Neuropathological and neuropsychological aspects in the behavioral variant of frontotemporal dementia (bvFTD)

Neuropathological and neuropsychological aspects in the behavioral variant of frontotemporal dementia (bvFTD)

The article offers an in-depth analysis of the neuropathological characteristics of the behavioral variant of Frontotemporal Dementia, in relation to the specific cognitive deficits and clinical signs that the syndrome entails.


Advertising message Frontotemporal dementia describes a group of syndromes that present deficits in executive functions, changes in behavior and language problems. There are two subtypes, behavioral and linguistic, the latter divided into non-fluent and semantic types. The behavioral type of frontotemporal dementia is the most common form within the large cluster of frontotemporal degeneration syndromes, which includes progressive supranuclear paralysis, corticobasal syndrome and precisely frontotemporal dementia (Murley et al., 2018).

The behavioral variant of Frontotemporal Dementia (bvFTD – behavioral variant frontotemporal dementia) is currently considered the second most common cause of dementia after Alzheimer’s (Young et al., 2018; Rascovsky et al., 2011; Harciarek et al., 2013) and it represents above all in the onset phase and due to the symptomatological heterogeneity, a diagnostic challenge for the clinician.

The changes in personality, behavior and cognitive faculties characteristic of bvFTD reflect dysfunctions affecting the reciprocal connections between the orbitofrontal, dorsolateral prefrontal and medial prefrontal cortex and the nuclei of the base and thalamus. These circuits are in turn influenced by cortical afferents from the temporal and parietal lobes (Lanata et al., 2016).

Normal activity in the medial prefrontal cortex, including the anterior cingulate cortex, is associated with motivation. Injuries in these areas result in a reduction in spontaneous motor behavior that includes initiating communication. They also lead to a deficit in generalized behavior. The anterior cingulate cortex is often compromised by neurodegenerative processes in bvFTD, particularly in the right lobe, and causes apathy and inertia. Patients with an apathetic form of bvFTD spend many hours watching television, they don’t care about their personal hygiene or their social responsibilities. They do not start a conversation and speak only when questioned.

While it is legitimate to assume that social cognition deficits may more generally reflect an executive dysfunction (for example, for the resolution of a social dilemma, related to empathy, cognitive flexibility is needed), there is evidence which demonstrate that in bvFTD changes in social cognition precede and overcome executive dysfunctions, in relation to the early impairment of the ventromedial and orbitofrontal prefrontal cortex and temporal lobe, rather than changes in the dorsolateral prefrontal cortex (Harciarek et al., 2013).

Other studies also confirm that with regard to social cognitive deficits, the loss of the ability to interpret the emotional states of others, the loss of awareness and empathy seem to be due to a dysfunction of the medial right orbitofrontal cortex and the anterior insula (Lanata et al., 2016).

Deficits in executive functions that are commonly observed in bvFTD, affecting working memory, mental flexibility, inhibitory control and planning, are not so common in the early stage of the disease.

A meta-analysis study on executive functions in bvFTD (Lough et al., 2001) revealed a preserved executive ability in a context of behavioral alteration and deficit in social cognition as a result of a primary impairment in the orbitofrontal, pre-ventromedial and anterior temporal, and not in the region of the dorsolateral prefrontal cortex. The authors described cases in which there were significant changes in behavior and personality, with a deficit in verbal fluency but with a normal performance in Wisconsin (WCST). The same study indicated in the results of the Theory of Mind tests the most evident deficit in formal tests,

Rahman and colleagues (Rahman et al., 1999) found a dissociation between executive functions in patients with bvFTD, with a decision-making deficit, while spatial working memory and programming were preserved. Results that other more recent studies also seem to confirm. In particular Vijverberg and collaborators (Vijverberg et al., 2017), in the comparison of the neuropsychological profile in bvFTD and the most common psychiatric disorders, showed a significant deficit in verbal fluency tasks (especially for animal names) and better results in attention , working memory and verbal memory compared to the group of schizophrenic subjects or with bipolar disorder.

Advertising message Another study (Ranasinghe et al., 2016) found different patterns of cognitive impairment in the different stages of bvFTD. In particular, it was observed that in the early stages of the disease neuropsychiatric disorders, insensitivity to errors, slow response times, naming deficits are more evident, while memory, attention and naming of the affective states of others are preserved. Gradually the decline extends to free re-enactment, shifting, visuospatial skills, semantic fluency, denomination of emotions, calculation and syntactic understanding. From the meta-analysis carried out in the study emerges an inhibitory control capacity below the average (z = -1.4 / -1.6) but not as compromised as would be expected given the characteristics of the disorder.

Related to inhibitory control, disinhibition is the most striking sign of bvFTD. A large role in cognitive control systems is played by the orbitofrontal cortex (OFC), which can be defined as a connecting station in the frontal cortex, because it has an inhibitory role in relation to the limbic cortex. OFC also plays a critical role in behavior modification in relation to rewards and punishments. OFC dysfunction is commonly associated with disinhibition and emotional lability, which can also manifest with impulsiveness (reckless driving, gambling, substance abuse, compulsive buying, criminal behavior, binge eating) (Christidi et al., 2018).

Instead, it appears that fronto-subcortical dysfunction may be responsible for repetitive (ritualistic and compulsive) movements and stereotyped verbal expressiveness.

Neurochemical dysfunctions also seem to play a fundamental role in the etiology of bvFTD disorders. In particular, a decrease in the density of serotonergic and dopaminergic neurons is observed, while the noradrenergic and cholinergic pathways are preserved. There has been documented a loss of up to 40% of serotonergic neurons in the Rafe nuclei and a dysfunctionality of the 5HT1 and 5HT2A receptors in the fronto-orbital, cingulate, medial frontal and temporal regions. A loss of glutamatergic and GABAergic neurons has been observed, but the functional consequence of this loss is still unclear, in part due to the complexity of the interaction dynamics between glutamatergic and GABAergic neurons in cortical circuits (Murley et al., 2018; Hughes et al., 2015).

In the current state of research, bvFTD appears to reflect a multi-domain neuropsychological deficit profile related to general cortical and subcortical dysfunction. The detection of the picture is made even more complex by the heterogeneity of the clinical signs in the onset phases, which may appear similar to those observed in a psychotic disorder. In addition, the structural brain changes, evident in the advanced stages of the syndrome, may not be documented until a few years after the onset of symptoms. For the purpose of early detection of bvFTD, the literature agrees with recommending an assessment that takes into account clinical signs, behavioral and psychological symptoms, as well as a measure of neuropsychological performance.