Anterior brain glucose hypometabolism predates dementia in progranulin mutation carriers

Neurology 2013 Oct 8; 81(15):1322-31.

Jacova C, Hsiung GYR, Tawankanjanachot T et al.




In this prospective cohort study we investigated cerebral glucose metabolism reductions on FDG-PET in progranulin (GRN) mutation carriers prior to Frontotemporal dementia (FTD) onset.


Nine mutation carriers (age 51.5+13.5) and 11 non-carriers (age 52.7+9.5) from 5 families with FTD due to GRN mutations underwent brain scanning with FDG-PET and MRI, and clinical evaluation. Normalized FDG uptake values were calculated with reference to the pons. PET images were analyzed with regions-of-interest (ROI) and statistical parametric mapping (SPM) approaches.


Compared with non-carriers, GRN mutation carriers had a lowered anterior-to-posterior (AP) ratio of FDG uptake (0.86+0.09 vs. 0.92+0.05) and less left-right asymmetry, consistent with an overall pattern of right anterior cerebral hypometabolism. This pattern was observed regardless of whether they were deemed Clinically Symptomatic Not Demented or Asymptomatic. Individual ROIs with lowered FDG uptake included right anterior cingulate, insula and gyrus rectus. SPM analysis supported and extended these findings, demonstrating abnormalities in the right and left medial frontal regions, right insular cortex, right precentral and middle frontal gyri and right cerebellum. Right AP ratio was correlated with cognitive and clinical scores (3MS r=0.74; FRS r=-0.73) but not age and years-to-estimated-onset in mutation carriers.


The frontotemporal lobar degenerative process associated with GRN mutations appears to begin many years prior to the average age of FTD onset (late 50s-early 60s). Right medial and ventral frontal cortex and insula may be affected in this process but the specific regional patterns associated with specific clinical variants remain to be elucidated.

PMID:  24005336



Frontotemporal Dementia (FTD) is a presenile disorder characterized by progressive deterioration in behavior (behavioral variant) or language (semantic and non-fluent variants of Primary Progressive Aphasia). In those aged 45-65 years, FTD is as prevalent as Alzheimer’s Disease (AD), with 10-15 per 100,000 individuals affected. FTD arises from degeneration of the frontal and temporal lobes of the brain referred to as Frontotemporal Lobar Degeneration (FTLD). There are three known neuropathological subtypes of FTLD resulting from abnormal protein accumulation. Since the identification in 2006 of mutations in the progranulin gene (GRN) as a major cause of familial FTD1 it has become possible to investigate the predementia stages of FTLD with Trans-activating DNA binding protein with molecular weight 43kDa (TDP-43) pathology in GRN mutation carriers. In the current study we were interested in characterizing brain metabolic abnormalities in non-demented mutation carriers using [18F]fluorodeoxyglucose (FDG) PET. FDG-PET uptake is considered an early indicator of synaptic dysfunction in neurodegeneration.2

Study participants were children or siblings of a proband with FTD due to a GRN mutation. Probands had different types of mutations but because mutations in GRN are believed or confirmed to result in a common disease mechanism of haploinsufficiency3 we evaluated mutation carriers as a group in comparison to noncarrier individuals from the same families. All participants, regardless of carrier status, had normal results on cognitive, motor, functional, and behavioral assessments, and visually rated structural MRI. Mutation carriers were on average 7 years younger than mean onset in their families. As a group, their FDG-PET scans showed lowered glucose uptake in anterior brain regions including the anterior cingulate, anterior insula, orbitofrontal cortex, and gyrus rectus, and in the caudate nucleus. These abnormalities were more evident in right- than left-sided regions. There was however substantial individual variability in the specific regions that were affected. No single regional glucose uptake measure separated the mutation carriers with high accuracy from the noncarriers. We computed global indices of FDG uptake that quantified: 1) left and right averaged anterior uptake; 2) left and right averaged posterior uptake; 3) left and right anterior-to-posterior (AP) ratio obtained by dividing A by P; 4) left-to-right ratio by dividing averaged left by averaged right regions (LR).As a group mutation carriers had significantly lower right anterior, and left and right AP ratios, as well as a higher LR ratio. The ROC analyses in Figure 1 indicate that the right AP ratio discriminates most accurately between mutation carriers and noncarriers.

The importance of the findings is twofold. First, brain glucose metabolism abnormalities can be observed in individuals with a GRN mutation that have normal scores on cognitive, functional, or motor assessments, a visually normal structural MRI, and that are years from expected disease onset. Half of the mutation carriers in the sample were at least a decade from the mean age of FTD onset in their family. FTLD associated with TDP-43 pathology due to mutations in the GRN gene precedes the appearance of clinical symptoms, and is likely to develop over many years. Second, FTLD-TDP-43 appears to be reliably measurable with FDG-PET. Early glucose metabolic abnormalities do not appear to affect a single brain region but rather manifest as an altered anterior-to-posterior brain region gradient, particularly in the right hemisphere. It is possible that regionally specific patterns of abnormalities can be identified retrospectively in relation to clinical variants of FTD when the mutation carriers in this and similar studies develop full-blown FTD.

CJ Fig1

Figure ROC analyses of global FTD uptake indices with Area Under the Curve, significance of the difference from AUC = 0.5, and 95% confidence interval and sensitivity/specificity estimates.



  1. Baker M, Mackenzie IR, Pickering-Brown SM, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916-919.
  2. Nestor PJ, Caine D, Fryer TD, Clarke J, Hodges JR. The topography of metabolic deficits in posterior cortical atrophy (the visual variant of Alzheimer’s disease) with FDG-PET. J Neurol Neurosurg Psychiatry 2003;74:1521-1529.
  3. Petkau TL, Leavitt BR. Progranulin in neurodegenerative disease. Trends Neurosci 2014;37:388-398.




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