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Brain (2002), 125, 24312445

Clinical correlates of selective pathology in the

amygdala of patients with Parkinson's disease
Antony J. Harding, Emily Stimson, Jasmine M. Henderson and Glenda M. Halliday

Prince of Wales Medical Research Institute and University Correspondence to: Dr Antony Harding, Prince of Wales
of New South Wales, Sydney, NSW, Australia Medical Research Institute, Barker Street, Randwick,
Sydney, NSW 2031, Australia

The amygdala exhibits signicant pathological changes Parkinson's disease (P = 0.02) and LB concentrated in
in Parkinson's disease, including atrophy and Lewy the cortical and basolateral nuclei. Lewy neurites were

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body (LB) formation. Amygdala pathology has been present in most cases but did not correlate with any
suggested to contribute to some clinical features of structural or functional variable. Amygdala volume loss
Parkinson's disease, including decits of olfaction and was largely due to a 30% reduction in volume (P =
facial expression. The degree of neuronal loss in amyg- 0.01) and the total estimated number of neurones (P =
dala subnuclei and the relationship with LB formation 0.007) in the corticomedial complex. The degree of neu-
in non-demented Parkinson's disease cases have not rone loss and the proportion of LB-containing neurones
been examined previously. Using stereological methods, in the cortical nucleus within this complex were con-
the volume of neurones and the number of neurones in stant across Parkinson's disease cases and neither vari-
amygdala subdivisions were estimated in 18 prospec- able was related to disease duration (R2 < 0.03; P > 0.5).
tively studied, non-demented patients with Parkinson's The cortical nucleus has major olfactory connections
disease and 16 age- and sex-matched controls. Careful and its degeneration is likely to contribute to the early
exclusion (all cortical disease) and inclusion (non- selective anosmia common in Parkinson's disease. There
demented, levodopa-responsive, idiopathic Parkinson's was a small reduction in neuronal density in the baso-
disease or controls) criteria were applied. Seven lateral nucleus in all Parkinson's disease cases, but no
Parkinson's disease cases experienced well-formed vis- consistent volume or cell loss within this region.
ual hallucinations many years after disease onset, while However, the proportion of LB-containing neurones in
nine Parkinson's disease cases and three controls were the basolateral nucleus was nearly doubled in cases that
treated for depression. Anatomically, the amygdala was exhibited visual hallucinations, suggesting that neuronal
subdivided into the lateral nucleus, the basal (basolat- dysfunction in this nucleus contributes to this late clin-
eral and basomedial) nuclei and the corticomedial (cen-
ical feature. Detailed quantitation of the other amygdala
tral, medial and cortical nuclei) complex. LB and Lewy
subdivisions failed to reveal any other substantial anom-
neurites were identied by immunohistochemistry for
alies or any associations with depression. Thus, the
a-synuclein and ubiquitin and were assessed semiquan-
impact of Parkinson's disease on the amygdala is highly
titatively. LB were found throughout the amygdala in
selective and correlates with both early and late clinical
Parkinson's disease, being present in ~4% of neurones.
Total amygdala volume was reduced by 20% in

Keywords: amygdala; Lewy body; neuronal loss; Parkinson's disease; a-synuclein

Abbreviations: LB = Lewy body; LN = Lewy neurite

Lewy bodies (LB) are the major pathology associated with lobe, the amygdala is a major component of the limbic system
idiopathic Parkinson's disease and the amygdala is one of the (Braak et al., 1994; Rezaie et al., 1996; Gloor, 1997;
most common brain regions likely to contain LB (Braak et al., Swanson, 2000), yet the clinical manifestations of amygdala
1994, 1995; Schmidt et al., 1996; Churchyard and Lees, pathology are poorly understood. Our understanding of the
1997; Mattila et al., 2000). Located in the medial temporal functions of the amygdala has been based either on extrapo-

Guarantors of Brain 2002

2432 A. J. Harding et al.

lation of the results from animal studies or on studies of stroke The majority of previous studies analysing amygdala
or surgical patients in whom the amygdala has been partially pathology have included cases with clinical dementia (e.g.
or wholly damaged and in whom the accompanying changes Double et al., 1996; Schmidt et al., 1996; Churchyard and
in behaviour have been determined. Examples of functional Lees, 1997; Darvesh et al., 1998; Cordato et al., 2000;
changes that have been shown to occur following amygdala Yamazaki et al., 2000; Iseki et al., 2001; Harding et al.,
damage include olfactory dysfunction (Aggleton, 1992), 2002a). In a mixed population of Parkinson's disease cases
visual disturbance (Anderson and Phelps, 1998; Broks et al., with and without dementia, it is known that LB and Lewy
1998; Gray, 1999), autonomic and endocrine dysfunction (de neurites (LN) concentrate regionally in certain subnuclei,
Olmos, 1990; Gloor, 1997), and emotional impairment, with only minor inter-individual variation (Braak et al.,
including increased fear, panic and anxiety (Aggleton, 1994). The most prominent accumulation of LB and LN
1992; Broks et al., 1998; Shekhar et al., 1999). described occurs in the cortical and central subregions of the
The amygdala contains a diversity of nuclei with specic amygdala, with less prominent changes elsewhere (Braak
anatomical connections. However, the localization of func- et al., 1994; McShane et al., 2001). Neuronal density
tions to specic nuclei within the amygdala remains a difcult calculations have shown no signicant neuronal loss associ-
task, which is further complicated because most amygdala ated with LB amygdala pathology in Parkinson's disease
subnuclei have multiple afferent and efferent connections cases with or without dementia (Churchyard and Lees, 1997).

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(Sims and Williams, 1990). The central, medial and cortical Our recent work has shown a strong association between
nuclei together make up the corticomedial complex of the intracellular LB accumulation in the amygdala and visual
amygdala (Gloor, 1997). The central nucleus is mainly hallucinations in cases with dementia (Harding et al., 2002a).
concerned with autonomic function, with prominent projec- To fully understand the clinical correlates of amygdala
tions to brainstem autonomic nuclei, while the cortical and pathology in Parkinson's disease, it is necessary to analyse
medial nuclei have functions related to aspects of olfaction. cases without dementia, as atrophy of the amygdala is still
The cortical nucleus has major connectivity with olfactory signicant in such Parkinson's disease cases (Cordato et al.,
2000), despite previous assertions of no neuronal loss
brain regions, including prominent input from the olfactory
(Churchyard and Lees, 1997). Furthermore, the relationships
bulb, and therefore exerts a signicant inuence on olfactory
between LB, neuronal densities and volume-corrected
function (Sims and Williams, 1990; Swanson and Petrovich,
neuronal numbers are unknown, as previous studies have
1998). The basal nuclei can be further subdivided into the
not performed unbiased quantitation. The aim of the present
basolateral and basomedial nuclei and have signicant
study was to systematically quantify regional cell loss and LB
connectivity with limbic regions and association cortices
formation in the amygdala and evaluate clinicopathological
(Sims and Williams, 1990; Braak et al., 1994; Gloor, 1997;
Swanson and Petrovich, 1998; Iseki et al., 2001; Petrovich
et al., 2001). The lateral nucleus is the largest nucleus of the
amygdala in humans (Sims and Williams, 1990; Gloor,
1997). The lateral and basolateral nuclei both have signicant Subjects and methods
connections with the association neocortex and modulate Cases
some of the many neocortical functions (Swanson, 2000; The present study included non-demented Parkinson's dis-
Petrovich et al., 2001). Overall, the amygdala contains a ease cases and age- and sex-matched controls. Prospective
diversity of nuclei with specic anatomical connections and a consent for brain donation was obtained from all cases and
range of diverse functions. their next of kin through the Parkinson's New South Wales
Clinically, Parkinson's disease is characterized by the brain donor programme. This programme was approved by
presence of at least two of bradykinesia, rigidity and tremor Human Ethics Committees of the Universities of New South
(Gelb et al., 1999). These decits appear after ~70% loss of Wales and Sydney and the Central and South Eastern Area
dopaminergic neurones from the substantia nigra and are Health Services and prospectively follows patients on a
responsive to dopamine-replacement therapy (Fearnley and regular basis (usually annually) using standardized recording
Lees, 1991; Halliday et al., 1996). In addition to these procedures. Controls had no history of neurological or
classical clinical features, there are other features of psychiatric symptoms. Control cases underwent the same
Parkinson's disease that are only mildly responsive or even clinical follow-up as the Parkinson's disease cases with the
non-responsive to dopamine replacement therapy. These same standardized recording procedures. Particulars of the
include decits in olfaction and autonomic function, subtle extensive clinical and neuropathological data collection
cognitive changes, postural instability and also facial procedures have been published recently (Harding et al.,
hypomimia, often referred to as a masked or expressionless 2002a). For the present study, all cases that had not been seen
face (Smith et al., 1996; Gelb et al., 1999). At least some of by their physicians within 6 months preceding death were
these additional features of Parkinson's disease have been excluded. Shortly after the patient's death, standardized
attributed to pathology in the amygdala (Adolphs et al., 1994; questionnaires were sent to the next of kin, as well as to the
Cahill et al., 1995; Jacobs et al., 1995; Young et al., 1995). patient's general and specialist medical practitioners to
The amygdala in Parkinson's disease 2433

Table 1 Demographic and clinical data in controls and cases being representative of non-demented Parkinson's
Parkinson's disease cases disease. All tissue analyses were performed blinded to
Controls Parkinson's classication.
disease patients

Number of cases 16 18
Male : female 11 : 5 13 :5
Evaluation of clinical features
Age at disease onset (years) 60 62 Data from clinical records and standardized forms were used
Age at death (years) 73 6 3 73 63 to assess the presence (including date of symptom onset) or
Post-mortem delay (h) 22 6 3 16 63 absence of the following clinical features for correlations:
Movement disorder severity bradykinesia and rigidity; rest tremor; hypomimia; well-
(Hoehn and Yahr)
formed visual hallucinations; and depression. Medications
Stage 23 0 4
Stage 4 0 6 and doses taken were recorded and updated, where applic-
Stage 5 0 8 able, at each clinical assessment. The dominant clinical
Other symptoms parkinsonian feature (tremor-dominant or akineticrigid) was
Late visual hallucinations 0 7 identied (Table 1). The age of onset of Parkinson's disease
Depression 3 9
was estimated from initial diagnosis and the severity of

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Medication used
Levodopa (mg/day) 0 1279 6 273 Parkinson's disease was assessed using the Hoehn and Yahr
Neuroleptics 0 3 scale (Hoehn and Yahr, 1967). The types of visual hallucin-
Anti-depressants 3 9 ations considered have been discussed in detail previously
Anxiolytics 0 4 (Harding et al., 2002a) and were mostly complex features
Sedativehypnotics 3 6
relating to people, objects and landscapes reported in the
Antihypertensives 5 5
Anticoagulants 1 2 presence of the examiner on at least one occasion and/or
Anti-inammatories 2 5 when there were consistent reports by the subject to a
Analgesics 3 5 caregiver. Flashing lights and similar phenomena reported to
occur with hallucinogenic drugs (Fenelon et al., 2000) were
Data are number of patients or mean 6 standard error of the mean
not considered well-formed visual hallucinations. The pres-
ence of depression was ascertained from the clinical diagno-
sis combined with the nature of the treatment (antidepressant
medications or other recognized treatments, such as electro-
update relevant details (covering the period from the time of
convulsive therapy), or if patients scored greater than 10 out
last assessment). No control or Parkinson's disease case was
of 30 on the geriatric depression scale (Yesavage et al., 1983).
included that had dementia according to both DSM-IV
Reactive depression to circumstances was included if medical
(American Psychiatric Association, 1994) and the Clinical practitioners deemed the depression of sufcient concern to
Dementia Rating criteria (Morris et al., 1989). Following record in clinical notes.
careful neuropathological screening, cases with signicant
neuropathology other than Parkinson's disease were excluded
(Gelb et al., 1999). Tissue preparation
Eighteen levodopa-responsive cases with Parkinson's Brains were removed at either full or limited brain-only
disease (13 male; 5 female) and 16 age- and sex-matched autopsy (mean post-mortem delay 19 6 2 h, range 345 h),
controls (11 male; 5 female) were selected for the present and the entire brain was xed by suspension in 15% buffered
study (Table 1). There were no signicant differences formalin for 2 weeks. The brains were then weighed and the
between groups in the age at death or post-mortem delay anteroposterior dimensions recorded prior to the brainstem
(Table 1). The causes of death were mainly related to and cerebellum being separated from the cerebrum at the
cardiorespiratory complications and cancer, which affected level of the superior colliculus. The cerebrum was embedded
similar numbers of patients in the control and Parkinson's in agar and cut into ~3 mm thick coronal slices using a rotary
disease groups. Recorded Mini-Mental State Examination slicer. The brainstem was embedded in agar and similarly cut
scores were >25. None of the selected Parkinson's disease into 3 mm thick slices in the transverse plane, as described
cases had more than isolated cortical LB in the cingulate, previously (Halliday et al., 1996). Tissue samples were
hippocampal or association cortices. Those fullling diag- prepared for routine neuropathological examination. Briey,
nostic criteria for dementia with LB were excluded (McKeith samples were taken from the frontal (Brodmann area 9),
et al., 1996). Controls did not exhibit LB. Cases with temporal (area 20), parietal (area 39), occipital (areas 17 and
substantial tau- or silver-positive neurobrillary tangles in the 18) and anterior cingulate (area 24) cortices, as well as from
amygdala were also excluded. Since there was no neuro- the hippocampus at the level of the lateral geniculate nucleus,
pathological evidence of dementing disorders or clinical amygdala, anterior and posterior basal ganglia (including the
history of dementia, and relatively long disease durations basal forebrain), thalamus, hypothalamus and cerebellum.
for Parkinson's disease cases, we are condent of these These were embedded in parafn and sectioned at 10 mm. The
2434 A. J. Harding et al.

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Fig. 1 (A). Diagram representing the systematic sampling scheme of the amygdala for the present study. Sections, represented by the
vertical lines, are spaced 750 mm apart. Lines marked BD in the diagram show the approximate anteroposterior locations of the
photomicrographs (BD), which are representative coronal sections from a control case, stained with cresyl violet to show the normal
appearance and location of the amygdaloid subnuclei. Scale in D also applies to B and C. Bas = basal nuclei, which can be further
subdivided into BM = basomedial nucleus and BL = basolateral nucleus; CM = corticomedial complex, which can be further subdivided
into Ce = central nucleus, Co = cortical nucleus and Me = medial nucleus; Lat = lateral nucleus; T = corticoamygdaloid transition area.

midbrain, pons and medulla oblongata were cryoprotected in area was removed from the cerebral slice, embedded in
30% sucrose in Tris buffer, then 20 and 30 mm thick sections parafn and 10 mm coronal sections were cut. Adjacent
were cut on a cryostat and the sections washed in buffer and sections were stained using anti-a-synuclein peroxidase
mounted on gelatinized glass slides. Sections from all regions immunohistochemistry (18-0215, diluted 1 : 200) and
were stained, as necessary, for routine screening using anti-ubiquitin peroxidase immunohistochemistry (Z0458,
currently recommended diagnostic protocols for Parkinson's diluted 1 : 200). The specicity of the immunohistochemistry
disease (Gelb et al., 1999), dementia with LB (McKeith et al., technique was tested by omitting the primary antibody
1996; Harding and Halliday, 1998) and Alzheimer's disease as described previously (Henderson et al., 2001). No
(Braak and Braak, 1991; Mirra et al., 1991; National Institute peroxidase reaction was observed in these sections. All
on Aging, and Reagan Institute Working Group on immunohistochemical stains were lightly counterstained with
Diagnostic Criteria for the Neuropathological Assessment cresyl violet.
of Alzheimer's Disease, 1997). Standard stains used included
haematoxylin and eosin, congo red and the modied
Bielschowsky silver stains, while immunohistochemistry
was performed using antibodies to ubiquitin (Z0458, diluted Quantitation of the amygdala and its
1:200; Dako, Glostrup, Denmark), tau II (T5530, diluted subdivisions
1 : 10 000; Sigma, St Louis, MO, USA) and a-synuclein (18- Semiquantitation
0215, diluted 1 : 200; Zymed Laboratories, San Francisco, The major amygdala subdivisions (Fig. 1) were examined for
CA, USA). the presence of pathology. From the parafn-embedded
Blocks of tissue containing the right amygdala were sections, the region with the greatest LB density was
removed from the cerebral slices and cryoprotected in 30% identied (a technique similar to that used for semiquantita-
sucrose in Tris buffer. Serial 50 mm thick sections were cut on tion of plaques and tangles in Alzheimer's disease and for LB
a cryostat, the sections washed in buffer and mounted onto in dementia with LB (Mirra et al., 1991; McKeith et al., 1996;
gelatinized glass slides, and every 15th section (i.e. 750 mm The National Institute on Aging, and Reagan Institute
apart; e.g. Fig. 1A) was stained with cresyl violet for Working Group on Diagnostic Criteria for the
stereological analysis (see below). The block of tissue Neuropathological Assessment of Alzheimer's Disease,
containing the left amygdala at its greatest cross-sectional 1997; Harding and Halliday, 1998). The number of (a-
The amygdala in Parkinson's disease 2435

synuclein-positive) LB and neurones (identied by the Neuronal density (coefcient of error range 0.030.06)
presence of nucleoli) per 2003 microscopic eld (eld was determined from the total number of neurones within
diameter 1 mm) was determined for each amygdaloid nucleus the sample volume. Regional neurone number was
and the proportion of neurones with LB calculated. There was estimated by multiplying the density and volume.
<5% variation in counts made by two investigators and no
difference between a-synuclein-positive LB counts and
ubiquitin-positive LB counts performed in adjacent sections Statistical analysis
(paired Student's t test, P > 0.26). The density of LN within Statistical analysis was performed with the Statview 5.0
the same eld was graded using previously described program (Abacus Concepts, Berkeley, CA, USA).
semiquantitative methods (Kim et al., 1995). Briey, LN Differences in clinical and pathological parameters between
were identied as thickened a-synuclein-positive deposits Parkinson's disease and control groups and between sub-
within neuronal processes and were semiquantitatively rated groups of Parkinson's disease patients were analysed using
as absent, sparse, moderate or many in number (Kim et al., unpaired t tests. Relationships within and between clinical
1995). variables (i.e. age at onset of Parkinson's disease, disease
severity at death, disease duration) and pathological variables
(volume, neurone number and LB density in the amygdala

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Stereological quantitation and its subregions) were analysed using multiple regression
The total volume of the amygdala was calculated by analyses. Mean and standard error of the mean are given for
point-counting photographic images from the 3 mm all variables and a P value less than 0.05 was accepted as
coronal brain slices, as detailed previously (Cordato being statistically signicant.
et al., 2000). To determine the volume and number of
neurones within the reliably identied amygdaloid sub-
nuclei, stereological analyses of the tissue sections was
performed as described previously (Harding et al., 1994; Results
Henderson et al., 2000). The identication of exact Clinical indices
boundaries for a number of smaller amygdaloid nuclei All patients presented with asymmetrical motor decits of
was unreliable for stereological analysis; consequently, Parkinson's disease (nine had tremor, two bradykinesia,
estimates of total neurone number for these smaller seven tremor and bradykinesia) without evidence of cognitive
amygdaloid nuclei could not be calculated. However, the dysfunction. All patients were levodopa-responsive and
three main amygdaloid subnuclei (the corticomedial displayed hypomimia early in the disease course (Table 1).
complex, the basal nuclei and the lateral nucleus) could Medication use was recorded for all cases and controls
be identied reliably in 50 mm thick sections spaced (Table 1). All Parkinson's disease cases regularly took
750 mm apart (e.g. Fig. 1A). The areas of each of the antiparkinsonian medication, including levodopa (Table 1).
main subnuclei were determined by tracing the boundary Seven controls took no medications, while six Parkinson's
(Fig. 1BD) using a computer mouse and an integrated disease patients took no medications other than antiparkin-
computerized microscopic system (Neurolucida; sonian medication. Neuroleptic medications were taken by
MicroBrightField, Colchester, VT, USA). The volumes three Parkinson's disease patients and antidepressants were
of the subnuclei were determined by multiplying the sum taken by three controls and nine Parkinson's disease patients
of their cross-sectional areas by the distance between the (Table 1). At the time of death, all patients had mild to
sections (750 mm), using Cavalieri's principle. The optical advanced disease (Table 1) according to the Hoehn and Yahr
disector technique was used to estimate neuronal number scale (Hoehn and Yahr, 1967), with disease duration varying
by optically placing on the tissue section disector frames from 8 to 28 years (Table 1). No patient exhibited symptoms
with sides 160 3 160 mm, spaced 2.5 mm apart, and considered atypical of Parkinson's disease according to
counting the number of neurones within the disector current diagnostic criteria (Gelb et al., 1999), and in
frame. Between cases, the number of sections used varied particular none had clinical dementia.
from 11 to 16 and the number of disector frames varied Seven Parkinson's disease cases reported visual hallu-
from 12 to 34. Only those neurones whose nucleolus fell cinations, which were episodic, and occurred late in the
entirely within the sampling frame or on adjacent disease course (Harding et al., 2002a) (Table 1). The
inclusion borders were counted. The number of neurones medical records for the Parkinson's disease patients with
counted varied between 156 and 249 for the corticomedial late visual hallucinations did not show any change in
complex, 154 and 194 for the basal nuclei and 156 and medication use associated with the phenomenon. There
234 for the lateral nucleus. Repeated measures of the was a non-signicant trend for the Parkinson's disease
neurone number in multiple sections from multiple cases cases who experienced visual hallucinations to be older
always gave similar results, even between different (78 6 2 versus 70 6 4 years; P = 0.18), to use less
investigators (<5% variation between investigators on levodopa (836 6 143 versus 1510 6 354 mg/day;
repeated measures, with Pearson's correlation 0.95). P = 0.15) and to have a longer duration of Parkinson's
2436 A. J. Harding et al.

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Fig. 2 (A and B) Haematoxylineosin-stained sections showing the pigmented neurones of the substantia
nigra in (A) a normal control case and (B) a case with Parkinson's disease. Whilst the dorsomedial nigra
is relatively spared in Parkinson's disease (top left quadrant of B), note the severe loss of pigmented
neurones from the ventrolateral nigra (lower left and right quadrants in B). Scale in B also applies to A.
(C) Haematoxylineosin-stained section from the substantia nigra. Typical Lewy bodies (arrowed) are
observed in pigmented neurones. Scale in F also applies to C. (D) Section from amygdala stained
immunohistochemically for a-synuclein and lightly counterstained with cresyl violet. Lewy bodies typical
of those found within neurones in the cortical nucleus of the amygdala are observed in a representative
Parkinson's disease case. (E) Thick a-synuclein-stained section with a cresyl violet counterstain from the
amygdala of a representative Parkinson's disease case showing a relative absence of Lewy bodies in the
lateral nucleus (left of dashed line) compared with an abundance of Lewy bodies (arrows) in the adjacent
basolateral nucleus (right of dashed line). (F) Thick ubiquitin-stained section counterstained with cresyl
violet from the basolateral nucleus of the amygdala of a representative Parkinson's disease case, showing
intracellular staining of Lewy bodies and many Lewy neurites within the neuropil. (G) Histogram of the
proportion of neurones containing LB (mean 6 standard error of the mean) in the subnuclei comprising
the basolateral and corticomedial complexes of the amygdala. Note the similarly high proportions of
neurones containing LB in the basolateral (BL) and cortical amygdaloid nuclei in Parkinson's disease.
BM = basomedial nucleus.

disease symptoms (17 6 2 versus 12 6 2 years; P = 0.16). cases given neuroleptic medications had experienced
Six cases not experiencing visual hallucinations were visual hallucination but had no signicant improvement
taking multiple medications. Two Parkinson's disease following neuroleptic treatment.
The amygdala in Parkinson's disease 2437

Table 2 Quantitative data in controls and Parkinson's disease cases

Controls Parkinson's disease P

Brain volume (ml) 1307 6 40 1254 6 32 0.31

Amygdala volume (ml) 1.82 6 0.12 1.45 6 0.08 0.02*
Corticomedial complex
Volume (ml) 0.52 6 0.05 0.36 6 0.02 0.01*
Neurone number (3 106) 1.92 6 0.13 1.35 6 0.13 0.007*
Neurone density
Cortical 174 6 5 122 6 4 P < 0.0001*
Medial 119 6 8 112 6 5 0.44
Central 129 6 6 128 6 8 0.92
Basal nuclei
Volume (ml) 0.49 6 0.04 0.43 6 0.03 0.24
Neurone number (3 106) 1.75 6 0.12 1.62 6 0.11 0.46
Neurone density
Basolateral nucleus 134 6 4 103 6 6 0.002*

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Basomedial nucleus 124 6 7 114 6 5 0.22
Lateral nucleus
Volume (ml) 0.85 6 0.04 0.76 6 0.05 0.18
Neurone number (3 106) 2.95 6 0.18 2.72 6 0.23 0.43
Neurone density 138 6 8 142 6 9 0.80

Data are mean 6 standard error of the mean from one hemisphere; neurone density is expressed as number per microscopic eld (2003
magnication, eld diameter 1 mm). *Signicant.

Nine Parkinson's disease patients and three controls Corticomedial complex

had a history of clinical depression, all of whom were Both the volume and the estimated number of neurones in
prescribed antidepressant medication (Table 1). the corticomedial complex were reduced by 30% in
Depression was also a late feature in the Parkinson's Parkinson's disease (P = 0.01 and P = 0.007, respect-
disease cases, and led to suicide in one instance. Five ively) (Table 2). There was little overlap in the estimates
depressed Parkinson's disease cases also experienced late of corticomedial complex neurone number between indi-
visual hallucinations. There were no signicant differ- viduals in the control and Parkinson's disease groups,
ences in age (76 6 4 versus 70 6 4 years, P = 0.31), indicating that cell loss in the cortical nucleus is
levodopa use (1367 6 419 versus 1081 6 134 mg/day, relatively consistent across Parkinson's disease cases.
P = 0.55) or duration of Parkinson's disease symptoms Only one Parkinson's disease case had a neuronal
(15 6 2 versus 15 6 2 years) for cases with and without estimate for this region within the control range (2.14
depression. There was also no signicant difference in the million neurones), despite also demonstrating high dens-
age of depressed controls compared with controls without ities of LN and LB (maximum of 3 LB per 2003 eld).
depression (75 6 3 versus 72 6 3 years, P = 0.72).
The cortical nucleus is the largest structure within the
corticomedial complex and is the only region of the
corticomedial complex that exhibited a signicant reduc-
Pathology and cell loss tion in neurone density (30% decrease in Parkinson's
As required for diagnosis, there was substantial pigmented disease, P < 0.0001) (Table 2, and compare Fig. 3A with
cell loss (compare Fig. 2A with Fig. 2B) and LB Fig. 3B), consistent with selective degeneration of this
formation (Fig. 2C) in the midbrain in all Parkinson's region. There was no signicant relationship between
disease cases. No LB were observed in the substantia neurone loss in the cortical nucleus and the duration or
nigra pars compacta or amygdala of control brains. LB severity of Parkinson's disease, indicating that the con-
were found within the amygdala in all Parkinson's disease sistent cell loss in the cortical nucleus is likely to occur
cases (Fig. 2D), the distribution of LB creating a early in the course of the disease.
distinctive pattern (Fig. 2G). The presence of amygdala The highest densities of LB in the corticomedial complex
LB correlated with a 20% reduction in the volume in were in the cortical nucleus (3.5 6 0.7 LB per 2003 eld)
Parkinson's disease (P = 0.02) (Table 2), with no left (Fig. 2D and G), being present in all but two Parkinson's
right asymmetry (P > 0.05). LN were present throughout disease cases. Relatively few neurones (3.0 6 0.7%) con-
the amygdala in all but one of the cases examined. There tained LB even in the area of maximum LB density (Fig. 2G).
was no correlation between the presence of LN in any The remaining nuclei of the corticomedial complex (central
region and any other variable (all P > 0.05). and medial nuclei) contained inconsistent and variable LB
2438 A. J. Harding et al.

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Fig. 3 High-power view of 50 mm thick sections stained with cresyl violet showing the morphology and
density of neurones in the cortical (A, B), basolateral (C, D) and lateral (E, F) nuclei in a Parkinson's
disease case (B, D, F) and a control (A, C, E). Note the obvious reduction in neurone density in the
cortical nucleus of this representative Parkinson's disease case (B) compared with the control (A). In the
basolateral nucleus, an example is given showing a severe reduction in neurone density in a Parkinson's
disease case (D) when compared with the same region of a control (C). Scale in F also applies to AE.

pathology. LN, however, were consistently found within the Basal nuclei
corticomedial complex and were present in high densities in There was no atrophy of the basal nuclei, nor was there an
nearly half of the Parkinson's disease cases. We could not overall loss of neurones using volume-corrected measures
nd a signicant relationship between the estimated number (Table 2). However, there was a signicant reduction in
of neurones and the level of LB pathology in this region (all neuronal density in the basolateral nucleus, but not in the
P > 0.05). There was also no signicant relationship between basomedial nucleus (compare Fig. 3C with Fig. 3D; Table 2),
LB density and the duration or severity of Parkinson's disease suggesting a small, selective loss of neurones in this
(P > 0.05). subnucleus.
The amygdala in Parkinson's disease 2439

LB were present in relatively high concentrations in the compared with those Parkinson's disease cases that did
basal nuclei of the amygdala in all Parkinson's disease cases, not report them (6.3 6 1.3 versus 3.2 6 0.4; P = 0.02).
especially in the basolateral nucleus (Fig. 2EG) and were Likewise, the proportion of neurones containing LB was also
accompanied by a few LN. The distribution of LB varied nearly double in those with hallucinations (5.7 6 0.9
within the basolateral nucleus such that the most basal regions versus 3.1 6 0.4; P = 0.01); however, there was no
had the greatest density of LB (4.5 6 0.7 LB per 2003 eld). signicant correlation with neurone loss in the basolateral
Relatively few neurones within this area contained LB nucleus and the presence of visual hallucinations. In no other
(4.2 6 0.5%) (Fig. 2G); however, there was a relationship region was there any difference between these groups (all
between the densities of neurones and LB in the basolateral P > 0.05).
nucleus (R2 = 0.24, P = 0.046). There was no such
relationship for the basomedial nucleus (R2 = 0.01, P = 0.68).
There was no relationship between the number or proportion Discussion
of basolateral or basomedial LB with either disease duration It is now well established that the amygdala is a preferential
or severity (P > 0.05) (Fig. 3CF), nor was there any site in the brain for LB formation in a variety of disorders,
relationship with variables quantied from other amygdala including Parkinson's disease (Lippa et al., 1998, 1999; Gelb
nuclei (all comparisons P > 0.05). et al., 1999; Hamilton, 2000; Yamazaki et al., 2000).

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Although the amygdala contains the characteristic pathology
of Parkinson's disease, our understanding of the importance
Lateral nucleus of amygdala pathology in the pathogenesis of the disease is
There was no signicant atrophy or neurone loss in the lateral limited. In this study, well-characterized patients with
nucleus in Parkinson's disease (Table 2). In every Parkinson's Parkinson's disease and no dementia were analysed to
disease case, at least one LB was found in the lateral nucleus. determine any clinical correlations for the pathological
Although the maximum density of LB in the lateral nucleus changes previously noted in the amygdala (see
was 2.4 6 0.3 LB per 2003 eld (Fig. 2G), the average Introduction). We identied a highly selective pattern of
density of LB and LN within the lateral nucleus was quite neuronal loss in the Parkinson's disease amygdala, cell loss
low, as many cases had only a few LB within the vast expanse which was accompanied by high concentrations of LB
of the lateral nucleus. Consequently, the majority of micro- formation. The two amygdala regions affected appear to
scopic elds of view in the lateral nucleus showed mostly no impact on specic clinical features prevalent in Parkinson's
LB within the neurones (Fig. 2E) and careful scanning of disease. One of these, the cortical nucleus, has a consistent
sections containing the lateral nucleus was required to locate signicant loss of both volume and neurone number, as well
LB in this region. There was no relationship between the as substantial LB formation. The cortical nucleus has a well-
number or proportion of LB or LN in the lateral nucleus and known involvement in olfactory function (Gloor, 1997;
any clinical or pathological variable (P > 0.05). Swanson and Petrovich, 1998). The second region affected
was the basolateral nucleus, which had a reduction in neurone
density in all Parkinson's disease cases, and also an increased
Clinicopathological correlations proportion of neurones containing LB in cases who had
Using multiple regression analyses, there were no correl- experienced well-formed visual hallucinations during life.
ations between the pathological variables (total neuronal Our results show that selective nuclei of the amygdala have
number, number of LB, presence or severity of LN, the considerable degenerative changes in Parkinson's disease and
estimated volume of the amygdala or its subregions) and the that the topography of the pathology correlates with specic
clinical variables (severity or duration of Parkinson's dis- clinical features.
ease). In particular, there was no correlation with duration of The number of cases studied is small but the Parkinson's
Parkinson's disease and the loss of neurones in the cortical disease cases examined were selected from a larger, longi-
nucleus. Nine Parkinson's disease patients had tremor- tudinally studied population (132 cases), as stringent selec-
dominant disease, two were mainly akineticrigid, and in tion criteria were necessary to evaluate the role of the
seven cases both types of motor decits were prominent. amygdala in the clinical features found in Parkinson's
Using unpaired t tests, there were no signicant differences disease. While for some variables correlations may be more
between tremor-dominant and akineticrigid patients in the evident in larger samples, the careful case selection procedure
estimated amygdala volume, neurone number or number of used in this study greatly strengthens any positive clinico-
LB or LN in any subregion (all P > 0.05). This lack of pathological correlations for the symptoms of Parkinson's
signicance was also the case when Parkinson's disease cases disease. The amygdala is a region in which age-related
were grouped according to the presence or absence of pathology is common (Iseki et al., 1996; Anderton, 1997;
depression (all P > 0.05). Davis et al., 1999), and the exclusion of cases with age- or
Using unpaired t tests, there was a signicant increase in dementia-related neurobrillary tangles in this region signi-
the density of LB in the basolateral nucleus (nearly double) in cantly restricted the number of Parkinson's disease cases that
Parkinson's disease cases that suffered from hallucinations could be examined. Our study sample is similar in number to
2440 A. J. Harding et al.

that described by Churchyard and Lees (1997) and signi- that dementia is related to signicant pathology in other
cantly larger than the samples used in other published studies associated nearby cortical regions, as we have shown recently
of the amygdala in Parkinson's disease. As the majority of (Harding et al., 2000, 2002a, b). Our results show that the
Parkinson's disease cases examined by Churchyard and Lees conclusions of studies considering amygdala LB formation in
(1997) were demented, our cohort is the largest non- relation to dementia should be interpreted with caution if non-
demented sample of Parkinson's disease patients yet studied, demented Parkinson's disease cases are not included as
and thus contributes signicantly to the literature on the disease controls (Schmidt et al., 1996; Yamazaki et al., 2000;
degree of pathology typical in such Parkinson's disease cases Iseki et al., 2001).
with restricted cortical disease. One of the main functions of the amygdala is considered to
In the non-demented Parkinson's disease patients exam- be emotional integration (Aggleton, 1992; Broks et al., 1998;
ined, much of the amygdala contained little or no pathology. Shekhar et al., 1999), and depression is particularly common
Like other authors, we found substantial LB in the cortical in patients with Parkinson's disease (Poewe and Luginger,
nucleus in Parkinson's disease (Braak et al., 1994; 1999). In the present study, several of the Parkinson's disease
Churchyard and Lees, 1997). However, in previous studies cases and controls had depression, but there was no relation-
ubiquitin immunohistochemistry was used to identify LB, and ship between depression and the concentration of histopathol-
other structures may have been stained, including corpora ogy, the size of the structure(s), or the density or number of

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amylacea and neurobrillary tangles. The use of a-synuclein neurones in either the Parkinson's disease cases or controls. A
immunohistochemistry (which does not identify these number of studies have reported hypertrophy of the amygdala
structures) provides a means of ensuring that the inclusions in patients with major depression (Tebartz van Elst et al.,
identied in the present study were indeed LB or LN 2001; Davidson et al., 2002) and with psychosis of epilepsy
(Dickson, 1998; Dickson, 1999; Hurtig et al., 2000). In our (Tebartz van Elst et al., 2002). However, such hypertrophy
stringently selected Parkinson's disease cases, comparable was not related to depression in the present study and is not
densities of LB or LN were identied using a-synuclein and generally seen in geriatric depression (Davidson et al., 2002).
ubiquitin immunohistochemistry, conrming that these It is interesting to note that increases in glucose metabolism
pathologies are consistent features in the amygdala in and blood ow in the amygdala have been reported with
Parkinson's disease. LN in the amygdala did not correlate depression (Drevets, 2001), suggesting that increased activity
with any other pathological or clinical variable, a nding in the amygdala rather than hypertrophy may be the dominant
similar to our observations in the hippocampus (Harding and clinical correlate.
Halliday, 2001). Our study conrms that both the lateral and Atrophy of the amygdala has been noted previously in
the basomedial nuclei are less consistently affected by LB Parkinson's disease (de la Monte et al., 1989; Cordato et al.,
(Braak et al., 1994), and that there is no change in neurone 2000); however, this atrophy is subtle and not easily detected
density for the central or lateral nuclei (Churchyard and Lees, either visually (Braak et al., 1994) or using quantitative
1997; Iseki et al., 2001). The LB pathology in the central single-section area analysis (Churchyard and Lees, 1997).
amygdaloid nucleus in Parkinson's disease may underlie This is consistent with the 20% atrophy noted using serial
autonomic dysfunction (Braak et al., 1994), although section analysis in the present study. The atrophy was
autonomic dysfunction correlates with degeneration in per- relatively small because it concentrates in the cortical
ipheral and other central autonomic nuclei (Hague et al., nucleus, where there is a corresponding decrease in neurone
1997; Wakabayashi and Takahashi, 1997). number and density. Although this discrete change was not
The majority of previous studies analysing amygdala detected in a previous study (Churchyard and Lees, 1997), we
pathology have included cases with clinical dementia (e.g. have analysed greater numbers of sections and used unbiased
Double et al., 1996; Schmidt et al., 1996; Churchyard and stereological techniques, which probably accounts for the
Lees, 1997; Darvesh et al., 1998; Cordato et al., 2000; different result obtained. The cortical nucleus receives input
Yamazaki et al., 2000; Iseki et al., 2001; Harding et al., from the olfactory bulb and has projections to the olfactory
2002a); some studies report that non-demented Parkinson's cortices (Gloor, 1997; Swanson and Petrovich, 1998;
disease cases have little amygdala pathology (Mattila et al., Swanson, 2000), and olfactory dysfunction is a common
2000) while others suggest substantial pathology in problem in Parkinson's disease (Doty et al., 1988; Hawkes
Parkinson's disease cases with or without dementia (Braak and Shephard, 1993;). Although the patients in the present
et al., 1994; Churchyard and Lees, 1997). Our results in non- study were not formally tested to determine if they had
demented Parkinson's disease cases support these latter olfactory decits, it has been well documented that
studies and data generated from patients with epilepsy which Parkinson's disease patients exhibit marked decits in
suggest that substantial loss of neurones in the lateral and odour identication, recognition and detection threshold
basolateral amygdaloid nuclei do not necessarily result in early in the disease course (Mesholam et al., 1998; Potogas
dementia (Yilmazer-Hanke et al., 2000). The high LB et al., 1998; Tissingh et al., 2001) and that odour discrim-
densities shown in the Parkinson's disease amygdala in the ination declines with increasing disease severity (Tissingh
present study cannot be a causative factor for dementia et al., 2001). This latter decit is likely to correlate with the
(which was absent in the present study). It is likely, however, progressive neuronal loss noted in the anterior olfactory
The amygdala in Parkinson's disease 2441

nucleus in Parkinson's disease (Pearce et al., 1995). The content (either pleasant or unpleasant feelings) associated
nding in the present study of consistent neuronal loss in the with the phenomenon (Santhouse et al., 2000). However,
cortical amygdaloid nucleus early in the disease course may visual dysfunction has also been associated with the
account for the earlier olfactory decits in Parkinson's amygdala (Anderson and Phelps, 1998; Broks et al., 1998;
disease. Only one study has performed formal olfactory Gray, 1999), with recent experiments showing an important
testing on controls and patients with neurodegenerative role for the amygdala in the integration of parallel visual
disorders with subsequent neuropathological examination systems. In a patient with cortical blindness in his right
(McShane et al., 2001). Dementia with LB patients with hemield, the amygdala, posterior thalamus and superior
anosmia had higher cortical LB counts than patients without colliculus were activated following the visual presentation of
olfactory impairment (McShane et al., 2001) and it was emotional facial expressions to his blindside and accurate
suggested that LB may be pathological markers of anosmia identication of these visual stimuli by the patient (Morris
(Mann, 2001). However, an alternative possibility is that, like et al., 2001). This indicates remarkable residual visual
Parkinson's disease, the selective anosmia in dementia with abilities mediated through subcortical extrageniculostriate
LB reects similar involvement of the cortical amygdaloid pathways. The amygdala therefore appears to be the nal
nucleus. processing centre for the ventral stream of the cortical visual
Hypomimia is one of the signs of Parkinson's disease that system subserving conscious visual identication and dis-

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develops during the disease process, but usually not as a crimination (Morris et al., 2001) and the extrageniculostriate
presenting symptom of Parkinson's disease. The Hoehn and (colliculo-thalamo-amygdala) visual system, which appears
Yahr scale (Hoehn and Yahr, 1967) uses hypomimia as a to subserve automatic, non-conscious emotional visual pro-
midline sign, indicating the progression from stage 1 to stage cessing (blindsight) (Morris et al., 2001). Dopamine receptor
1.5. Numerous studies have been performed investigating the activation in the basolateral nucleus removes prefrontal
role of the amygdala in a person's ability to identify facial cortex-induced suppression of neuronal output and enhances
expression in others (e.g. Gorno-Tempini et al., 2001; Morris activity driven by sensory inputs (Rosenkranz and Grace,
et al., 2001), including a recent report that recognition of 2002). Thus, in the absence of other cortical changes,
facial expression in Parkinson's disease is intact (Adolphs dopamine plays a signicant role in the neural integration
et al., 1994). However, studies of the causes of hypomimia within the amygdala. In our Parkinson's disease patients, the
are signicantly fewer (Smith et al., 1996). It has been found dopamine medication usage did not appear to precipitate
that only spontaneous facial expression is affected in hallucinations, with no signicant difference in dosage
Parkinson's disease (Smith et al., 1996), as forced smiles between hallucinators and non-hallucinators. This implicates
etc. can still be consciously elicited. At the present time, it is the LB pathology in the basolateral amygdala as more critical
speculated that hypomimia is most likely due to combined for the phenomenon. The increased density of LB in the
loss of neurones in the substantia nigra, striatum and basolateral amygdaloid nucleus is likely to disrupt the ability
amygdala (Aggleton, 1992; Cordato et al., 2000), which are of the amygdala to integrate coordinated behavioural
signicantly interconnected (Gloor, 1997). Location of a responses between the two visual systems and, in association
precise site in the amygdala in humans responsible for with dopamine replacement therapies, precipitate the visual
hypomimia is difcult, as all Parkinson's disease cases will hallucinations experienced by the patients with Parkinson's
have this clinical feature at the end stage and differential disease.
involvement over time cannot be determined. If the amygdala In our previous clinicopathological analysis of demented
does play a role in the development of hypomimia, the patients with LB, we showed that hallucinations presenting as
consistent small loss of basolateral neurones in all the an early clinical feature (i.e. either as the initial presenting
Parkinson's disease patients examined may contribute to this symptom or presenting within the rst 2 years of disease
clinical feature. onset) were associated with higher densities of LB in the
Our recent clinicopathological analysis of demented ventral temporal lobe stream of the cortical visual system
patients with LB disease revealed high amygdala LB (Harding et al., 2002a). Such early cortical LB disruption
densities in patients who had well-formed visual hallucin- appears to cause clinical features similar to those observed in
ations during life (Harding et al., 2002a). In the present study people with well-formed visual hallucinations due to ocular
of non-demented Parkinson's disease patients, a similar pathology (Santhouse et al., 2000). The well-formed visual
correlation was observed, with the subregion involved hallucinations in these people are associated with increased
localized to the basolateral nucleus. Selective basolateral temporal lobe activity due to reduced visual cortical inhib-
neurone loss has been reported previously in temporal lobe ition (Santhouse et al., 2000), and similar patterns of cortical
epilepsy (Yilmazer-Hanke et al., 2000), where memory-like activation have been identied in dementia patients with LB
hallucinations and feelings of deja vu were evoked from and well-formed visual hallucinations (Imamura et al., 1999).
amygdala stimulation in 73% of cases, and every case with These data show that the phenomenon of well-formed visual
spontaneous symptoms had amygdala activation (Bancaud hallucinations in these cohorts is associated with altered
et al., 1994). Detailed factor analysis of these types of well- cortical activity and that LB density appears to be associated
formed visual hallucinations has revealed an emotional with this increased cellular activity. Of course, all the
2442 A. J. Harding et al.

demented LB patients we studied previously also had Acknowledgements

substantial numbers of LB in the amygdala (Harding et al., The authors would like to thank Mrs Heidi Cartwright for
2002a). In this regard, they are similar to the cases in this preparing the gures, Professor Elspeth McLachlan and Mr
study in whom visual hallucinations were all of late onset. Paul Lund for providing technical assistance, and Dr Mariese
The main differences between these cohorts are the absence Hely and Professor John Morris for clinical details. We would
of signicant neocortical LB and clinical dementia (see also also like to acknowledge support from Parkinson's New
Harding and Halliday, 2001). It is not surprising that changes South Wales, the Australian Brain Foundation, the National
in cortical activity patterns may be associated with a dementia Health and Medical Research Council of Australia, the Clive
syndrome, but all LB dementia cases also have signicant and Vera Ramaciotti Foundation and the Ian Potter
numbers of LB concentrating in limbic neocortices (Harding Foundation.
and Halliday, 2001) and LB cases with early dementia have
additional selective neuronal loss in the hippocampus
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