas of brain inflammation in patients with FTD. Unfortunately, [11C]PK11195 has several limitations, such as low brain uptake and low specific signal. A recently developed radioligand, [11C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine (PBR28), has higher affinity than [11C]PK11195 for PBR. [11C]PBR28 has never been used to study inflammation in FTD.

Study population

In this protocol, we wish to evaluate 10 patients with FTD and 10 healthy volunteers.

Design

Subjects will undergo screening with a history, physical exam, ECG, and blood and urine laboratory testing. Subjects will receive a whole body PET scan using [11C]PBR28 to determine if the subject has peripheral PBR binding. Humans express PBR in the lung, kidney, and endocrine glands under normal conditions and should have low amounts of [11C]PBR28 binding on whole body imaging. We discovered that 4 of 30 subjects scanned with [11C]PBR28 do not demonstrate peripheral PBR binding. In this protocol, subjects that have negative whole body [11C]PBR28 PET scans "(non-binders)" will be excluded from further study. The rest of the subjects ( binders ) will undergo a dedicated brain PET with [11C]PBR28 and a brain MRI.

Outcome measures

Outcome measures will be the amount of [11C]PBR28 binding in the brain in FTD patients and in healthy controls. We will quantify the radioligand's brain uptake, washout, plasma clearance, and distribution volume using compartmental modeling. Distribution volume is proportional to the density of receptors and is equal to the ratio at equilibrium of uptake in brain to the concentration of parent radiotracer in plasma.

• INCLUSION CRITERIA:
• Frontotemporal dementia (FTD) patients with or without motor involvement. Patients with either the frontal variant (also known as the behavioral variant) or the language variant of FTD may be included. FTD patients must either meet capacity criteria to consent to research, or be able to assign a surrogate decision-maker who is able to consent to research on the subject's behalf.
• Healthy volunteers.

EXCLUSION CRITERIA:

• Current psychiatric disease, substance abuse or severe systemic disease based on history and physical exam.
• Laboratory tests with clinically significant abnormalities.
• Prior participation in other research protocols or clinical care in the last year such that radiation exposure, including that from this protocol, would exceed the guidelines set by the Radiation Safety Committee (RSC).
• Pregnancy or breast feeding.
• Positive result on urine screen for illicit drugs.
• Subjects who cannot lie on their back for extended periods of time.
• History of neurological disease other than FTD.
• Presence of ferromagnetic metal in the body or heart pacemaker.