Comparative Cognitive Neuropsychological Studies of Frontal Lobe Function: Implications for Therapeutic Strategies in Frontal Variant Frontotemporal Dementia

Abstract

Patients with mild frontal variant frontotemporal dementia (fvFTD) who attend the clinic are usually unaware of the pervasive changes in their personality and behaviour, despite the fact it is these changes which have prompted the referral from the patient’s spouse or carer. Comparative studies across various species offer unique insights into the heterogeneous structure and functions of the prefrontal cortex, and can allow a novel approach to the precise identification of the neuropsychological deficits present in these patients. We have found that they may show marked deficits on tests sensitive to ventromedial prefrontal or orbitofrontal function, in the relative absence of impairments on tests sensitive to dorsolateral prefrontal function. We highlight important differences in the neurocognitive profile of these patients with that of patients with other neurodegenerative conditions, including basal ganglia diseases and dementia of the Alzheimer type. The specific nature of these neuropsychological deficits, together with converging evidence from clinical and neuropathological studies, may provide useful clues about the predominant locus of dysfunction in the early stages of fvFTD and possible underlying neurotransmitter abnormalities. This is important for the successful development of therapeutic intervention strategies for both cognitive and behavioural symptoms in fvFTD. Finally, we evaluate critically the rationales for therapeutic modulation of noradrenergic, serotonergic and dopaminergic neurotransmitter systems at various stages of disease.

Forebrain connectivity of the prefrontal cortex in the marmoset monkey (Callithrix jacchus): An anterograde and retrograde tract‐tracing study

“…Thus, higher-order attentional selection is disrupted by dopaminergic (Crofts et al, 2001), but not serotonergic lesions, of the PFC (Clarke et al, 2005), while the ability to reverse responding following changes in reward contingencies is impaired by serotonergic (Clarke et al, 2004) but not dopaminergic lesions (Roberts et al, 1994, Clarke et al, 2007. A similar dissociation between impairments in discrimination reversal and attentional set-shifting is evident in the pattern of behavioral impairments reported in patients with Parkinson's disease (Downes et al, 1989), Huntington's disease (Lange et al, 1995), and dementia of the frontal lobe type (Rahman et al, 1999). In addition, in human functional neuroimaging studies attentional set-shifting and discrimination reversal induce distinct patterns of task-dependent activations within the prefrontal cortex (Konishi et al, 1998;Nakahara et al, 2002;Kringelback and Rolls, 2003;O'Doherty et al, 2003;Hampshire and Owen, 2006).…”

Affective neuroscience of pleasure: reward in humans and animals

“…This progressive neurodegenerative disorder is associated with major and pervasive behavioral changes in personality and social conduct resembling those produced by orbitofrontal lesions (although it should be noted that more focal lesions to the orbitofrontal cortex have not to date been associated with obesity; Rahman et al 1999).…”

The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers

“…For example, performance on the TOL planning task and the test of spatial working memory is significantly impaired by the dopamine D2 receptor antagonist sulpiride (Mehta et al 1999) and improved by the indirect agonist methylphenidate (Elliott et al 1997;Mehta et al 2000). However, the ability to reverse an association between stimulus and rewardthought to be sensitive to reduced plasma TRP (Park et al 1994;Rogers et al 1999) and dysfunction of orbitofrontal sectors of PFC (Rolls et al 1994;Dias et al 1996;Rahman et al 1999;Rogers et al 2000) -is unimpaired following administration of methylphenidate (Elliott et al 1997) or clonidine .…”