In this study, the first to examine the timing of symptoms in the tvFTD, we reviewed the clinical records of six patients with left and six patients with right tvFTD matched for severity and asymmetry of anterior temporal involvement. Our findings suggest that the earliest symptoms of tvFTD depend on the side of predominant temporal degeneration. When the disease begins with semantic loss, the left temporal lobe is more markedly affected. In contrast, behavioral changes at onset herald right temporal degeneration. Despite these initial differences, the two variants progressively merge. After an average of 3 years, the second symptom type to arise is most often the one, semantic or behavioral, not present at inception. After 5 to 7 years, disinhibition, compulsions, face recognition problems, altered food preference, and weight gain emerge. A first evaluation is typically sought during this stage of the illness, perhaps due to rising caregiver distress. The longer symptoms go on before evaluation, the more severe the bitemporal atrophy is at initial imaging.
In our sample, patients with tvFTD were symptomatic an average of 7 years before presentation. In an uncommon dementia with such an insidious disease course, it is difficult to collect prospective natural history data. The retrospective method used here provides a viable alternative but brings with it potential biases relating to informant recall and symptom abstraction. Informants may have reported the most striking, rather than the earliest, changes when queried about first symptoms. We attempted to reduce abstraction bias by pulling out each symptom for each patient, while focusing on first and most common symptoms in the subsequent analyses. Although our sample was small, its cases were defined by matching temporal atrophy severity and asymmetry scores that were similar to those of the 13 patients with LTLV not included in the study, suggesting that our natural history data may generalize to other patients with tvFTD.
The anterior temporal lobes remain largely uncharted brain regions, in part due to the scarcity of naturally occurring isolated temporopolar lesions. Elegant studies of semantic dementia (LTLV) have begun to reveal how the left anterior temporal lobe supports semantic knowledge,14
but less is known about anterior temporal contributions to social and emotional behavior. Anterior temporal lesions impair emotional attachment to family, as reported in an adult after right temporal lobectomy15
and children recovering from herpes encephalitis.16
Deficits reading facial affect are seen in early right mesiotemporal epilepsy17
and after right temporal lobectomy18
and correlate with right amygdala and ventromedial frontal cortex atrophy in tvFTD.12
In the present study, related behavioral functions were disrupted early in the course of tvFTD. Right temporoamygdalar degeneration began with emotional distance (blunting, withdrawal, apathy, depression), irritability, and altered physiologic drives (sleep, appetite, libido). LTLV typically began with semantic loss, but its first behavioral symptoms largely simulated those seen at RTLV onset. Further, the 3-year semantic prelude to the behavioral first symptom cluster in LTLV was echoed in RTLV, which averaged 3 years of behavioral change before semantic loss took hold. Given the symmetry of these profiles and the close link between disease duration and anterior temporal atrophy, we propose that tvFTD becomes bitemporal early in its course.
If the early symptoms of tvFTD reflect its anterior temporal origins, what might its later evolving symptoms tell us about its anatomic progression? In this cohort, the most common downstream symptoms began an average of 5 to 7 years into the illness. Disinhibition and compulsions, the most ubiquitous later symptoms, have been associated with ventromedial and orbital frontal cortex dysfunction.19,20
Problems with face recognition are known to occur in RTLV8,21,22
and likely reflect progressive inferior temporal cortex injury, especially on the right.23
Altered food preferences suggest misprocessing of insular disgust signals24
in some patients and derailed satiety controls, perhaps due to orbital frontal pathology, in others.25
Weight gain may result from appetite dysregulation, the hyperorality of bilateral temporoamygdalar damage,26
the motor inactivity of dorsomedial frontal involvement,19
or a combination. Somehow, patients at this stage of the illness are no longer able to match caloric expenditure to their often copious, idiosyncratic intake. These functional-anatomic correlations, combined with the natural history data from our patients, should serve as a guide for researchers seeking to establish the regional progression of tvFTD.
Compulsions are a prominent feature in FTLD,27,28
trouble family members, and at times respond to treatment, but their neuroanatomic and mechanistic underpinnings are unclear. Some authors emphasize the importance of frontal pathology,29
while others stress temporal involvement,30
especially when it is asymmetric.4
The relevance of striatal pathology is suspected, but attempts to confirm it have failed.4,30
Patients with tvFTD are often fixated on their compulsions, tolerate interruption poorly, and adopt rigid performance schedules, leading to the suggestion that tvFTD compulsions are more compulsive than those of fvFTD.30
Addressing these issues was not an initial goal of this study, but our data suggest that compulsions occur later in the course of tvFTD than would be expected if asymmetric temporal atrophy were the primary cause. In addition, our data suggest a driving force behind the specific types, and perhaps also the immediacy, of tvFTD compulsions. In LTLV, words lose meaning but visual attention is heightened, and compulsions are focused on visually conspicuous objects. In RTLV, however, complex social and visual esthetic cues are devalued, and patients favor games with letters, words, and playing cards, perhaps to draw meaning from uniform, easily interpretable symbols. Therefore, it appears that temporal lobe asymmetry may perturb environmental stimulus appraisal such that excess salience is conferred on particular stimulus classes. In return, compulsions targeting overvalued stimuli can become a dominant expression of behavior. Further investigation of this preliminary hypothesis is required.
Available imaging data1,3
combined with the regional volumes presented here suggest that, by presentation, tvFTD has often devastated one temporal lobe, encroached on the other, spread to the amygdala (ipsilateral worse than contralateral, especially in RTLV), and, to a lesser extent, involved the frontal, insular, and inferoposterior temporal cortices. Considering the known functions of these structures, our natural history data provide clinical evidence that regional degeneration in tvFTD occurs in a predictable sequence. Although LTLV appears to be threefold more common than RTLV,8
the overlap shown here supports the view that both variants reflect the same pathophysiologic process and that greater left temporal vulnerability to that process should be explored.