Elsevier

Neurobiology of Aging

Volume 29, Issue 3, March 2008, Pages 418-426
Neurobiology of Aging

Neural networks in frontotemporal dementia—A meta-analysis

https://doi.org/10.1016/j.neurobiolaging.2006.10.023Get rights and content

Abstract

Objective

Frontotemporal dementia is the most common form of frontotemporal lobar degeneration. It is characterized by deep alterations in behavior and personality. We conducted a systematic and quantitative meta-analysis to examine its neural correlates and place the disease in a framework of cognitive neuropsychiatry.

Methods

MedLine and Current Contents search engines were used to identify imaging studies investigating frontotemporal dementia between 1980 and 2005. Nine studies were identified reporting either atrophy or decreases in glucose utilization. Finally, the analysis involved 132 patients and 166 controls. A quantitative meta-analysis was performed. Maxima of the studies resulted in activation likelihood estimates.

Results

The meta-analysis revealed a particularly frontomedian network impaired in frontotemporal dementia. Additionally, right anterior insula, and medial thalamus were identified.

Conclusions

Our study specifies frontotemporal dementia as the frontomedian variant of frontotemporal lobar degeneration. The disease affects neural networks enabling self-monitoring, theory of mind capabilities, processing/evaluation of internal mental states, perception of pain and emotions, and sustaining personality and self. Our study contributes to placing frontotemporal dementia in cognitive neuropsychiatry.

Introduction

Recent studies suggest that frontotemporal lobar degeneration is the second most common diagnosis of dementia in individuals younger than 65 years (Johnson et al., 2005). However, several factors have limited research into this disease. The size of cohorts is modest at any one center. Furthermore, until recently, diagnostic accuracy was low. Recent establishment of consensus criteria for frontotemporal lobar degeneration (The Lund and Manchester Groups, 1994; Neary et al., 1998) represents an opportunity to begin large-scale studies. Criteria suggested previously divide frontotemporal lobar degeneration into three major subgroups: frontotemporal dementia (FTD), semantic dementia, and progressive non-fluent aphasia (Neary et al., 1998). FTD, the most common subtype, is characterized by alterations in behavior and personality, namely decline in social interpersonal conduct, impairment in regulation of personal conduct, emotional blunting, and loss of insight (‘diagnostic core features’ (Neary et al., 1998)). Moreover, FTD patients are impaired in social cognition (Gregory et al., 2002, Lough et al., 2006). Both other subtypes lack in their early stages behavioral impairments, rather language domain is mainly affected (Neary et al., 1998, Snowden et al., 1996).

Although FTD is clinically well characterized (Neary et al., 1998), and several hints for specific cognitive deficits were recently published, there is still controversy with regard to the neural basis of disease. Some authors proposed in their brain imaging criteria that FTD is characterized by bilateral impairment in (pre-)frontal and anterior temporal brain regions, whereas others related FTD specifically to frontal lobes and, hence called it frontal variant of frontotemporal lobar degeneration (Perry and Hodges, 2000). Accordingly, one aim of our study was to focus neural impairments in FTD to specific brain regions. Moreover, we wanted to place FTD in a framework of cognitive neuropsychiatry by relating the neural deficits to clinical and cognitive impairments (Halligan and David, 2001). Because patients with FTD show particularly alterations in behavior, personality, and social cognition (Gregory et al., 2002, Lough et al., 2006, Neary et al., 1998), we hypothesized impairments in anterior medial frontal neural networks (Gallagher and Frith, 2003).

As size of cohorts is modest in recently published studies we conducted a systematic function/location meta-analysis including morphometric studies with magnetic resonance imaging (MRI) and functional imaging studies applying (18F) fluorodeoxyglucose positron emission tomography (FDG-PET) (Fox et al., 1998). We chose the method developed by Turkeltaub et al. (2002) as it enables a quantitative meta-analytic approach.

Section snippets

General study selection criteria

MedLine and Current Contents search engines were used to identify studies on morphometry and glucose utilization in FTD. The following search strategy was applied: ((frontotemporal AND dementia) OR Pick) AND (PET OR MRT OR MRI). Studies were included if they fulfilled the following criteria: (1) published between 1980 and 2005, (2) peer-reviewed, (3) patients diagnosed according to internationally recognized diagnostic criteria (The Lund and Manchester Groups, 1994; Neary et al., 1998, Perry

Results

Fig. 1 shows maxima of studies, which were included in the meta-analysis. Note that several maxima are superimposed, and that shifting maxima on the z-axis to the respective slices for illustration purposes may have led to virtual localization outside the brain. Coordinates of maxima are described in detail in Appendix A. Results of the quantitative meta-analysis are summarized in Table 2 and illustrated in Fig. 2, if studies applying FDG-PET and MRI are pooled. Seven significant

Discussion

Our study supports previous notions classifying FTD as frontal variant of frontotemporal lobar degeneration (Perry and Hodges, 2000). More specifically, data confirm our hypothesis that FTD affects mainly frontomedian structures that are relatively spared in normal aging (Grieve et al., 2005, Raz et al., 2004, Salat et al., 2004). In the following, we want to place anatomical impairments in a framework of cognitive neuropsychiatry by relating neural networks to cognitive functions (Halligan and

Acknowledgments

The authors thank Evelyn Ferstl and Kirsten Volz for discussing the manuscript, and Stephan Liebig for help in preparing the figures.

Disclosure statement: There are no actual or potential conflicts of interest for any of the authors.

References (67)

  • M.F. Mendez

    What frontotemporal dementia reveals about the neurobiological basis of morality

    Med. Hypotheses

    (2006)
  • S. Nakano et al.

    Relationship between antisocial behavior and regional cerebral blood flow in frontotemporal dementia

    NeuroImage

    (2006)
  • D. Neary et al.

    Frontotemporal dementia

    Lancet Neurol.

    (2005)
  • G. Northoff et al.

    Cortical midline structures and the self

    Trends Cogn. Sci.

    (2004)
  • M.P. Paulus et al.

    Increased activation in the right insula during risk-taking decision making is related to harm avoidance and neuroticism

    NeuroImage

    (2003)
  • S. Rahman et al.

    Decision making and neuropsychiatry

    Trends Cogn. Sci.

    (2001)
  • N. Raz et al.

    Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume

    Neurobiol. Aging

    (2004)
  • E. Salmon et al.

    Predominant ventromedial frontopolar metabolic impairment in frontotemporal dementia

    NeuroImage

    (2003)
  • E.J.A. Scherder et al.

    Pain processing in dementia and its relation to neuropathology

    Lancet Neurol.

    (2003)
  • J.S. Snowden et al.

    Social cognition in frontotemporal dementia and Huntington's disease

    Neuropsychologia

    (2003)
  • P.E. Turkeltaub et al.

    Meta-analysis of the functional neuroanatomy of single-word reading: method and validation

    NeuroImage

    (2002)
  • G.B. Williams et al.

    Neural correlates of semantic and behavioural deficits in frontotemporal dementia

    NeuroImage

    (2005)
  • S. Zysset et al.

    The anterior frontomedian cortex and evaluative judgment: an fMRI study

    NeuroImage

    (2002)
  • S.W. Anderson et al.

    Impairment of social and moral behavior related to early damage in human prefrontal cortex

    Nat. Neurosci.

    (1999)
  • S. Baron-Cohen

    Mindblindness: An Essay on Autism and Theory of Mind

    (1997)
  • D. Bathgate et al.

    Behaviour in frontotemporal dementia, Alzheimer's disease and vascular dementia

    Acta Neurol. Scand.

    (2001)
  • C.S. Carter et al.

    Anterior cingulate cortex, error detection, and the online monitoring of performance

    Science

    (1998)
  • K. Christoff et al.

    The frontopolar cortex and human cognition: evidence for a rostrocaudal hierarchical organization within the human prefrontal cortex

    Psychobiology

    (2000)
  • A.R. Damasio

    The somatic marker hypothesis and the possible functions of the prefrontal cortex

    Phil. Trans. R. Soc. Lond. B

    (1996)
  • J. Derrfuss et al.

    Involvement of the inferior frontal junction in cognitive control: meta-analyses of switching and Stroop studies

    Hum. Brain Mapp.

    (2005)
  • P.J. Eslinger et al.

    Metacognitive deficits in frontotemporal dementia

    J. Neurol. Neurosurg. Psychiatry

    (2005)
  • P.T. Fox et al.

    Coordinate-based voxel-wise meta-analysis: dividends of spatial normalization. Report of a virtual workshop

    Hum. Brain Mapp.

    (2005)
  • M. Franceschi et al.

    Glucose metabolism and serotonin receptors in the frontotemporal lobe degeneration

    Ann. Neurol.

    (2005)
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