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To provide better care for patients, physicians most often seek to determine the cause of symptoms by recognizing a clinical phenotype and then relating that phenotype to known disease mechanisms, including genetic variations and pathology. This approach has been particularly difficult with frontotemporal dementias (FTD), because of the diversity and continuous evolution of its behavioral, language and cognitive symptoms. Recent systematic clinical-pathological observations have resulted in proposed clinical criteria for FTD, but accurate diagnosis remains challenging and, in clinical practice, the phenotype of FTD can easily be confused with other disorders.

Positron emission tomography with [F]fluorodeoxyglucose (FDG-PET) can aid in the recognition of clinical phenotype and explore disease mechanisms. We reviewed the results of FDG-PET in 19 patients who subsequently had FTD confirmed at postmortem examination, including one with a known tau gene mutation. A comparison of scans from normal elderly controls with scans of patients with pathologically confirmed Alzheimer's disease (AD) demonstrates that FTD causes a distinctive pattern of hypometabolism, with considerable individual variability within this general pattern. FTD consistently causes predominant hypometabolism in frontal association, anterior cingulate, and anterior temporal regions, but the involvement of each region is variable and can be either symmetric or asymmetric. As the illness progresses, glucose hypometabolism becomes more pervasive, extending into regions characteristically affected early in AD. Although FDG-PET abnormalities accurately reflect clinical phenotype, neither pathological diagnosis nor genotype reliably predicts the variations observed in the pattern of glucose hypometabolism in FTD.

The vast majority of families with presenilin (PSEN) mutations have the clinical phenotype of Alzheimer's disease. However, there are reports of patients who carry PSEN mutations and have Alzheimer's disease with a variety of other clinical phenotypes including spastic paraplegia, seizures, myoclonus, parkinsonism, epilepsy and amyloid angiopathy. Remarkably, three of the studied families have frontotemporal dementia (FTD). The mutations associated with FTD are L113P (Raux et al. 2000), Ins R362 (Tang-Wai et al. 2002) and G183V (Dermaut et al. 2004). Raux and colleagues (2000) reported six members from four generations of the SAL family who had early onset FTD. Tang-Wai and colleagues (2002) reported three patients from three generations who had FTD in their 50s and 60s. Dermaut and colleagues (2004) reported a large family from two generations. Three were definitely affected and a total of 12 members were evaluated. Again the disease was of early onset. In all three families, the clinical phenotype was convincingly FTD in nature. In the first two families (L113P and Ins R362), no autopsy was available, but in the third family (G183V), one case had an autopsy and the pathology showed Pick's disease with Pick bodies and no Alzheimer pathology. Usually PSEN1 mutations enhance the γ-secretase effect on the amyloid precursor protein (APP), increasing Aβ42 protein, but a study by Amtul and colleagues (2002) found that the InsR 362 (but not L113P, which they also tested) caused a “dominant negative” effect on the metabolism of APP (and NOTCH), decreasing Aβ42 production. The G183V mutation does not have the same effect. In this family, there are two siblings without the mutation (II-3 age 67 and II-4 age 66) who had abnormal SPECT scans and mild dysexecutive function, and II-3 had anomia and mild MRI atrophy. All of these findings raise the possibility that FTD might not be linked to the G183V mutation. In conclusion, in the families described so far, there is suggestive but not conclusive evidence that PSEN1 mutations can cause FTD.