Visual attentional assessment in mild cognitive impairment and Alzheimer’s disease based on a theory of visual attention
Beschreibung
vor 14 Jahren
In the following sections, English summaries of the three studies
presented in this dissertation are given. For a detailed German
synopsis of the present work, see chapter 8 (pp. 118 et seqq.).
Research in the field of aging and dementia is a main concern as
the population of elderly people is growing continuously due to
increasing life expectancy and thus, an accumulative number of
people who live well beyond 65 years of age run a risk of
developing age-associated neurodegenerative disorders of cognitive
function, such as Alzheimer’s disease (AD), emerging as a major
health problem. The present work is based on growing evidence that
deficits in visual selective attention occur early in the
progression to AD (Foldi et al., 2002) and therefore might be
present as the first non-memory deficits (Perry & Hodges, 1999)
at the early prodromal stage of mild cognitive impairment (MCI;
Petersen et al., 1999). The present dissertation was performed to
contribute to the still ongoing debate as to whether certain
aspects of visual selective attention are par-ticularly vulnerable
or preserved, especially at the stage of MCI, and whether
attentional func-tioning might be qualitatively and/ or
quantitatively different from attentional performance at the AD
stage on the one hand or normal functioning on the other hand. As
theoretical basis, Bundesen’s theory of visual attention (TVA;
Bundesen, 1990, 1998) was employed to assess several latent,
mathematically independent and quantitative parameter es-timates
which are derived from two highly comparable paradigms –
computerized whole re-port and partial report of briefly presented
visual letter arrays. Central conclusions arising out of TVA-based
investigations (e.g., Bublak et al., 2005; Bublak, Redel, &
Finke, 2006; Duncan et al., 1999; Duncan et al., 2003; Finke et
al., 2006; Gerlach, Marstrand, Habekost, & Gade, 2005; Habekost
& Bundesen, 2003; Habekost & Rostrup, 2006; Peers et al.,
2005) point at four central strengths of this tool for attentional
assessment – the quality criteria sensitivity, specificity,
reliability and validity. Study 1: In AD, the amyloid cascade
hypothesis (Hardy & Selkoe, 2002) assumes that rising plaque
and tangle burden invokes loss of nerve cells through direct and
indirect effects on synaptic, neuronal and neuritic function (see
e.g. Cirrito et al., 2005), resulting in progressive intellectual
decline. Thus, sensitive biomarkers loading functionally on the
neural alterations invoked by AD from early on, might improve the
possibility to identify at risk subjects in time, providing a
chance for effective treatment (Shah et al., 2008). The first study
(see chapter 4, pp. 31 et seqq.) examined whether cognitive
parameters for estimating the capacity of visual attention might
serve that purpose. Based on Bundesen’s (1990) TVA, visual
information uptake was analyzed in 18 subjects with probable AD, 18
subjects with amnestic MCI, and 18 healthy elderly control
subjects. Groups were matched for gender, age, and education. From
a whole report task requiring ver-bal report of briefly presented
letters, four parameters were derived, characterizing different
aspects of visual processing capacity: perceptual threshold t0,
iconic memory μ, processing speed C, and visual short-term memory
(VSTM) storage capacity K. Comparison of these attentional
parameters between groups revealed an elevation of the per-ceptual
threshold already in MCI subjects, while processing speed and VSTM
storage capacity showed a significant decline for AD patients,
only. AD patients on medication with acetyl-choline esterase
inhibitors had higher processing speed, but were still below the
level of MCI patients. Perceptual threshold values were
significantly correlated with disease duration, but not with
cognitive measures. Conversely, speed and VSTM were significantly
related to cog-nitive scores, but not to disease duration. In
particular, VSTM storage was related to neurop-sychological tasks
applying visual material (picture naming and visuo-construction),
while speed showed an additional relationship also to measures of
verbal memory. These results indicate a staged pattern of deficits
affecting pre-attentive visual processing in MCI, and attentive
processing in AD. They fit into the amyloid cascade hypothesis
according to which the neuropathology of AD is characterized by a
net accumulation and deposition of β-amyloid (Aβ) in the initial
phase, giving rise to neuronal and neuritic dysfunction. Later,
gradual neuronal loss and transmitter disturbances finally cause
the increasing intellectual de-cline during further progression of
the disease. A threshold elevation may thus be considered as a
possible index of impaired neuronal functioning prior to cell
death, while speed and VSTM deficits may be indicative already of a
substantial loss of neuronal cell assemblies and a degeneration of
neurotransmitter systems. Study 2: AD is the most frequent form of
dementia which appears both as a familial and a sporadic va-riant.
In the by far more frequent sporadic form, a genetic risk factor is
also implicated, in that carriers of the apolipoprotein E ε4 allele
(ApoE4) have a 3 to 15 times higher risk of develop-ing the
disease, compared to non-carriers (Blennow, de Leon, &
Zetterberg, 2006). Using an identical TVA-based partial report
paradigm as in the present study, Finke et al. (2006) had found a
close relationship between the severity of the underlying genetic
pathology in another neurodegenerative, namely Huntington’s,
disease and the direction and degree of spatial attentional
weighting. Sensitive tools for assessing selective visual attention
might serve as early cognitive markers in the course of AD and
therefore enhance the identification rate of at-risk subjects at
the MCI stage (Shah et al., 2008) as well as of subjects with
underlying genetic risk (ApoE4). The second study (see chapter 5,
pp. 60 et seqq.) aimed at examining whether attentional parameters
of visuospatial and task-related selection are appropriate means
for that purpose. Visual selective attention was investigated in 32
patients with amnestic MCI, 16 patients with probable AD, and 36
healthy elderly control subjects. Groups were matched for age,
gender and educational level. In combination with Bundesen’s (1990)
TVA, two mathematically in-dependent and quantitative parameter
estimates were derived from a partial report of briefly presented
letter arrays: top-down control of attentional selection,
representing task-related at-tentional weighting for prioritizing
relevant visual objects, and spatial distribution of atten-tional
weights across the left and right visual hemifield. Compared to
controls, MCI patients showed significantly reduced top-down
controlled selec-tion which further deteriorated in AD subjects.
Moreover, attentional weighting was signifi-cantly unbalanced
across hemifields in MCI and tended to be more lateralized in AD.
The ma-jority of patients was biased to the left. Across MCI and AD
patients, ApoE4 carriers revealed a leftward spatial bias. The
leftward bias was the more pronounced the younger the
ApoE4-positive patients and the earlier disease onset.
ApoE4-negative subjects showed balanced attentional weighting.
These results indicate that impaired top-down control may be linked
to early dysfunction of cortico-cortical networks connecting
parietal and frontal lobes. Accompanying, an early
inter-hemispheric asymmetry in temporo-parietal cortical
interactions might cause a pathological spatial bias. As the
inheritance of ApoE4 is associated with an interhemispheric
imbalance in parietal cortical interactions, a pathological spatial
bias may function as early cognitive marker for detecting subjects
at risk for probable AD. Study 3: In the latter study, the
TVA-based partial report paradigm proved to be a sensitive tool for
ve-rifying that both, deficits in task-related selection and a
pathological attentional imbalance, are already present at the
early stage of amnestic MCI and increase further at the AD stage
(see second study, chapter 5, pp. 60 et seqq.). It was hypothesized
that these deficiencies in selective attention may result from an
early disconnection syndrome and an interhemispheric imbalance in
cortical interactions, respectively, in the fronto-parietal
attention network, before gradual neuronal loss leads to further
decline in selective attentional and intellectual functions at
later stages. In the third study (see chapter 6, pp. 93 et seqq.),
these hypotheses were tested by investigat-ing the relationship of
both partial report parameters, top-down control α and especially
the laterality index of attentional weighting wλ, to regional
glucose metabolism measured by rest-ing-state positron emission
tomography (PET) in a sample of 30 amnestic MCI or mild AD
patients. Hypometabolism across all patients was slightly increased
in the left hemisphere. Interestingly, the more reduced the
metabolism in the left temporo-parietal junction (TPJ) the more
pro-nounced was the top-down control deficit. Accordingly,
hypometabolism in the left TPJ pre-dicted the magnitude of the
spatial bias. Furthermore, relative hypometabolism in the left TPJ
and left inferior parietal lobe (IPL) as compared to the right TPJ
and right IPL, respectively, was correlated with direction and
degree of spatial bias. Taken together, PET imaging results support
the hypotheses that, one the one hand, early def-icits in
task-related weighting may result from a fronto-parietal
disconnection syndrome al-ready at the stage of MCI. On the other
hand, very early AD seems to be also associated with an
interhemispheric imbalance of metabolism, particularly in the
temporo-parietal cortices, resulting in a correspondingly directed
and distinctive visuo-spatial attentional bias. Conclusions and
outlook: This dissertation intended to investigate the probable
valuable contribution of the whole and partial report of briefly
presented letter arrays based on Bundesen’s theory of visual
attention (TVA; Bundesen, 1990, 1998; Bundesen, Habekost, &
Kyllingsbaek, 2005) in assessing am-nestic MCI and AD patients in
comparison to healthy elderly control subjects. The results of the
three presented studies suggest a staging model of visual selective
atten-tional impairments in MCI and AD. Deficits of pre-attentive
processing (perceptual threshold t0), task-related (top-down
control α) and spatial weighting (laterality index of attentional
weighting wλ) were already detectable in MCI patients, while
aspects of processing capacity (perceptual processing speed C and
VSTM storage capacity K) were still intact. At a later stage of the
disease, further deterioration of top-down control α and increasing
lateralization of spatial weighting wλ accompanied impairments in
perceptual processing speed C and VSTM storage capacity K. In
conclusion, the TVA-based assessment of selective visual attention
proved to be a sensitive diagnostic tool for revealing subtle
deficits already at the stage of MCI which might exhibit the
capability of an early cognitive marker for the identification of
subjects at risk of AD. To address this question, this survey needs
to be complemented by longitudinal studies.
presented in this dissertation are given. For a detailed German
synopsis of the present work, see chapter 8 (pp. 118 et seqq.).
Research in the field of aging and dementia is a main concern as
the population of elderly people is growing continuously due to
increasing life expectancy and thus, an accumulative number of
people who live well beyond 65 years of age run a risk of
developing age-associated neurodegenerative disorders of cognitive
function, such as Alzheimer’s disease (AD), emerging as a major
health problem. The present work is based on growing evidence that
deficits in visual selective attention occur early in the
progression to AD (Foldi et al., 2002) and therefore might be
present as the first non-memory deficits (Perry & Hodges, 1999)
at the early prodromal stage of mild cognitive impairment (MCI;
Petersen et al., 1999). The present dissertation was performed to
contribute to the still ongoing debate as to whether certain
aspects of visual selective attention are par-ticularly vulnerable
or preserved, especially at the stage of MCI, and whether
attentional func-tioning might be qualitatively and/ or
quantitatively different from attentional performance at the AD
stage on the one hand or normal functioning on the other hand. As
theoretical basis, Bundesen’s theory of visual attention (TVA;
Bundesen, 1990, 1998) was employed to assess several latent,
mathematically independent and quantitative parameter es-timates
which are derived from two highly comparable paradigms –
computerized whole re-port and partial report of briefly presented
visual letter arrays. Central conclusions arising out of TVA-based
investigations (e.g., Bublak et al., 2005; Bublak, Redel, &
Finke, 2006; Duncan et al., 1999; Duncan et al., 2003; Finke et
al., 2006; Gerlach, Marstrand, Habekost, & Gade, 2005; Habekost
& Bundesen, 2003; Habekost & Rostrup, 2006; Peers et al.,
2005) point at four central strengths of this tool for attentional
assessment – the quality criteria sensitivity, specificity,
reliability and validity. Study 1: In AD, the amyloid cascade
hypothesis (Hardy & Selkoe, 2002) assumes that rising plaque
and tangle burden invokes loss of nerve cells through direct and
indirect effects on synaptic, neuronal and neuritic function (see
e.g. Cirrito et al., 2005), resulting in progressive intellectual
decline. Thus, sensitive biomarkers loading functionally on the
neural alterations invoked by AD from early on, might improve the
possibility to identify at risk subjects in time, providing a
chance for effective treatment (Shah et al., 2008). The first study
(see chapter 4, pp. 31 et seqq.) examined whether cognitive
parameters for estimating the capacity of visual attention might
serve that purpose. Based on Bundesen’s (1990) TVA, visual
information uptake was analyzed in 18 subjects with probable AD, 18
subjects with amnestic MCI, and 18 healthy elderly control
subjects. Groups were matched for gender, age, and education. From
a whole report task requiring ver-bal report of briefly presented
letters, four parameters were derived, characterizing different
aspects of visual processing capacity: perceptual threshold t0,
iconic memory μ, processing speed C, and visual short-term memory
(VSTM) storage capacity K. Comparison of these attentional
parameters between groups revealed an elevation of the per-ceptual
threshold already in MCI subjects, while processing speed and VSTM
storage capacity showed a significant decline for AD patients,
only. AD patients on medication with acetyl-choline esterase
inhibitors had higher processing speed, but were still below the
level of MCI patients. Perceptual threshold values were
significantly correlated with disease duration, but not with
cognitive measures. Conversely, speed and VSTM were significantly
related to cog-nitive scores, but not to disease duration. In
particular, VSTM storage was related to neurop-sychological tasks
applying visual material (picture naming and visuo-construction),
while speed showed an additional relationship also to measures of
verbal memory. These results indicate a staged pattern of deficits
affecting pre-attentive visual processing in MCI, and attentive
processing in AD. They fit into the amyloid cascade hypothesis
according to which the neuropathology of AD is characterized by a
net accumulation and deposition of β-amyloid (Aβ) in the initial
phase, giving rise to neuronal and neuritic dysfunction. Later,
gradual neuronal loss and transmitter disturbances finally cause
the increasing intellectual de-cline during further progression of
the disease. A threshold elevation may thus be considered as a
possible index of impaired neuronal functioning prior to cell
death, while speed and VSTM deficits may be indicative already of a
substantial loss of neuronal cell assemblies and a degeneration of
neurotransmitter systems. Study 2: AD is the most frequent form of
dementia which appears both as a familial and a sporadic va-riant.
In the by far more frequent sporadic form, a genetic risk factor is
also implicated, in that carriers of the apolipoprotein E ε4 allele
(ApoE4) have a 3 to 15 times higher risk of develop-ing the
disease, compared to non-carriers (Blennow, de Leon, &
Zetterberg, 2006). Using an identical TVA-based partial report
paradigm as in the present study, Finke et al. (2006) had found a
close relationship between the severity of the underlying genetic
pathology in another neurodegenerative, namely Huntington’s,
disease and the direction and degree of spatial attentional
weighting. Sensitive tools for assessing selective visual attention
might serve as early cognitive markers in the course of AD and
therefore enhance the identification rate of at-risk subjects at
the MCI stage (Shah et al., 2008) as well as of subjects with
underlying genetic risk (ApoE4). The second study (see chapter 5,
pp. 60 et seqq.) aimed at examining whether attentional parameters
of visuospatial and task-related selection are appropriate means
for that purpose. Visual selective attention was investigated in 32
patients with amnestic MCI, 16 patients with probable AD, and 36
healthy elderly control subjects. Groups were matched for age,
gender and educational level. In combination with Bundesen’s (1990)
TVA, two mathematically in-dependent and quantitative parameter
estimates were derived from a partial report of briefly presented
letter arrays: top-down control of attentional selection,
representing task-related at-tentional weighting for prioritizing
relevant visual objects, and spatial distribution of atten-tional
weights across the left and right visual hemifield. Compared to
controls, MCI patients showed significantly reduced top-down
controlled selec-tion which further deteriorated in AD subjects.
Moreover, attentional weighting was signifi-cantly unbalanced
across hemifields in MCI and tended to be more lateralized in AD.
The ma-jority of patients was biased to the left. Across MCI and AD
patients, ApoE4 carriers revealed a leftward spatial bias. The
leftward bias was the more pronounced the younger the
ApoE4-positive patients and the earlier disease onset.
ApoE4-negative subjects showed balanced attentional weighting.
These results indicate that impaired top-down control may be linked
to early dysfunction of cortico-cortical networks connecting
parietal and frontal lobes. Accompanying, an early
inter-hemispheric asymmetry in temporo-parietal cortical
interactions might cause a pathological spatial bias. As the
inheritance of ApoE4 is associated with an interhemispheric
imbalance in parietal cortical interactions, a pathological spatial
bias may function as early cognitive marker for detecting subjects
at risk for probable AD. Study 3: In the latter study, the
TVA-based partial report paradigm proved to be a sensitive tool for
ve-rifying that both, deficits in task-related selection and a
pathological attentional imbalance, are already present at the
early stage of amnestic MCI and increase further at the AD stage
(see second study, chapter 5, pp. 60 et seqq.). It was hypothesized
that these deficiencies in selective attention may result from an
early disconnection syndrome and an interhemispheric imbalance in
cortical interactions, respectively, in the fronto-parietal
attention network, before gradual neuronal loss leads to further
decline in selective attentional and intellectual functions at
later stages. In the third study (see chapter 6, pp. 93 et seqq.),
these hypotheses were tested by investigat-ing the relationship of
both partial report parameters, top-down control α and especially
the laterality index of attentional weighting wλ, to regional
glucose metabolism measured by rest-ing-state positron emission
tomography (PET) in a sample of 30 amnestic MCI or mild AD
patients. Hypometabolism across all patients was slightly increased
in the left hemisphere. Interestingly, the more reduced the
metabolism in the left temporo-parietal junction (TPJ) the more
pro-nounced was the top-down control deficit. Accordingly,
hypometabolism in the left TPJ pre-dicted the magnitude of the
spatial bias. Furthermore, relative hypometabolism in the left TPJ
and left inferior parietal lobe (IPL) as compared to the right TPJ
and right IPL, respectively, was correlated with direction and
degree of spatial bias. Taken together, PET imaging results support
the hypotheses that, one the one hand, early def-icits in
task-related weighting may result from a fronto-parietal
disconnection syndrome al-ready at the stage of MCI. On the other
hand, very early AD seems to be also associated with an
interhemispheric imbalance of metabolism, particularly in the
temporo-parietal cortices, resulting in a correspondingly directed
and distinctive visuo-spatial attentional bias. Conclusions and
outlook: This dissertation intended to investigate the probable
valuable contribution of the whole and partial report of briefly
presented letter arrays based on Bundesen’s theory of visual
attention (TVA; Bundesen, 1990, 1998; Bundesen, Habekost, &
Kyllingsbaek, 2005) in assessing am-nestic MCI and AD patients in
comparison to healthy elderly control subjects. The results of the
three presented studies suggest a staging model of visual selective
atten-tional impairments in MCI and AD. Deficits of pre-attentive
processing (perceptual threshold t0), task-related (top-down
control α) and spatial weighting (laterality index of attentional
weighting wλ) were already detectable in MCI patients, while
aspects of processing capacity (perceptual processing speed C and
VSTM storage capacity K) were still intact. At a later stage of the
disease, further deterioration of top-down control α and increasing
lateralization of spatial weighting wλ accompanied impairments in
perceptual processing speed C and VSTM storage capacity K. In
conclusion, the TVA-based assessment of selective visual attention
proved to be a sensitive diagnostic tool for revealing subtle
deficits already at the stage of MCI which might exhibit the
capability of an early cognitive marker for the identification of
subjects at risk of AD. To address this question, this survey needs
to be complemented by longitudinal studies.
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