Abstracts
Neuropsychiatric symptoms in Alzheimer’s disease (AD) are prevalent, however their relationship with patterns of cortical atrophy is not fully known.
Objectives
To compare cortical atrophy’s patterns between AD patients and healthy controls; to verify correlations between neuropsychiatric syndromes and cortical atrophy.
Method
33 AD patients were examined by Neuropsychiatric Inventory (NPI). Patients and 29 controls underwent a 3T MRI scanning. We considered four NPI syndromes: affective, apathy, hyperactivity and psychosis. Correlations between structural imaging and neuropsychiatric scores were performed by Freesurfer. Results were significant with a p-value < 0.05, corrected for multiple comparisons.
Results
Patients exhibited atrophy in entorhinal cortices, left inferior and middle temporal gyri, and precuneus bilaterally. There was correlation between affective syndrome and cortical thickness in right frontal structures, insula and temporal pole.
Conclusion
Cortical thickness measures revealed atrophy in mild AD. Depression and anxiety symptoms were associated with atrophy of right frontal, temporal and insular cortices.
depression; anxiety; MRI; neurodegenerative disease; neuropsychiatry
Os sintomas neuropsiquiátricos na doença de Alzheimer (DA) são prevalentes, porém suas relações com padrões de atrofia cortical não são totalmente compreendidas.
Objetivos
Comparar padrões de atrofia cortical entre DA e controles; verificar se há correlações entre sintomas neuropsiquiátricos e atrofia cortical.
Método
33 pacientes com DA foram examinados pelo Inventário Neuropsiquiátrico. Os pacientes e 29 controles foram submetidos à RNM. Consideramos quatro síndromes: afetiva, apatia, hiperatividade e psicose. Correlações entre imagens estruturais e os scores foram feitas pelo Freesurfer. Os resultados foram significantes com um valor de p < 0,05, corrigido para múltiplas comparações.
Resultados
Pacientes exibiram atrofia nos córtices entorrinais, giros temporal médio e inferior esquerdos, e precuneo bilateralmente. Houve correlação entre síndrome afetiva e espessura cortical em estruturais frontais direitas, ínsula e polo temporal.
Conclusão
Medidas de espessura cortical revelaram atrofia na DA. Sintomas de depressão e ansiedade foram associados à atrofia dos córtices frontal direito, temporal e ínsula.
depressão; ansiedade; RNM; doença neurodegenerativa; neuropsiquiatria
Neuropsychiatric syndromes (NPS) in dementia due to Alzheimer’s disease (AD) have received growing attention across clinical centers and research settings in the last few decades. The high prevalence of NPS and their increasing severity in AD patients aggravate the disease’s course and cause distress for caregivers. These symptoms, once considered secondary behavior due to cognitive and functional impairment in dementia, have shown patterns of temporal course, which do not necessarily follow the linear decline of cognitive impairment.
Several NPS seem to be more prevalent and clinically prominent in distinct stages of the disease. Depression is the most common syndrome in mild-to-moderate AD, while delusions, hallucinations, and aggression seem to be more common as the disease progresses, whereas apathy remains across all stages of AD, worsening as the global deterioration aggravates. However, these manifestations, also detected in mild cognitive impairment (MCI), increase the risk of dementia and may occur in prodromal AD.
Moreover, aberrant vocalizations commonly emerge when patients are in advanced stages of
dementia. Despite the fact that NPS and cognitive alterations may considerably overlap,
these findings suggest distinct etiologies for both conditions. Furthermore, over the
course of the disease, the prevalence of NPS reaches 50–90% of patients with
dementia11 . Aalten P, Verhey FRJ, Boziki M, Bullock R, Byrne EJ, Camus V et
al. Neuropsychiatric syndromes in dementia. Results from the European Alzheimer
Disease Consortium: part I. Dement Geriatr Cogn Disord. 2007;24(6):457-63.
http://dx.doi.org/10.1159/000110738
https://doi.org/10.1159/000110738...
.
A better understanding of NPS could enable more efficient treatments of neuropsychiatric disorders to be developed. There is therefore a need to learn more about the neurobiology and pathophysiological mechanisms of these symptoms.
Several studies supported by neuroimaging have disclosed findings about neuroanatomy and
functional connectivity that can increase knowledge about NPS. One study proposed an
association between anatomic regions and NPS in moderate-to-severe stages of AD, even at
early stages22 . Bruen PD, McGeown WJ, Shanks MF, Venneri A. Neuroanatomical
correlates of neuropsychiatric symptoms in Alzheimer’s disease. Brain.
2008;131(9):2455-63. http://dx.doi.org/10.1093/brain/awn151
https://doi.org/10.1093/brain/awn151...
. Despite the difficulty
that the authors had performing discriminatory analyses of psychopathological
manifestations, delusions were associated with decreased gray matter (GM) on the frontal
lobe, right frontoparietal cortex, and left claustrum. Furthermore, an increased density
of senile plaques and neurofibrillary tangles in the middle frontal cortex and
presubiculum has been related to psychosis in AD.
Patients with AD, particularly women showing paranoid delusions, had cortical atrophy in
the left medial orbitofrontal, left superior temporal cortices, and the left insula,
independent of cognitive decline33 . Whitehead D, Tunnard C, Hurt C, Wahlund LO, Mecocci P, Tsolaki M
et al. Frontotemporal atrophy associated with paranoid delusions in women with
Alzheimer’s disease. Int Psychogeriatr. 2012;24(1):99-107.
http://dx.doi.org/10.1017/S1041610211000974
https://doi.org/10.1017/S104161021100097...
.
Other studies have associated certain neurodegenerative diseases with distinct brain
structures and disturbances in specific neuronal networks. Another study found that
agitation was correlated with a decreased GM density on the left insula and bilateral
anterior cingulate cortex22 . Bruen PD, McGeown WJ, Shanks MF, Venneri A. Neuroanatomical
correlates of neuropsychiatric symptoms in Alzheimer’s disease. Brain.
2008;131(9):2455-63. http://dx.doi.org/10.1093/brain/awn151
https://doi.org/10.1093/brain/awn151...
.
Furthermore, hyperactivity syndrome was correlated with increased connectivity in the
salience network (SN) in the anterior cingulated cortex and right insula. Although these
networks showed alterations, some anatomical structures did not exhibit cortical
atrophy, which suggests that behavioral disorders may be triggered by disruptions in
functional connectivity with or without the atrophy of the structures of these networks.
In addition, NPS could be related to disruptions in functional connectivity before
evidence for cortical changes44 . Balthazar MLF, Pereira FRS, Lopes TM, Silva EL, Coan AC, Campos BM
et al. Neuropsychiatric symptoms in Alzheimer’s disease are related to
functional connectivity alterations in the salience networks. Hum Brain Mapp.
2014;35(4):1237-46. http://dx.doi.org/10.1002/hbm.22248
http://dx.doi.org/10.1002/hbm.22248...
.
Voxel-based Morphometry (VBM) has recently been used in research to verify the possible correlation between GM density and NPS. In these studies, AD patients with apathy showed damage on anterior cingulated and middle frontal cingulated regions. Another group used VBM to confirm the association between reduced GM of the hippocampus and the occurrence of delusions in mild-to-moderate AD patients.
Voxel-based Cortical Thickness (VBCT) testing may provide more reliable measurements than
VBM, as shown in a study of decreased GM and normal aging55 . Hutton C, Draganski B, Ashburner J, Weiskopf N. A comparison
between voxel-based cortical thickness and voxel-based morphometry in normal
aging. Neuroimage. 2009;48(2):371-80.
http://dx.doi.org/10.1016/j.neuroimage.2009.06.043
https://doi.org/10.1016/j.neuroimage.200...
. In the same way, Dickerson et al. showed that asymptomatic
subjects who converted to AD had a pattern of cortical thinning in a set of regions,
almost 10 years before developing dementia66 . Dickerson BC, Stoub TR, Shah RC, Sperling RA, Killiany RJ, Albert
MS et al. Alzheimer-signature MRI biomarker predicts AD dementia in cognitively
normal adults. Neurology. 2011;76(16):1395-402.
http://dx.doi.org/10.1212/WNL.0b013e3182166e96
https://doi.org/10.1212/WNL.0b013e318216...
.
In light of this information and the desire to provide data for a better understanding of neuroanatomy and neurobiology of NPS, the present study aims to compare: the differences in whole brain cortical thickness between mild-to-moderate AD patients and the normal elderly; and to verify the possible correlations between neuroanatomical structures with NPS using VBCT testing.
METHOD
Subjects
The sample consisted of 62 subjects (33 mild or moderate AD patients and 29 controls) who were at least 50 years old. The subjects were treated at the Neuropsychology and Dementia Outpatient Clinic (Unicamp University Hospital, Campinas, Brazil) and the local ethics committee approved these experiments. Both groups were matched regarding gender, age, and educational level.
The diagnosis of probable AD was based on criteria established by the National Institute of Aging and the Alzheimer’s Association criteria for probable AD. We only included patients who were classified with a clinical dementia rating (CDR) of 1 (23 patients) or 2 (10 patients). All patients had had at least one psychiatric symptom in the previous month and were referred on the basis of a neuropsychiatric inventory (NPI) from a caregiver. Exclusion criteria included a history of other neurological or psychiatric diseases, previous head injury with a loss of consciousness, drug or alcohol addiction, prior chronic exposure to neurotoxic substances, and a Hachinski ischemic score > 4. Patients who met the clinical criteria for probable AD but had extensive white matter (WM) hyperintensities on T2-weighted MRI were also excluded. The control group consisted of subjects who were classified as CDR 0 and had no memory complaints or history of neurological and psychiatric diseases.
Neuropsychological and neuropsychiatric examination
Global cognitive state was assessed by the Mini-Mental State Examination. Episodic memory was evaluated by Rey’s Auditory Verbal Learning Test. Subtests of Luria’s neuropsychological investigation verified visual and spatial perception. Constructional praxis was examined by the Rey-Osterrieth Complex Figure Test. Linguistic tests included Boston Naming and verbal fluency for category (animals) and phonological (FAS). Working memory was assessed by forward and backward digit span subtests of Wechsler’s Adult Intelligence Scale Revised. Executive functions were examined by trail making test B, Stroop Test, and the Clock Drawing Test. Pfeffer’s functional activities questionnaire complemented our evaluation on functional dependence.
Neuropsychiatric examination was based on NPI, which consisted of an interview
with the closest caregiver. NPI is an assessment of 12 neuropsychiatric domains:
hallucinations, delusions, agitation/aggression, anxiety, depression/dysphoria,
irritability/lability, disinhibition, elation/euphoria, apathy/indifference,
aberrant motor behavior, sleep and night time behavior disorders, and appetite
and eating disorders. Questions were read to the caregiver exactly as written.
If the caregiver did not understand the question, it was repeated with synonyms.
After reading the question, the caregiver was asked if he/she noticed the
behavior of the patient. If the answer was negative, the next set of questions
was asked. If the answer was positive, subquestions were read and possible
answers were “yes” or “no.” The caregiver was then instructed to state the
frequency and severity of the behavior in that domain, regarding alterations
revealed by the subquestions. Scores were calculated by multiplying the
frequency (1–4: rarely, sometimes, often, and very often) and the severity (1–3:
mild, moderate, and severe). Based on a study by Aalten et al.11 . Aalten P, Verhey FRJ, Boziki M, Bullock R, Byrne EJ, Camus V et
al. Neuropsychiatric syndromes in dementia. Results from the European Alzheimer
Disease Consortium: part I. Dement Geriatr Cogn Disord. 2007;24(6):457-63.
http://dx.doi.org/10.1159/000110738
https://doi.org/10.1159/000110738...
, we considered the following
four subsyndromes: apathy, hyperactivity (the sum of agitation, disinhibition,
irritability, euphoria, and aberrant motor behavior scores), psychosis
(delusions, hallucinations, and night-time behavior disturbances), and affective
syndrome (depression and anxiety). CDR was based on a semi-structured interview
and the classification was based on the guidelines.
MRI acquisition and analysis
The data were obtained by a 3T MRI scanner (Philips Achieva, Best, Netherlands).
A set of structural images was composed of the following sequences: a) sagittal
high-resolution T1-weighted with gradient echo images that were acquired with
TR/TE = 7/3.2 ms, field of view (FOV) = 240×240, and isotropic voxels of 1
mm33 . Whitehead D, Tunnard C, Hurt C, Wahlund LO, Mecocci P, Tsolaki M
et al. Frontotemporal atrophy associated with paranoid delusions in women with
Alzheimer’s disease. Int Psychogeriatr. 2012;24(1):99-107.
http://dx.doi.org/10.1017/S1041610211000974
https://doi.org/10.1017/S104161021100097...
, b) coronal and axial
Fluid-attenuated Inversion Recovery, T2-weighted images, anatomically aligned at
the hippocampus with image parameters set to TR/TE/TI = 12000/140/2850, FOV =
220×206, voxels reconstructed to 0.45×0.45×4.00 mm33 . Whitehead D, Tunnard C, Hurt C, Wahlund LO, Mecocci P, Tsolaki M
et al. Frontotemporal atrophy associated with paranoid delusions in women with
Alzheimer’s disease. Int Psychogeriatr. 2012;24(1):99-107.
http://dx.doi.org/10.1017/S1041610211000974
https://doi.org/10.1017/S104161021100097...
, and gap between slices set to 1 mm, c) coronal
inversion recovery T1-weighted images with TR/TE/TI = 3550/15/400, FOV =
180×180, and voxels reconstructed to 0.42×0.42×3.00 mm3, and d)
coronal multi-echo (5 echoes) T2-weighted images with TR/TE = 3300/30, FOV =
180×180, voxels reconstructed to 0.42×0.42×3.00 mm3.
Cortical thickness was determined using FreeSurfer software v.5.3. Measurements
were performed according to the protocol suggested by Fischl and Dale77 . Fischl B, Dale AM. Measuring the thickness of the human cerebral
cortex from magnetic resonance images. Proc Natl Acad Sci USA.
2000;97(20):11050-5. http://dx.doi.org/10.1073/pnas.200033797
https://doi.org/10.1073/pnas.200033797...
. First, the images were aligned
to the Talairach and Tournoux atlas. Next, the image’s grayscale intensity was
normalized and corrected for magnetic field inhomogeneity. The extra-cerebral
voxels were removed by the skull-stripped protocol. Next, the voxels were
labeled as GM, WM, or cerebral spinal fluid and two surfaces were created: pial
and white77 . Fischl B, Dale AM. Measuring the thickness of the human cerebral
cortex from magnetic resonance images. Proc Natl Acad Sci USA.
2000;97(20):11050-5. http://dx.doi.org/10.1073/pnas.200033797
https://doi.org/10.1073/pnas.200033797...
,88 . Fischl B, Liu A, Dale AM. Automated manifold surgery: constructing
geometrically accurate and topologically correct models of the human cerebral
cortex. IEEE Trans Med Imaging. 2001;20(1):70-80.
http://dx.doi.org/10.1109/42.906426
https://doi.org/10.1109/42.906426...
. Cortical thickness was
calculated as the shortest distance between the pial and white surface at each
vertex across the cortical mantle. For all analyses, a Gaussian filter with 10
mm full width at half maximum was used for smoothing the surface. To evaluate
possible cortical thickness differences, we used a General Linear Model with age
as regressor. In order to correct for multiple comparisons, a False Discovery
Rate test (FDR) was applied over the t-score maps generated from group analysis,
enabling the identification of significant clusters. To assess possible
correlations between NPS and cortical thickness of patients, we performed a
Pearson correlation. All correlation analyses were corrected for multiple
comparisons using FDR test.
Informed consent
All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients.
RESULTS
Demographic and cognitive results are shown in Table 1. The distributions of NPI scores for each neuropsychiatric syndrome are shown in Figure 1.
Box-and-whiskers plot showing the distribution of NPI syndromes scores: hyperactivity (mean ± SD: 3.18 ± 5.19), apathy (3.72 ± 2.91), affective syndrome (3.69 ± 0.64) and psychosis (1.51 ± 2.32). The box extends from the 25th percentile to the 75th percentile, with a horizontal line at the median. Whiskers extend down to the smallest value and up to the largest.
We performed the analysis considering groups CDR 1 and CDR 2 as one group, since we hypothesized that both groups could represent a continuum regarding AD’s course: the more atrophy due to neurodegeneration, the more prominent are the neuropsychiatric symptoms. In fact, in our sample, CDR 2 group had much more neuropsychiatric symptoms (Total NPI score mean ± SD: 18.0 ± 13.49) than CDR 1 group (8.43 ± 4.37), p = 0.03.
We found significant differences between cortical thickness measures in AD patients compared with the normal elderly, as shown by cortical atrophy in the AD group in the temporal lobe areas, the bilateral entorhinal cortex, the left middle and left inferior temporal gyrus, the posterior regions of right superior temporal sulcus, the bilateral precuneus, the bilateral superior frontal gyrus, and the bilateral lateral orbitofrontal gyri. We also found significant differences in the bilateral insula, the isthmus of cingulate gyrus, the bilateral anterior cingulate cortex, the left posterior cingulate cortex, the bilateral supramarginal gyri, the right fusiform gyrus, the inferior parietal gyrus, and the superior parietal gyrus in both hemispheres. All results were FDR-corrected for multiple comparisons (Figure 2 and Tables 2 and 3).
Cortical regions with significant thickness differences between Alzheimer’s disease and controls in the left hemisphere.
Cortical regions with significant thickness differences between patients and controls in the right hemisphere.
Simple regressions between NPS and cortical thickness in AD patients
We found significant correlations between cortical thickness and affective syndrome (depression and anxiety) (Figure 3 and Table 4). All the other regressions (apathy, psychosis, and hyperactivity) did not survive multiple comparison corrections.
Areas with significant correlations between cortical thickness and affective syndrome in AD patients (FDR corrected).
DISCUSSION
The significant differences found in the cortical thickness of the AD group and the normal elderly corresponds to the well-established cortical atrophy of AD patients, even in mild and moderate stages. According to the pattern of AD atrophy, earlier atrophic sites are related to temporal and parietal lobes. As the degeneration progresses, areas of the frontal lobe may be affected.
One important issue is the overlapping of cognitive symptoms from depression or early dementia. This overlapping sometimes makes it difficult to distinguish affective syndrome and dementia. Depression may predict a faster cognitive deterioration; depressed patients with MCI have twice the risk of progressing to AD compared with non-depressed patients.
In this study, we found significant correlations between cortical structures in the
right hemisphere and affective syndrome. Interestingly, some of the more correlated
regions (insula, lateral orbitofrontal, and temporal pole) are important parts of
brain networks that process emotional information. Although insular functions are
not fully understood, there is evidence that the insula, especially its anterior
part, processes emotional experiences. Based on the role of the insula encoding
interoceptive signals from the body’s internal milieu that reflect autonomic
activity, Damasio argued that the insula is the location within the brain where
subjective feelings of emotion are generated99 . Damasio, AR. Feeling of emotion and the self. Ann N Y Acad Sci.
2003;1001(1):253-61. http://dx.doi.org/10.1196/annals.1279.014
https://doi.org/10.1196/annals.1279.014...
. The anterior insula is also a key region of the SN,
which is involved in detecting, integrating, and filtering relevant interoceptive,
autonomic, and emotional information. The SN, with the anterior insula as its
integral outflow hub, assists target brain regions to generate behavioral responses
to salient stimuli1010. Menon V. Large-scale brain networks and psychopathology: a
unifying triple network model. Trends Cogn Sci. 2011;15(10):483-506.
http://dx.doi.org/10.1016/j.tics.2011.08.003
https://doi.org/10.1016/j.tics.2011.08.0...
. In a
previous study of our group, we showed that connectivity in the right insula of AD
patients was related to symptoms of agitation, disinhibition, irritability,
euphoria, and aberrant motor behavior44 . Balthazar MLF, Pereira FRS, Lopes TM, Silva EL, Coan AC, Campos BM
et al. Neuropsychiatric symptoms in Alzheimer’s disease are related to
functional connectivity alterations in the salience networks. Hum Brain Mapp.
2014;35(4):1237-46. http://dx.doi.org/10.1002/hbm.22248
http://dx.doi.org/10.1002/hbm.22248...
. Moreover, task-based functional MRI studies showed that
hyperactivity of anterior insula has been consistently implicated with anxiety
disorders1111 . Paulus MP, Stein MB. An insular view of anxiety. Biol Psychiatry.
2006;60(4):383-7.
http://dx.doi.org/10.1016/j.biopsych.2006.03.04
https://doi.org/10.1016/j.biopsych.2006....
. Takahashi et al.
also found GM volume reductions in the left anterior insula in depression1212 . Takahashi T, Yücel M, Lorenzetti V, Tanino R, Whittle S, Suzuki M
et al. Volumetric MRI study of the insular cortex in individuals with current
and past major depression. J Affect Disord. 2010;121(3):231-8.
http://dx.doi.org/10.1016/j.jad.2009.06.003
https://doi.org/10.1016/j.jad.2009.06.00...
.
We also found a significant correlation between affective syndrome and the
orbitofrontal cortex (a region involved with socioemotional processing) and the
right temporal pole. Although temporal pole atrophy is more commonly seen in a
temporal variant of frontotemporal dementia than in AD, dysfunctions in the right
side of this region are associated with changes in personality and social behavior.
Moreover, other affect-related problems in temporal pole atrophy include depression,
irritability, apathy, and emotional blunting. Increased associations between the
left temporal lobe and depressive and anxiety symptoms are recurrent in the
literature, despite the existence of controversies concerning laterality. Mendez et
al., for example, verified a correlation between anxiety and dysthymia with
hypoperfusion of the right temporal lobe1313 . Mendez MF, McMurtray A, Chen AK, Shapira JS, Mishkin F, Miller BL.
Functional neuroimaging and presenting psychiatric features in frontotemporal
dementia. J Neurol Neurosurg Psychiatry. 2006;77(1):4-7.
http://dx.doi.org/10.1136/jnnp.2005.072496
https://doi.org/10.1136/jnnp.2005.072496...
. Other studies have also examined the correlation
between depression and a reduction in cortical thickness on the entorhinal cortex
and the anterior cingulated cortex1414 . Zahodne LB, Gongvatana A, Cohen RA, Ott BR, Tremont G. Are apathy
and depression independently associated with longitudinal trajectories of
cortical atrophy in mild cognitive impairment? Am J Geriatr Psychiatry.
2013;21(11):1098-106.
http://dx.doi.org/10.1016/j.jagp.2013.01.043
https://doi.org/10.1016/j.jagp.2013.01.0...
. Because of these findings, it is possible to note the
relevance of correlations between affective syndrome and the frontal and temporal
lobes. The most likely hypothesis to explain the pathophysiology of affective
syndrome is based on the proposition that disturbances in the temporal and frontal
lobes may influence brain network disruptions, which occurs, for instance, in the
limbic system. These disruptions may disorganize serotonergic and dopaminergic
neurotransmitters in frontal-subcortical pathways and impact behavior. Thus,
depressive symptoms in MCI and AD patients become clinically relevant and reflect
dysfunctions in the frontal lobe with associated behavioral manifestations –
agitation, disinhibition, and restlessness1515 . Van der Mussele S, Bekelaar K, Le Bastard N, Vermeiren Y, Saerens
J, Somers N et al. Prevalence and associated behavioral symptoms of depression
in mild cognitive impairment and dementia due to Alzheimer’s disease. Int J
Geriatr Psychiatry. 2013;28(9):947-58.
http://dx.doi.org/10.1002/gps.3909
https://doi.org/10.1002/gps.3909...
.
Our findings of a correlation between affective syndrome and frontal atrophy are also
supported by information from the literature. A post-mortem study demonstrated a
reduction in the density of prefrontal cortical glial cells, as well as providing
convincing evidence for diminished prefrontal neuronal size in patients with
depression1616 . Cotter D, Mackay D, Landau S, Kerwin R, Everall I. Reduced glial
cell density and neuronal size in the anterior cingulate cortex in major
depressive disorder. Arch Gen Psychiatry. 2001;58(6):545-53.
http://dx.doi.org/10.1001/archpsyc.58.6.545
https://doi.org/10.1001/archpsyc.58.6.54...
, 1717 . Cotter D, Mackay D, Chana G, Beasley C, Landau S, Everall IP.
Reduced neuronal size and glial cell density in area 9 of the dorsolateral
prefrontal cortex in subjects with major depressive disorder. Cereb Cortex.
2002;12(4):386-94. http://dx.doi.org/10.1093/cercor/12.4.386
https://doi.org/10.1093/cercor/12.4.386...
. A recent meta-analysis involving
MRI studies in late-life depression reported significant volume reductions in the
orbitofrontal cortex, putamen, and thalamus1818 . Sexton CE, Mackay CE, Ebmeier KP. A systematic review and
meta-analysis of magnetic resonance imaging studies in late-life depression. Am
J Geriatr Psychiatry. 2013;21(2):184-95.
http://dx.doi.org/10.1016/j.jagp.2012.10.019
https://doi.org/10.1016/j.jagp.2012.10.0...
. The authors hypothesized that disruption of networks
linking these frontal-subcortical structures, as well as limbic networks, exert an
important role in the pathophysiology of late-life depression. Furthermore, the
interactions between episodic memory decline and depression in patients with volume
loss in several brain structures, including the right inferior frontal gyrus, left
medial frontal gyrus, and the posterior mesial temporal gyrus, have been suggested
as potential markers for an increased risk of AD1919 . Xie C, Li W, Chen G, et al. The co-existence of geriatric
depression and amnestic mild cognitive impairment detrimentally affect gray
matter volumes: voxel-based morphometry study. Behav Brain Res.
2012;235(2):244-50. http://dx.doi.org/10.1016/j.bbr.2012.08.007
https://doi.org/10.1016/j.bbr.2012.08.00...
. In addition, a comprehensive review concerning
neurobiological correlations with depression based on neuroimaging and post-mortem
investigations of depressed patients demonstrated cell loss in several brain
structures, particularly in the prefrontal cortex2020 . Bewernick BH, Schlaepfer TE. Chronic depression as a model disease
for cerebral aging. Dialogues Clin Neurosci. 2013;15(1):77-85..
Patients with late-onset depression that evolved to AD showed a reduced volume of
several structures, such as orbitofrontal, mediofrontal, parietal, and temporal
regions, including the hippocampus, amygdala, and parahippocampal area2121 . Andreescu C, Butters MA, Begley A, Rajji T, Wu M, Meltzer CC et
al. Gray matter changes in late life depression: a structural MRI analysis.
Neuropsychopharmacology. 2008;33(11):2566-72.
http://dx.doi.org/10.1038/sj.npp.1301655
https://doi.org/10.1038/sj.npp.1301655...
. The authors suggested that
depression could reflect a prodromal stage of dementia. In this scenario, a
significant reduction of β-amyloid peptide and a high Aβ40/Aβ42 ratio in depressed
patients have been reported and these findings increase the risk for dementia2222 . Piccinni A, Origlia N, Veltri A, Vizzaccaro C, Marazziti D,
Vanelli F et al. Neurodegeneration, β-amyloid and mood disorders: state of the
art and future perspectives. Int J Geriatr Psychiatry. 2013;28(7):661-71.
http://dx.doi.org/10.1002/gps.3879
https://doi.org/10.1002/gps.3879...
. However, this result remains to
be clarified since another group that aimed to analyze the impact of depression on
incident dementia developed a population-based prospective study of a large cohort
of the elderly and the authors found no clear association between both
conditions2323 . Luppa M, Luck T, Ritschel F, Angermeyer MC, Villringer A,
Riedel-Heller SG. Depression and incident dementia: an 8-year population-based
prospective study. PLoS One. 2013;8(3):e59246.
http://dx.doi.org/10.1371/journal.pone.0059246
https://doi.org/10.1371/journal.pone.005...
.
With respect to correlations between anxiety and brain structures, controversies
remain. One study suggested that social anxiety disorder implicates GM alterations
over the whole brain2424 . Frick A, Gingnell M, Marquand AF, et al. Classifying social
anxiety disorder using multivoxel pattern analyses of brain function and
structure. Behav Brain Res. 2014;259:330-5.
http://dx.doi.org/10.1016/j.bbr.2013.11.003
https://doi.org/10.1016/j.bbr.2013.11.00...
. On the
other hand, this syndrome may be characterized by disrupted neural activity in the
fear network composed of the amygdala, anterior cingulate cortex, hippocampus, and
insula. Another review described greater activation, mainly in the amygdala,
hippocampus, and frontolimbic region of individuals with exposure to fearful
stimuli2525 . Dalrymple KL. Issues and controversies surrounding the diagnosis
and treatment of social anxiety disorder. Expert Rev Neurother.
2012;12(8):993-1008. http://dx.doi.org/10.1586/ern.12.81
https://doi.org/10.1586/ern.12.81...
. Another wide review
using neuroimaging techniques reported that social anxiety disorder has been
implicated with certain cerebral networks composed of the limbic and cortical
areas2626 . Freitas-Ferrari MC, Hallak JE, Trzesniak C, Santos Filho A,
Machado de Sousa JP, Chagas MHN et al. Neuroimaging in social anxiety disorder:
a systematic review of the literature. Prog Neuropsychopharmacol Biol
Psychiatry. 2010;34(4):565-80.
http://dx.doi.org/10.1016/j.pnpbp.2010.02.028
https://doi.org/10.1016/j.pnpbp.2010.02....
. In addition, there is
evidence supporting that pathological anxiety may be related to an imbalance among
activities from the prefrontal cortex, amygdala, and anterior cingulate and that
elderly patients do not effectively engage these structures and networks in order to
control emotional reactivity2727 . Blay SL, Marinho V. Anxiety disorders in old age. Curr Opin
Psychiatry. 2012;25(6):462-7.
http://dx.doi.org/10.1097/YCO.0b013e3283578cdd
http://dx.doi.org/10.1097/YCO.0b013e3283...
.
Despite these considerations, there is no widespread agreement in the literature regarding the laterality of the frontal lobe and its correlation with depression2828 . Filley C. Neurobehavioral anatomy. 3rd ed. Colorado: University Press of Colorado, 2011.. We highlight the frequent association between anxiety and frontal lobe and amygdala disruptions, where these disruptions are a structure related to fear and anxiety.
We did not find any association of apathy with cortical atrophy, despite several
studies showing correlations between them. It has been acknowledged that
dysfunctions in anterior cingulate in AD patients with apathy are associated with
diminished goal-directed behavior and motivation, a reduction in interest related to
goal-directed cognition, and emotional blunting22 . Bruen PD, McGeown WJ, Shanks MF, Venneri A. Neuroanatomical
correlates of neuropsychiatric symptoms in Alzheimer’s disease. Brain.
2008;131(9):2455-63. http://dx.doi.org/10.1093/brain/awn151
https://doi.org/10.1093/brain/awn151...
,2929 . Robert PH, Darcourt G, Koulibaly MP, Clairet S, Benoit M, Garcia R
et al. Lack of initiative and interest in Alzheimer’s disease: a single photon
emission computed tomography study. Eur J Neurol. 2006;13(7):729-35.
http://dx.doi.org/10.1111/j.1468-1331.2006.01088.x
http://dx.doi.org/10.1111/j.1468-1331.20...
,3030 . Levy R, Dubois B. Apathy and the functional anatomy of the
prefrontal cortex-basal ganglia circuits. Cereb Cortex. 2006;16(7):916-28.
http://dx.doi.org/10.1093/cercor/bhj043
https://doi.org/10.1093/cercor/bhj043...
. The fact that we did not find a significant
correlation between both cortical atrophy and apathy, psychosis and hyperactive
syndrome may suggest that anatomic alteration on mild AD may not be enough to cause
network disruptions: atrophy could be compensated by an increase in connectivity,
which guarantees functional integrity. In this way, a recent study using
resting-state fMRI in mild to moderate AD patients demonstrated a SN
hyperconnectivity in the anterior cingulate cortex and right insula. These
alterations may predict behavioral disturbances in these patients, even before the
evidence of atrophy44 . Balthazar MLF, Pereira FRS, Lopes TM, Silva EL, Coan AC, Campos BM
et al. Neuropsychiatric symptoms in Alzheimer’s disease are related to
functional connectivity alterations in the salience networks. Hum Brain Mapp.
2014;35(4):1237-46. http://dx.doi.org/10.1002/hbm.22248
http://dx.doi.org/10.1002/hbm.22248...
. In addition,
our small sample size may have contributed to this lack of significant correlation.
Therefore, in order to elucidate psychopathology, it is essential to conduct
additional studies that correlate anatomic and connectivity disruptions in AD
patients.
Limitations
Our study has limitations that must be highlighted: first, we evaluated only cortical structures. Other subcortical structures potentially related to NPS were not studied. Secondly, we performed simple regressions between the syndromes and whole brain cortical thickness. However, we believe that our results are robust, since the analysis was conservatively corrected for multiple comparisons.
In conclusion, we have found that right hemisphere structures that are part of brain networks that process socioemotional functions are related to affective syndrome in patients with mild and moderate AD. We did not find significant correlations between cortical thickness and other NPS.
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» http://dx.doi.org/10.1111/j.1468-1331.2006.01088.x -
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» https://doi.org/10.1093/cercor/bhj043
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Support: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). Processo 2011/17092-0 e 2012/08291-1.
Publication Dates
-
Publication in this collection
July 2015
History
-
Received
31 Dec 2014 -
Reviewed
25 Feb 2015 -
Accepted
17 Mar 2015