Clinical Phenotypes in Corticobasal Syndrome with or without Amyloidosis Biomarkers

Abstract

Corticobasal syndrome (CBS) is a neuropathologically heterogeneous entity. The use of cerebrospinal fluid and amyloid biomarkers enables detection of underlying Alzheimer’s disease (AD) pathology. We thus compared clinical, eye movement, and ¹⁸FDG-PET imaging characteristics in CBS in two groups of patients divided according to their amyloid biomarkers profile. Fourteen patients presenting with CBS and amyloidosis (CBS-A⁺) were compared with 16 CBS patients without amyloidosis (CBS-A^-). The two groups showed similar motor abnormalities (parkinsonism, dystonia) and global cognitive functions. Unlike CBS-A⁺ patients who displayed more posterior cortical abnormalities, CBS-A^- patients demonstrated more anterior cortical and brain stem dysfunctions on the basis of neuropsychological testing, study of saccade velocities and brain hypometabolism areas on ¹⁸FDG-PET. Interestingly, Dopamine Transporter SPECT imaging showed similar levels of dopaminergic degeneration in both groups. These findings confirm common and distinct brain abnormalities between the different neurodegenerative diseases that result in CBS. We demonstrate the importance of a multidisciplinary approach to improve diagnosis in vivo in particular on oculomotor examination.

Keywords

Alzheimer’s disease corticobasal syndrome eye movements video-oculography

INTRODUCTION

Corticobasal syndrome (CBS) is a progressive clinical entity characterized by the development of asymmetric motor (at least two of dystonia, limb rigidity, or akinesia, myoclonus) and non-motor symptoms (at least two of limb apraxia, cortical sensory deficit, or alien limb phenomenon), related to asymmetric dysfunction of frontoparietal cortex and basal ganglia [1, 2].

CBS typically occurs in corticobasal degeneration (CBD), but has also been reported in other neurodegenerative diseases such as Alzheimer’s disease (AD) [3 –10], progressive supranuclear palsy (PSP) [11, 12], frontotemporal lobar degeneration (FTLD) (including Pick’s disease [13], FTLD associated with MAPT [14], TDP43 [15], Progranulin [16], and C9ORF72 mutations [17]), neurofilament inclusion body disease [18], Lewy bodies disease [19], Creutzfeldt-Jakob disease [20], argyrophilic grain disease [21], and cerebrovascular disease [22]. Therefore, the term CBS is currently used to describe the clinical syndrome regardless of the underlying pathological process [13].

Recently, an international consortium of behavioral neurology, neuropsychology, and movement disorder specialists developed new criteria for CBD disease [1]. Four main CBD phenotypes emerged, probable and possible CBS, frontal behavioral-spatial syndrome, non-fluent/agrammatic variant of primary progressive aphasia, and PSP syndrome. Consensus criteria for probable and possible CBD were also defined.

These new criteria for CBD were tested in a longitudinal retrospective study that compared diagnosis accuracy with postmortem neuropathological data obtained from 33 patients [23]. In patients with pathologically confirmed CBD, 47% met criteria for probable CBD at first assessment, 68% at last clinical assessment. All patients presenting with CBS met criteria for possible or probable CBD, although this diagnosis was not consistently confirmed by postmortem brain analysis. Therefore, these new criteria cannot exclude patients with CBS and without CBD disease, nor identify primary tauopathies, since most ‘CBD-mimics’ were either AD or mixed pathologies (AD associated with Lewy bodies).

Thus, despite advances in nosology and clinical criteria, it remains difficult to propose a reliable pathological diagnosis on clinical grounds in patients presenting with isolated CBS. Several studies compared CBS associated with AD versus CBS non-associated with AD [2 , 24–28]. Several features were retained as suggestive of AD, including long disease duration, younger age of onset [24], initial memory loss [10, 27], hemicorporeal sensory disorders, hemisensory neglect, memory impairment, visuospatial dysfunction [25, 26], dressing apraxia, and myoclonus [10, 24]. In contrast, early frontal lobe symptoms [10, 28], rigidity, tremor [24], oculomotor disorders, agrammatic aphasia, and oro-buccal apraxia [10, 28] appeared to be more associated with CBD. It is noteworthy that aphasia, limb apraxia, alien limb phenomenon, parkinsonism, limb dystonia and gait, and family history were not significantly discriminating [2]. Neuropsychological assessment was not discriminating either [24].

Over the past two decades, new diagnosis tools have been developed with the aim of improving diagnosis of neurodegenerative diseases by providing in vivo disease biomarker surrogates, in particular for AD, including measures of amyloid burden (cerebrospinal fluid (CSF) Aβ₄₀ and Aβ₄₂, amyloid-PET), tau pathology (CSF T-Tau and P-Tau, Tau-PET) and neurodegeneration (MRI). This issue is of particular importance, given the near-future emergence of disease-modifying therapies (anti-amyloid and/or anti-tau aggregation agents).

The aim of the present study is to evaluate in patients with CBS the distinctive clinical and neuroimaging characteristics when CSF and/or amyloid-PET markers are suggestive of cerebral amyloid pathology. To address this issue, we compared data from neurological, neuropsychological and oculomotor assessment, and molecular imaging (¹⁸FDG-PET, Dopamine Transporter SPECT imaging), in a retrospective clinical population presenting with CBS divided into two groups according to their amyloid profile on CSF and/or amyloid-PET imaging.

MATERIALS AND METHODS

Patients

All patients included in the study were referred to two tertiary care departments, the Department of Neurology and Neuropsychology and the Department of Neurology and Movement Disorders of Timone Hospital (AP-HM, Marseille). We only used data obtained from routine clinical practice, and the protocol was approved by the local research ethics committee.

To be included, all patients had to fulfill the criteria of probable or possible CBS according to Armstrong et al. [1], and had undergone a CSF AD biomarkers assessment: beta-amyloid-42 protein (Aβ₄₂), beta-amyloid-40 protein (Aβ₄₀), total tau protein (T-Tau), phosphorylated tau protein (P-Tau). The following ratios were calculated: IATI (Aβ₄₂ / (240 + 1.18 * T-Tau)), Aβ₄₂ / Aβ₄₀ ratio, P-Tau / Aβ₄₂ ratio, T-Tau / Aβ₄₂ and Aβ₄₂ / P-Tau ratio.

Amyloid-PET imaging was performed in cases of: 1) lumbar puncture contraindications, especially in patients with constitutional or acquired coagulopathy or under anticoagulant treatment; 2) lumbar puncture refused; 3) CSF biomarkers that could not be interpreted (pre- and/or per-analytical technical problems, traumatic lumbar puncture); 4) discordant/ambiguous results of CSF markers in relation to clinical [29].

Amyloidosis was defined by a decreased CFS Aβ₄₂ concentration (<500 pg/ml), Aβ₄₂/Aβ₄₀ <0.1, or a positive ¹⁸F-Florbetaben amyloid-PET visually interpreted on the basis of the recommendations of the EMA radiopharmaceutical approval.

Patients were then divided into two groups according to their CSF and/or PET imaging amyloid profile: CBS with amyloidosis (CBS-A⁺) and CBS without amyloidosis (CBS-A^-).

Evaluation criteria

The following evaluations were all performed within the 6 months following the diagnosis of CBS:

Motor skills: predominant asymmetric side, presence of limb rigidity, axial rigidity, akinesia, resting/postural/action tremor; clumsiness, micrographia, dystonia, myoclonus, gait abnormalities, cortical sensory loss, pyramidal syndrome, postural instability reflexes (from 0: “no trouble” to 4: ‘cannot stand alone’); Autonomy was assessed by the Lawton’s Instrumental Activities of Daily Living (IADL) scale (physical autonomy and instrumental activities), in which a high score reflects a high level of dependency;

Cognitive-behavioral assessment: the presence of memory or language complaints, limb or orobuccal apraxia, apraxia of speech, alien limb phenomenon, psychomotor slowing, anosognosia. In addition, subjective assessment of frontal behavioral disturbances was performed for each patient, including apathy, disinhibition, perseveration, echolalia, prehension behavior, emotional lability, applause sign, and depression;

Neuropsychological assessment: Global cognitive assessment by the Mini-Mental State Examination (MMSE) [30], Evaluation of verbal episodic memory with the Five-words test of Dubois [31]: immediate free recall, free delayed recall, immediate total recall and delayed total recall, and total score, Ideomotor and motor praxis evaluation with the gestural praxis battery of Mahieux-Laurent [32], Visuospatial capacities with the Benton line orientation test [33], Executive functions with the FAB (Frontal Assessment Battery) [34] and Part A of the Trail Making Test (TMT A) [35], Working memory with forward and backward verbal Span scores, Language with a French picture naming task, the DO80 [36] and verbal fluency tasks (letter P and animal categories);

Analysis of eye movements: Video-oculography was performed using a recording system (EyeBRAIN^® tracker, now distributed by SURICOG, 21-inch screen with 1920×1080-pixel resolution). An off-line automated analysis of eye movements was performed using EyeBRAIN^® software meye Paradigm and meye Analysis version 1.18.1 that allowed automated recording (binocular mode, eye position sampled at 300 Hz, spatial precision of 0.5°) and analysis of different parameters of pro-saccades tasks (horizontal gap and vertical step): latency, mean velocity, peak velocity and gain; and for the anti-saccade task: percentage of errors (wrong direction). Each task presented one block of 12 trials, each trial ending when the central fixation point returned.

Horizontal stimulus elicited pro-saccades (gap condition): A green central fixation square was presented with durations ranging from 2400 to 3600 ms, then disappeared for 200 ms (black screen), then a white target was presented±20° horizontally (right or left) in a random manner for 1000 ms. The participants were instructed to look as precisely and as fast as possible at the horizontal target and then back to the fixation point after disappearance of the target.

Vertical stimulus elicited pro-saccades (step condition): A green central fixation point was presented with durations ranging from 2400 to 3600 ms, immediately followed by a white target presented for 1000 ms at±12 degrees vertically (up or down) in a random manner. The participants were instructed to look as precisely and as fast as possible at the vertical target and then back to the fixation point after the target disappeared.

Anti-saccades (gap condition): Each trial in the anti-saccade task began with the presentation of a green center-screen fixation point for 3000 ms to 5500 ms, then 200 ms after its extinction (dark screen), a white target randomly appeared horizontally at±20° laterally (left or right) from center for 1000 ms. The participants were instructed to look in the direction opposite to the lateral target as fast as possible but were told they could correct direction errors.

Then each sequence of auto-coded saccades derived from the trace was verified manually. Saccades were deleted, added, or adjusted in cases where the automated analysis inserted false saccades, omitted true saccades, or inaccurately parsed saccade boundaries. Mean and peak velocity of horizontal and vertical pro-saccades as well as latency of horizontal and vertical pro-saccades were collected for each trial of each patient. Trials with latencies less than 75 ms or greater than 800 ms were excluded to avoid artefacts related to anticipated saccades and random responses. The average over each trial was then calculated for each patient. The percentage of anti-saccadic errors was also evaluated.

Cerebral ¹⁸FDG-PET was performed in all patients with an integrated PET/CT device (Discovery ST, GE Healthcare, Waukesha, WI) with an axial resolution of 6.2 mm, 47 contiguous transverse sections of the brain of 3.27 mm thick. Fluorodeoxyglucose (150 MBq) was injected intravenously at rest, with eyes closed in a calm environment. Image acquisition started 30 min after injection, for 15 min. Images were reconstructed using the ordered subset expectation maximization algorithm with five iterations and 32 subsets and corrected for attenuation by the scanner.

Amyloid-PET imaging was performed using ¹⁸F-Florbetaben and the same PET scanner previously described in some patients defined above. Images were acquired during 20 min, 90 min after intravenous injection of 300 MBq of the radiopharmaceutical according to a standardized acquisition and image-processing protocol [29, 37].

Some patients also underwent Dopamine Transporter SPECT imaging 4 h after intravenous injection of ¹²³I-FP-CIT (150 MBq, DaTSCAN^©) on dual-headed gamma-camera (ECAM Signature, Siemens, Erlangen).

Statistical analyses

Direct group comparisons were performed for the different variables. Demographic, clinical, neuropsychological and CSF results were presented in median (interquartile) for quantitative variables and in ratio of number of patients concerned/total of the group (%) for qualitative variables. For oculomotor variables, the mean (standard deviation) of variables studied was calculated from the means of trials of each patient. The difference between groups for quantitative variables was analyzed using the Kruskal Wallis non-parametric test. Qualitative variables were compared using a Fisher’s exact test. We used non-parametric tests because of sample sizes and normality issues.

DaTSCAN^© data were qualitatively analyzed (i.e., presence or absence of dopaminergic denervation and asymmetry). Statistical comparison was performed with a Fisher’s exact test. Statistical analyses and graphs were computed with R statistical software [38]. A p-value≤0.05 was considered significant.

For ¹⁸FDG-PET, images were realigned, reoriented, and spatially normalized into Montreal Neurological Institute space, to obtain images that could be compared to each other. A voxel-based comparison between the CBS-A⁺ and CBS-A^- groups was carried out, using SPM12 software (Wellcome Department of Cognitive Neurology, University College, London, UK, http://fil.ion.ucl.ac.uk/spm). A two-sample t-test was used, at the significance threshold of 3.46 T-score, corresponding to a p-value threshold of 0.001 and a cluster size greater than 100 voxels.

RESULTS

Thirty patients were included in the study between May 2013 and April 2018. On the basis of CSF+/– amyloid-PET analysis, the patient group was then divided into two subgroups: 14 patients with the CBS-A⁺ group and 16 patients with the CBS-A^- group.

Only one patient could not perform a lumbar puncture due to medical contraindications. In this case, a positive amyloid-PET allowed him to be classified in the CBS-A⁺ group. Two other patients performed an amyloid-PET in addition to the lumbar puncture. They were positive in both cases, consistent with CSF biomarker results.

CSF biomarker results are presented in Table 1. CSF AD biomarkers were within normal range in the CBS-A^- group. All ratios usually used in AD diagnosis were significantly different between the two groups. In addition, in the CBS-A⁺ group, there were 11/14 patients with all CSF biomarkers and ratios usually used in AD diagnosis (Aβ₄₂ (<500 pg / ml), T-Tau (>450 pg / ml), P-Tau (>60 pg / ml) and IATI index <0.8) positives.

Table 1

CSF Alzheimer’s disease biomarkers results according to group

	CBS-A⁺	CBS-A^-	p ^§§
CSF Biomarkers ^**
Level of Aβ₄₂ (ng/ml)	361 (307–397)	843 (521.25–1140.75)	<0.001
Level of Aβ₄₀ (ng/ml)	6457.5 (4814.75–9470.25)	6489 (5394.5–10588.5)	0.67
Level of T-Tau (ng/ml)	593 (348–809)	279.5 (193.75–3479.25)	0.004
Level of P-Tau (ng/ml)	83 (65–123)	45.5 (33.5–61.5)	<0.001
IATI	0.36 (0.26–0.49)	1.61 (1.11–1.97)	<0.001
Aβ₄₂/Aβ₄₀	0.06 (0.04–0.07)	0.14 (0.10–0.16)	<0.001
P-Tau/Aβ₄₂	0.26 (0.19–0.38)	0.05 (0.04–0.07)	<0.001
T-Tau/Aβ₄₂	1.7 (1.16–2.49)	0.33 (0.22–0.51)	<0.001
Aβ₄₂/P-Tau	3.89 (2.67–5.21)	21.12 (14.62–26.68)	<0.001

^**median (1st-3rd quartiles). ^§§Kruskal-Wallis test (significant when p < 0.05).

Demographic description of population

The two groups were comparable to each other regarding age, sex, handedness, age at disease onset and level of autonomy.

Patients in the CBS-A⁺ group had a higher educational level than CBS-A^- patients. Time interval between the first clinical signs and the putative etiological diagnosis was slightly longer in CBS-A⁺ compared to CBS-A^- patients (3 years versus 2 years) (Table 2).

Table 2

Demographic features according to group

	CBS-A⁺	CBS-A^-	p
Number of patients	14	16
Gender^*			0.73^§
Female	6/16 (42.86%)	8/16 (50%)
Male	8/16 (57.14%)	8/16 (50%)
Laterality^*			1^§
Right	14/14 (100%)	15/16 (93.75%)
Left	0/14 (0%)	1/16 (6.25%)
Formal education^*			0.02^§
Primary	0/14 (0%)	6/16 (37.5%)
Secondary	11/14 (78.57%)	9/16 (56.25%)
Higher	3/14 (21.43%)	1/16 (6.25%)
Family history of dementia^*	3/14 (21.43%)	5/16 (31.25%)	0.69^§
Age at disease onset (y)^**	64 (61.25–68)	65.5 (62.5–70.25)	0.5^§§
Time to diagnosis (y)^**	3 (2–3.75)	2 (1–2.25)	0.02 ^§§
Autonomy^**
IADL (physical autonomy /30)	6 (6-6)	6 (6-6)	0.13^§§
IADL (Instrumental activities /36)	11.5 (8.75–17)	9 (8.75–15.75)	0.77^§§

^*in number of individuals (%). ^**median (1st-3rd quartiles). ^§Fisher’s exact test (significant when p < 0.05). ^§§Kruskal-Wallis test (significant when p < 0.05).

Patient clinical presentation

Intergroup comparison for motor, cognitive and behavioral symptoms is presented in Table 3. Weaker postural reflexes were more often present in the CBS-A^- group (p = 0.01). Myoclonus, postural or action tremor tended to be associated with the CBS-A⁺ group (p = 0.07). Behavioral frontal syndrome features, with significant disinhibition (p = 0.04) and a tendency for perseveration (p = 0.06), were more frequently present in the CBS-A^- group.

Table 3

Clinical features according to group

		CBS-A⁺	CBS-A^-	p ^§
Motor signs ^*
Right asymmetry		7/14 (50%)	5/16 (31.25%)	0.46
Left asymmetry		7/14 (50%)	11/16 (68.75%)
Clumsiness		11/14 (78.57%)	11/16 (68.75%)	0.69
Limb rigidity		11/14 (78.57%)	12/16 (75%)	1
Axial rigidity		1/14 (9.1%)	3/16 (18.75%)	0.6
Akinesia		12/14 (85.71%)	12/16 (75%)	0.66
Resting tremor		4/14 (28.57%)	2/16 (12.5%)	0.38
Postural or action tremor		5/14 (35.71%)	1/16 (6.25%)	0.07
Micrographia		3/14 (21.43%)	2/16 (12.5%)	0.64
Dystonia		5/14 (35.71%)	5/16 (31.25%)	1
Myoclonus		5/14 (35.71%)	1/16 (6.25%)	0.07
Walking disorders		8/14 (57.14%)	13/16 (81.25%)	0.24
Postural reflexes (/4)	0/4	3/14 (21.43%)	4/16 (25%)	0.01
	1/4	0/14 (0%)	6/16 (37.5%)
	2/4	0/14 (0%)	1/16 (6.25%)
Oculomotors disorders		3/14 (21.43%)	9/16 (56.25%)	0.07
Sensory loss		1/14 (9.1%)	1/16 (6.25%)	1
Pyramidal syndrome		2/14 (14.29%)	3/16 (18.75%)	1
Cognitive signs ^*
Memory complaints		9/14 (64.29%)	8/16 (50%)	0.48
Language complaints		10/14 (71.43%)	8/16 (50%)	0.28
Psychomotor slowing		9/14 (64.29%)	11/16 (68.75%)	1
Orobuccal apraxia		4/14 (28.57%)	3/16 (18.75%)	0.67
Apraxia of speech		2/14 (14.29%)	1/16 (6.25%)	0.59
Alien limb phenomena		1/14 (9.1%)	2/16 (12.5%)	1
Anosognosia		3/14 (21.43%)	4/16 (25%)	1
Behavioral signs ^*
Apathy		4/14 (28.57%)	6/16 (37.5%)	0.71
Disinhibition		1/14 (9.1%)	7/16 (43.75%)	0.04
Perseverations		2/14 (14.29%)	8/16 (50%)	0.06
Echolalia		3/14 (21.43%)	4/16 (25%)	1
Prehension behavior		3/14 (21.43%)	2/16 (12.5%)	0.64
Emotional lability		0/14 (0%)	4/16 (25%)	0.1
Applause sign		2/14 (14.29%)	6/16 (37.5%)	0.23
Depression		5/14 (35.72%)	3/16 (18.75%)	0.42

^*in number of individuals (%); ^§Fisher’s exact test (significant when p < 0.05).

Neuropsychological assessment

There was no significant difference between the two groups in global cognitive, verbal episodic memory, working memory, executive functions and visuospatial function assessments (Table 4).

Table 4

Neuropsychological test results according to group

	CBS-A⁺	CBS-A^-	p
MMSE (/30)^**	23 (20–26)	24 (20.25–26.5)	0.66^§§
Praxis
Ideomotor praxis (/23)^**	16.5 (12.5–19.5)	20 (16–21)	0.08^§
Motor praxis (/8)^**	4 (3–5)	4 (3–6.5)	0.55^§§
Alteration of constructive praxis^*	7/10 (70%)	4/11 (36.4%)	0.2^§§
Verbal episodic memory
Five-words: Total (/10)^**	8 (7–10)	9 (7–10)	0.52^§§
Five-words: IFR (/5)^**	4 (2.75–4.25)	4 (3-4)	0.88^§§
Five-words: ITR (/5)^**	5 (4-5)	5 (4.75–5)	0.43^§§
Five-words: FDR (/5)^**	1.5 (0.75–2.25)	3 (0–4)	0.44^§§
Five-words: TDR (/5)^**	3 (2–4)	4.5 (2–5)	0.53^§§
Working memory
Forward verbal Span (number of numbers)^**	5 (4–6)	6 (4.5–6)	0.72^§§
Backward verbal Span (number of numbers)^**	3 (2–4)	3 (3–3.5)	0.64^§§
Executives functions
FAB (/18)^**	13 (10.25–15)	13 (9.5–15)	0.76^§§
TMT A (s)^**	107.5 (90–133.25)	83.5 (74.25–101.5)	0.36^§§
Visuospatial capacities
Benton line orientation test (/30)^**	23 (6–25)	17 (16.5–21)	0.92^§§
Language
DO 80 (%)^**	93.8 (91.9–98.8)	97.5 (91.3–98.8)	0.51^§§
Categorial verbal fluency (number of words)^**	14 (10.5–20)	12.5 (10.25–15)	0.55^§§
Alphabetic verbal fluency (number of words)^**	16 (11–19.75)	7 (3–9)	0.002^§§

MMSE, Mini-Mental State Examination; IFR, Immediate Free Recall; ITR, Immediate Total Recall, FDR, Free Delayed Recall; TDR, Total Delayed Recall; FAB, frontal assessment Battery; TMT A, Trail Making Test A. ^*in number of individuals (%); ^**median (1st-3rd quartiles) ^§Fisher’s exact test (significant when p < 0.05) ^§§Kruskal-Wallis test (significant when p < 0.05).

Language evaluation revealed a significant impairment in the CBS-A^- group regarding the alphabetic verbal fluency task (p = 0.002) compared to the CBS-A⁺ group. There was no difference between the two groups in the categorical fluency task, nor in picture naming test (DO80) performances. In addition, ideomotor praxis tended to be more altered in the CBS-A⁺ group than in CBS-A^- group (p = 0.08). There was no between groups difference in motor praxis assessment.

Eye movements study

All patients performed a study of eye movements by video-oculography. Quantitative comparison of means between groups is presented in Table 5.

Table 5

Results of eye movements study

	CBS-A⁺	CBS-A^-	p ^§§
Mean velocities ^***
- horizontal saccades	235.39 (72.64)	207.25 (90.07)	0.18
- vertical saccades	175.42 (68.95)	134.9 (45.66)	0.21
Maximal velocities ^***
- horizontal saccades	444.66 (111.42)	362.43 (79.32)	0.04
- vertical saccades	329.75 (131.85)	264.42 (68.32)	0.28
Latencies ^***
- horizontal saccades	278.18 (90.56)	260.75 (93.09)	0.51
- vertical saccades	327.48 (103.55)	334.17 (73.89)	0.51
Anti-saccades ^***
- % of errors	70.27% (26.79%)	67.78% (24.41%)	0.77

^***mean (SD). ^§§Kruskal-Wallis test (significant when p < 0.05).

Average Peak velocity of horizontal pro-saccades was reduced in the CBS-A^- group compared to the CBS-A⁺ group (p = 0.04). Average mean velocity of horizontal saccades also tended to be lower in the CBS-A^- group in comparison to the CBS-A⁺ group (p = 0.18). Mean velocities of vertical saccades also seem to be lower in the CBS-A^- group without reaching statistical significance (p = 0.21). There is no difference for the percentage of anti-saccadic errors.

Molecular imaging

¹⁸FDG-PET imaging

On ¹⁸FDG-PET imaging of the 30 patients, 27 examinations were compared, the three others having been carried out at other centers (one in the CBS-A⁺ group and two in the CBS-A^- group).

Direct comparison of cerebral glucose metabolism between the groups found that patients in the CBS-A⁺ group had more hypometabolism in the left posterior parietal area (in comparison with the CBS-A^- group), and that patients in the CBS-A^- group had more hypometabolism in the fronto-cingulate, putamen, caudate and precentral cortex (compared to the CBS-A⁺ group) (p < 0.001, corrected by cluster volume) (Figs. 1 and 2).

Fig.1

Comparison of glucose metabolism in ¹⁸FDG-PET between groups: Hypometabolism in CBS-A⁺ group versus CBS-A^- group. p < 0.001, corrected by cluster volume, k>100 voxels, T-test. The CBS-A+ group had more hypometabolism in the left posterior parietal area.

Fig.2

Comparison of glucose metabolism in ¹⁸FDG-PET between groups: Hypometabolism in CBS-A^- group versus CBS-A⁺ group. p < 0.001, corrected by cluster volume, k>100 voxels, T-test. The CBS-A^- group had more hypometabolism in the fronto-cingulate, putamen, caudate, and precentral cortex.

DaTSCAN^©

DaTSCAN^© was performed in 19 patients (11 patients from the CBS-A⁺ group and 8 patients from the CBS-A^- group).

No significant difference was found between the two groups in terms of dopaminergic denervation. Denervation was present in 72.5% of cases in the CBS-A^- group. The same percentage (73%) was found in the CBS-A⁺ group.

DISCUSSION

The aim of the present study was to explore the clinical and metabolic characteristics of patients with CBS according to the likelihood of underlying amyloid pathology, as evaluated by CSF (or amyloid-PET) assessment. Therefore we selected, in a retrospective study, patients with clinical CBS and divided them into two subgroups according to their amyloid profile in CSF and/or in amyloid-PET imaging (positive or negative) to identify neurological, neuropsychological, oculo-motor or imaging correlates that may guide the etiological diagnosis in current clinical practice.

Motor features

The sensory/motor features of the CBS-A⁺ group showed substantial overlap with those of the CBS-A^- group.

In contrast to previous studies that showed a preponderance of limb dystonia in CBS-CBD compared to CBS-AD [11, 39], the present study did not demonstrate any such difference between the two groups. Limb dystonia was subjectively assessed and, possibly, variously appreciated according to the specificity of the recruitment center (memory versus movement disorders clinic). As in previous studies, we found no group differences between other parkinsonian symptoms (rigidity, akinesia, tremor). These findings were expected since they are part of the definition of CBS.

They are also consistent with the results obtained from the nigro-striatal presynaptic molecular imaging (DaTSCAN^©) that showed no difference in dopaminergic depletion in the striatum between the two groups. A decrease in striatal uptake (both in the putamen and caudate nucleus) of a dopamine transporter ligand (11Cβ-CFT) has already been reported in AD patients with extrapyramidal symptoms [40], suggesting AD-related neurodegenerative changes in basal ganglia [41, 42]. These results stand in contrast with those usually found in the literature [43 –45] in which no dopaminergic striatal denervation is found in AD patients with parkinsonism. Therefore, within the spectrum of CBS, the relationship between striatal dopamine depletion and parkinsonism in AD remains subject of debate.

Moreover, DaTSCAN^© has been found reliable to differentiate Lewy body disease and AD in the absence of parkinsonism, with a sensitivity of 80% and a specificity of 92% in studies with autopsy [46 –48], implying that 8% of patients with positive DaTSCAN^© might have underlying AD pathology [46].

These discrepancies suggest that parkinsonism in CBS due to AD can be attributed either to post-synaptic changes (loss of dopamine D2 receptors) that cannot be detectable by DaTSCAN^© imaging or to pre-synaptic changes accessible to DaTSCAN^© imaging such as neurofibrillary tangles (NFTs)/amyloid deposition in the substantia nigra [39]. It is noteworthy that in CBD, DaTSCAN^© may be normal in 10% of cases [49], may remain normal despite pronounced parkinsonian syndrome [50, 51], or may become positive later on [43]. Our results show that dopaminergic denervation is frequent and occurs irrespective of the presence or absence of amyloidosis in CBS patients. Thus, DaTSCAN^© cannot be used as a specific molecular imaging marker to distinguish CBS-A⁺ from CBS-A^-.

Several pathological hypotheses could explain similar movement disorders in the two groups, despite distinct neuropathological substrates. One possibility is that CBS-A⁺ is the result of mixed pathology and that basal clinical symptoms are related to the co-occurrence of non-amyloid neurodegenerative process, such as Lewy bodies – alpha synucleinopathy, TDP43, or other tauopathies. However, in this study, no patient exhibited autonomic dysfunction, REM (rapid eye movement) sleep disorder behavior, visual hallucinations, or motoneuron disease signs that could suggest associated alpha synuclein or TDP43 pathology [52 –54]. Alternatively, CBS-A⁺ and CBS-A^- may belong to a common spectrum of tauopathies that consequently results in corticobasal clinical syndrome. A recent clinico-pathological study found increased regional tau burden in perirolandic cortices (motor cortex and somatosensory cortex) as well as NFTs in locus niger in AD patients presenting with CBS [39]. Similar cortical and subcortical tau pathology distribution was observed in CBS due to CBD or PSP [39]. Therefore, the comparable motor features observed in the two CBS groups could be related to the analogous distribution of tau pathology across motor cortical and sub-cortical brain areas.

Even if our findings suggest that the distinction between the two CBS groups does not depend on motor features, we nevertheless evidenced several characteristics that could be interesting markers for clinical practice and useful for research purposes.

Detection of a more pronounced alteration of postural reflexes in the CBS-A^- group compared to the CBS-A⁺ group is consistent with earlier descriptions in which non-mechanical falls were more frequent in CBS-CBD groups compared to CBS-AD groups [11]. This can be explained by the fact that brain structures involved in postural reflexes, namely the basal ganglia and the frontal regions, might be less affected in AD [55].

Cognitive and behavioral features

Ideomotor apraxia seems to be more present in CBS-A⁺ patients than in CBS-A^- patients. At the clinical level, apraxia is the most common cortical symptom associated with CBS, but may be difficult to evidence because of additional subcortical motor disorders. According to theoretical models, praxis relies on two major components, a conceptual system that includes knowledge of tool use and mechanical knowledge, and a production system responsible for programming skilled motor acts [56]. The conceptual dimension of gesture seems to be preserved in CBS due to PSP/CBD tau pathology and gesture disorders predominate on production [57]. In line with previous studies, it appears that the conceptual dimension of gesture that underlies sensorimotor knowledge of tool manipulation as well as mechanical knowledge for any tool-use involves the left inferior parietal cortex [58, 59]. Recent findings suggest a higher involvement of the inferior parietal cortex in CBS due to AD compared with CBS due to PSP/CBD [60]. These findings are in line with the results obtained from the ¹⁸FDG-PET imaging analysis in this study. Patients in the CBS-A⁺ group have a more pronounced hypometabolism in the posterior left parietal regions, which is also consistent with the affinity of NFTs topographic distribution in posterior cerebral cortices [61]. Moreover, in AD patients, alterations of brain metabolism are typically found at the temporoparietal junction, the posterior cingulate cortex and precuneus, and are often asymmetrical in early stages of the disease [62].

Patients in the CBS-A^- group had more frequent impaired regulation of instinctual behaviors (’disinhibition’) than in the CBS-A⁺ group. Behavioral executive disorders are related to functional impairment of the prefrontal cortex, suggesting greater frontal impairment in the CBS-A^- group than in the CBS-A⁺ group.

In addition, the neuropsychological assessment showed a decrease in the alphabetic verbal fluency in the CBS-A^- group in comparison with CBS-A⁺ patients. Verbal fluency relies on mental flexibility, active and strategic research, processes that are affected in sub-cortico-frontal pathologies [63, 64]. In line with these findings, our ¹⁸FDG-PET results demonstrated in the CBS-A^- group a preferential hypometabolism in the fronto-cingulate regions, the putamen and caudate nuclei, compared to the CBS-A⁺ group. This pattern of brain metabolism is typically observed in patients with PSP and FTLD, and is usually explained by a frontal deafferentation due to basal ganglia degeneration which in turn alters functional prefrontal- basal ganglia loops [65], or a direct involvement of prefrontal cortical areas.

However, other cognitive executive and verbal working memory tests were equally altered in the two groups. No differences between groups were found in short verbal episodic memory test, as demonstrated in previous studies. In addition, and in contrast to previous works [24 , 67], we did not find more visuospatial impairment in CBS-A⁺ than in CBS-A^- patients. Visuospatial skills seemed relatively spared in both groups. Taken together, these data suggest a probably greater left than right hemisphere involvement in a CBS group taken as a whole in this study.

Oculomotor features

Overall, our results show reduced peak velocities of the horizontal and also vertical pro-saccades in the CBS-A^- group compared to the CBS-A⁺ group. This is consistent with the control exerted by the brainstem nuclei on saccade velocities [68]. These brain regions are not typically involved in the amyloid pathological process in AD, but are rather dysfunctional in the spectrum of atypical Parkinson’s syndromes, and in particular in PSP. In PSP-Richardson’s syndrome, reduced velocity of vertical saccades is the most specific oculomotor impairment, probably related to degenerative lesions in the mesencephalic reticular formation [69]. Slightly decreased velocity of horizontal saccades related to alteration in pons reticular formation can also be observed in Richardson’s syndrome [69, 70]. Patients with CBD are characterized by increased latency of horizontal saccades, which can be asymmetrical and greater on the side of the upper limb exhibiting apraxia [71, 72]. Delayed initiation of horizontal saccades can be related to impairment of automatic control of spatial attention observed after lesion of the dorsal posterior parietal cortex, and in particular the parietal eye field, involved in reflexive saccades [69 , 74]. Saccade velocities are rather preserved in CBD. In typical AD with memory onset, latencies of horizontal saccades are commonly less altered than in visual forms of the disease in which a delayed initiation of horizontally guided saccade can be observed [75 –77].

Interestingly, latencies of horizontal saccades were within normal range in both groups of patients in our study. The percentage of anti-saccadic errors was equally higher in both groups, as previously reported in literature [68 , 78]. Taken together, data obtained from video-ocular recording in our study suggest that a majority of CBS-A^- patients might have an underlying PSP pathology since saccades velocity depends on integrity of brain stem reticulate which is more altered in PSP that in CBD, and latencies of horizontal saccades (frequently altered in CBD) were preserved.

To conclude, although CBS-A⁺ and CBS-A^- subgroups share numerous similarities that may be related to a common topographical distribution of the underlying pathological process, we also found subtle differences between groups. Thus, in our study, two phenotypes of CBS seem to emerge: one ‘parietal’ or posterior profile associated with the presence of amyloid biomarkers, and one ‘pre-motor’ or anterior profile in the group without amyloidosis. Furthermore, anterior brain structures as well as brain stem involvement seem to be predominant in early primary tau pathology [79], whereas posterior brain areas such as inferior parietal cortex are more involved in tau pathology associated with amyloidopathy [60], which is consistent with the hypothesis of an antero-posterior gradient already mentioned in CBD [79, 80]. Such a pattern of lesion distribution probably depends on differential affinity of underlying proteinopathies for different brain regions, independently of individual vulnerabilities [61].

One of the main limitations of our study is the lack of autopsy confirmation of clinically diagnosed patients. It has been shown that the use of CSF and amyloid-PET biomarkers in the diagnosis of AD in a context of focal onset disease, and in particular of CBS, is quite suitable [27 , 81]. However, comorbidities are possible between groups [82] and we cannot be sure that CBS-A⁺ patients are only affected by AD.

We show here the usefulness of neuropsychological testing, and in particular the relevance of careful praxis examination, as well as the study of eye movements, in the etiological diagnosis of CBS. ¹⁸FDG-PET could be useful too, if it shows predominant anterior abnormalities that could help to distinguish CBS due to amyloid pathology from that due to another pathology. In contrast, Dopamine Transporter SPECT imaging does not seem useful but merely reflects the parkinsonian features in CBS irrespective of the presence or absence of amyloidosis.

Further prospective, multicenter studies based on the methodology set up here with additional tau imaging biomarkers would provide a better description of CBS according to the underlying pathological process.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-0961r1).

References

Armstrong

, Litvan

, Lang

, Bak

, Bhatia

, Borroni

, Boxer

, Dickson

, Grossman

, Hallett

, Josephs

, Kertesz

, Lee

, Miller

, Reich

, Riley

, Tolosa

, Tröster

, Vidailhet

, Weiner

(2013) Criteria for the diagnosis of corticobasal degeneration? Neurology 80, 496–503.

Hassan

, Whitwell

, Josephs

(2011) The corticobasal syndrome-Alzheimer’s disease conundrum. Expert Rev Neurother 11, 1569–1578.

Ouchi

, Toyoshima

, Tada

, Oyake

, Aida

, Tomita

, Satoh

, Tsujihata

, Takahashi

, Nishizawa

, Shimohata

(2014) Pathology and sensitivity of current clinical criteria in corticobasal syndrome. Mov Disord 29, 238–244.

Imamura

, Wszolek

, Lucas

, Dickson

(2009) Corticobasal syndrome with Alzheimer’s disease pathology. Mov Disord 24, 152–153.

Chand

, Grafman

, Dickson

, Ishizawa

, Litvan

(2006) Alzheimer’s disease presenting as corticobasal syndrome. Mov Disord 21, 2018–2022.

Lleó

, Rey

, Castellví

, Ferrer

, Blesa

(2002) Asymmetric myoclonic parietal syndrome in a patient with Alzheimer’s disease mimicking corticobasal degeneration. Neurologia 17, 223–226.

Kaida

, Takeda

, Nagata

, Kamakura

(1998) Alzheimer’s disease with asymmetric parietal lobe atrophy: A case report. J Neurol Sci 160, 96–99.

Ball

, Lantos

, Jackson

, Marsden

, Scadding

, Rossor

(1993) Alien hand sign in association with Alzheimer’s histopathology. J Neurol Neurosurg Psychiatry 56, 1020–1023.

Crystal

, Horoupian

, Katzman

, Jotkowitz

(1982) Biopsy-proved Alzheimer disease presenting as a right parietal lobe syndrome. Ann Neurol 12, 186–188.

10.

Shelley

, Hodges

, Kipps

, Xuereb

, Bak

(2009) Is the pathology of corticobasal syndrome predictable in life? Mov Disord 24, 1593–1599.

11.

Ling

, O’Sullivan

, Holton

, Revesz

, Massey

, Williams

, Paviour

, Lees

(2010) Does corticobasal degeneration exist? A clinicopathological re-evaluation. Brain 133, 2045–2057.

12.

Tsuboi

, Josephs

, Boeve

, Litvan

, Caselli

, Caviness

, Uitti

, Bott

, Dickson

(2005) Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome. Mov Disord 20, 982–988.

13.

Boeve

, Maraganore

, Parisi

, Ahlskog

, Graff-Radford

, Caselli

, Dickson

, Kokmen

, Petersen

(1999) Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 53, 795–800.

14.

Rossi

, Marelli

, Farina

, Laurà

, Maria Basile

, Ciano

, Tagliavini

, Pareyson

(2008) The G389R mutation in the MAPT gene presenting as sporadic corticobasal syndrome. Mov Disord 23, 892–895.

15.

Tartaglia

, Sidhu

, Laluz

, Racine

, Rabinovici

, Creighton

, Karydas

, Rademakers

, Huang

, Miller

, DeArmond

, Seeley

(2010) Sporadic corticobasal syndrome due to FTLD-TDP. Acta Neuropathol 119, 365–374.

16.

C-E

, Bird

, Bekris

, Montine

, Leverenz

, Steinbart

, Galloway

, Feldman

, Woltjer

, Miller

, Wood

, Grossman

, McCluskey

, Clark

, Neumann

, Danek

, Galasko

, Arnold

, Chen-Plotkin

, Karydas

, Miller

, Trojanowski

, Lee

VM-Y

, Schellenberg

, Van Deerlin

(2010) The spectrum of mutations in progranulin: A collaborative study screening 545 cases of neurodegeneration. Arch Neurol 67, 161–170.

17.

Lindquist

, Duno

, Batbayli

, Puschmann

, Braendgaard

, Mardosiene

, Svenstrup

, Pinborg

, Vestergaard

, Hjermind

, Stokholm

, Andersen

, Johannsen

, Nielsen

(2013) Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease. Clin Genet 83, 279–283.

18.

Josephs

, Holton

, Rossor

, Braendgaard

, Ozawa

, Fox

, Petersen

, Pearl

, Ganguly

, Rosa

, Laursen

, Parisi

, Waldemar

, Quinn

, Dickson

, Revesz

(2003) Neurofilament inclusion body disease: A new proteinopathy? Brain 126, 2291–2303.

19.

Horoupian

, Wasserstein

(1999) Alzheimer’s disease pathology in motor cortex in dementia with Lewy bodies clinically mimicking corticobasal degeneration. Acta Neuropathol 98, 317–322.

20.

Kleiner-Fisman

, Bergeron

, Lang

(2004) Presentation of Creutzfeldt-Jakob disease as acute corticobasal degeneration syndrome. Mov Disord 19, 948–949.

21.

Rippon

, Staugaitis

, Chin

SSM

, Goldman

, Marder

(2005) Corticobasal syndrome with novel argyrophilic glial inclusions. Mov Disord 20, 598–602.

22.

Kreisler

, Mastain

, Tison

, Fénelon

, Destée

(2007) Multi-infarct disorder presenting as corticobasal degeneration (DCB): Vascular pseudo-corticobasal degeneration? Rev Neurol (Paris) 163, 1191–1199.

23.

Alexander

, Rittman

, Xuereb

, Bak

, Hodges

, Rowe

(2014) Validation of the new consensus criteria for the diagnosis of corticobasal degeneration. J Neurol Neurosurg Psychiatry 85, 925–929.

24.

, Rippon

, Boeve

, Knopman

, Petersen

, Parisi

, Josephs

(2009) Alzheimer’s disease and corticobasal degeneration presenting as corticobasal syndrome. Mov Disord 24, 1375–1379.

25.

Alladi

, Xuereb

, Bak

, Nestor

, Knibb

, Patterson

, Hodges

(2007) Focal cortical presentations of Alzheimer’s disease. Brain 130, 2636–2645.

26.

Lee

, Rabinovici

, Mayo

, Wilson

, Seeley

, DeArmond

, Huang

, Trojanowski

, Growdon

, Jang

, Sidhu

, See

, Karydas

, Gorno-Tempini

M-L

, Boxer

, Weiner

, Geschwind

, Rankin

, Miller

(2011) Clinicopathological correlations in corticobasal degeneration. Ann Neurol 70, 327–340.

27.

Borroni

, Premi

, Agosti

, Alberici

, Cerini

, Archetti

, Lanari

, Paghera

, Lucchini

, Caimi

, Padovani

(2011) CSF Alzheimer’s disease-like pattern in corticobasal syndrome: Evidence for a distinct disorder. J Neurol Neurosurg Psychiatry 82, 834–838.

28.

Pillon

, Blin

, Vidailhet

, Deweer

, Sirigu

, Dubois

, Agid

(1995) The neuropsychological pattern of corticobasal degeneration: Comparison with progressive supranuclear palsy and Alzheimer’s disease. Neurology 45, 1477–1483.

29.

Ceccaldi

, Jonveaux

, Verger

, Krolak-Salmon

, Houzard

, Godefroy

, Shields

, Perrotin

, Gismondi

, Bullich

, Jovalekic

, Raffa

, Pasquier

, Semah

, Dubois

, Habert

M-O

, Wallon

, Chastan

, Payoux

, NEUUS in AD study group, Stephens

, Guedj

(2018) Added value of 18F-florbetaben amyloid PET in the diagnostic workup of most complex patients with dementia in France: A naturalistic study. Alzheimers Dement 14, 293–305.

30.

Folstein

, Folstein

, McHugh

(1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12, 189–198.

31.

Dubois

, Touchon

, Portet

, Ousset

, Vellas

, Michel

(2002) “The 5 words”: A simple and sensitive test for the diagnosis of Alzheimer’s disease. Presse Med 31, 1696–1699.

32.

Mahieux-Laurent

, Fabre

, Galbrun

, Dubrulle

, Moroni

(2009) Validation d’une batterie brève d’évaluation des praxies gestuelles pour consultation Mémoire. Evaluation chez 419 témoins, 127 patients atteints de troubles cognitifs légers et 320 patients atteints d’une démence. Rev Neurol 165, 560–567.

33.

Benton

, Varney

, Hamsher

(1978) Visuospatial judgment. A clinical test. Arch Neurol 35, 364–367.

34.

Dubois

, Slachevsky

, Litvan

, Pillon

(2000) The FAB: A Frontal Assessment Battery at bedside. Neurology 55, 1621–1626.

35.

Reitan

(1955) The relation of the trail making test to organic brain damage. J Consult Psychol 19, 393–394.

36.

Deloche

, Hannequin

(1997) DO 80, épreuve de dénomination orale d’images, Edition du centre de psychologie appliquée, Paris.

37.

Sabri

, Sabbagh

, Seibyl

, Barthel

, Akatsu

, Ouchi

, Senda

, Murayama

, Ishii

, Takao

, Beach

, Rowe

, Leverenz

, Ghetti

, Ironside

, Catafau

, Stephens

, Mueller

, Koglin

, Hoffmann

, Roth

, Reininger

, Schulz-Schaeffer

, Florbetaben Phase 3 Study Group (2015) Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer’s disease: Phase 3 study. Alzheimers Dement 11, 964–974.

38.

R Core Team (2017) R: A language and environment for Statistical Computing, https://www.r-project.org/, Vienna, Austria.

39.

Sakae

, Josephs

, Litvan

, Murray

, Duara

, Uitti

, Wszolek

, van Gerpen

, Graff-Radford

, Dickson

(2019) Clinicopathologic subtype of Alzheimer’s disease presenting as corticobasal syndrome. Alzheimers Dement 15, 1218–1228.

40.

Rinne

, Sahlberg

, Ruottinen

, Någren

, Lehikoinen

(1998) Striatal uptake of the dopamine reuptake ligand [11C]beta-CFT is reduced in Alzheimer’s disease assessed by positron emission tomography. Neurology 50, 152–156.

41.

Burns

, Galvin

, Roe

, Morris

, McKeel

(2005) The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs. Neurology 64, 1397–1403.

42.

Horvath

, Burkhard

, Herrmann

, Bouras

, Kövari

(2014) Neuropathology of parkinsonism in patients with pure Alzheimer’s disease. J Alzheimers Dis 39, 115–120.

43.

Ceravolo

, Rossi

, Cilia

, Tognoni

, Antonini

, Volterrani

, Bonuccelli

(2013) Evidence of delayed nigrostriatal dysfunction in corticobasal syndrome: A SPECT follow-up study. Parkinsonism Relat Disord 19, 557–559.

44.

Ceravolo

, Volterrani

, Gambaccini

, Bernardini

, Rossi

, Logi

, Tognoni

, Manca

, Mariani

, Bonuccelli

, Murri

(2004) Presynaptic nigro-striatal function in a group of Alzheimer’s disease patients with parkinsonism: Evidence from a dopamine transporter imaging study. J Neural Transm (Vienna) 111, 1065–1073.

45.

Washida

, Kowa

, Yamamoto

, Kanda

, Toda

(2017) Dopamine transporter imaging as a diagnostic modality for atypical Alzheimer’s disease mimicking corticobasal degeneration. Psychogeriatrics 17, 73–75.

46.

Thomas

, Attems

, Colloby

, O’Brien

, McKeith

, Walker

, Lee

, Burn

, Lett

, Walker

(2017) Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB. Neurology 88, 276–283.

47.

McKeith

, O’Brien

, Walker

, Tatsch

, Booij

, Darcourt

, Padovani

, Giubbini

, Bonuccelli

, Volterrani

, Holmes

, Kemp

, Tabet

, Meyer

, Reininger

, DLB Study Group (2007) Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: A phase III, multicentre study. Lancet Neurol 6, 305–313.

48.

Koric

, Guedj

, Habert

, Semah

, Branger

, Payoux

, Le Jeune

, CMMR study group (2016) Molecular imaging in the diagnosis of Alzheimer’s disease and related disorders. Rev Neurol (Paris) 172, 725–734.

49.

Booth

, Nathan

, Waldman

, Quigley

A-M

, Schapira

, Buscombe

(2015) The role of functional dopamine-transporter SPECT imaging in parkinsonian syndromes, part 2. Am J Neuroradiol 36, 236–244.

50.

Kaasinen

, Gardberg

, Röyttä

, Seppänen

, Päivärinta

(2013) Normal dopamine transporter SPECT in neuropathologically confirmed corticobasal degeneration. J Neurol 260, 1410–1411.

51.

O’Sullivan

, Burn

, Holton

, Lees

(2008) Normal dopamine transporter single photon-emission CT scan in corticobasal degeneration. Mov Disord 23, 2424–2426.

52.

Mendoza-Velásquez

, Flores-Vázquez

, Barrón-Velázquez

, Sosa-Ortiz

, Illigens

B-MW

, Siepmann

(2019) Autonomic dysfunction in α-synucleinopathies. Front Neurol 10, 363.

53.

Barone

, Henchcliffe

(2018) Rapid eye movement sleep behavior disorder and the link to alpha-synucleinopathies. Clin Neurophysiol 129, 1551–1564.

54.

Brandmeir

, Geser

, Kwong

, Zimmerman

, Qian

, Lee

VM-Y

, Trojanowski

(2008) Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease. Acta Neuropathol 115, 123–131.

55.

Braak

, Braak

(1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82, 239–259.

56.

Rothi

LJG

, Ochipa

, Heilman

(1991) A cognitive neuropsychological model of limb praxis. Cogn Neuropsychol 8, 443–458.

57.

Blondel

, Eustache

, Schaeffer

, Marié

, Lechevalier

, de la Sayette

(1997) Clinical and cognitive study of apraxia in cortico-basal atrophy. A selective disorder of the production system. Rev Neurol (Paris) 153, 737–747.

58.

Buxbaum

, Kalénine

(2010) Action knowledge, visuomotor activation, and embodiment in the two action systems. Ann N Y Acad Sci 1191, 201–218.

59.

Osiurak

, Jarry

, Allain

, Aubin

, Etcharry-Bouyx

, Richard

, Bernard

, Le Gall

(2009) Unusual use of objects after unilateral brain damage: The technical reasoning model. Cortex 45, 769–783.

60.

Josephs

, Whitwell

, Boeve

, Knopman

, Petersen

, Hu

, Parisi

, Dickson

, Jack

(2010) Anatomical differences between CBS-corticobasal degeneration and CBS-Alzheimer’s disease. Mov Disord 25, 1246–1252.

61.

Arnold

, Toledo

, Appleby

, Xie

, Wang

L-S

, Baek

, Wolk

, Lee

, Miller

, Lee

VM-Y

, Trojanowski

(2013) A comparative survey of the topographical distribution of signature molecular lesions in major neurodegenerative diseases. J Comp Neurol 521, 4339–4355.

62.

Teune

, Bartels

, de Jong

, Willemsen

ATM

, Eshuis

, de Vries

, van Oostrom

JCH

, Leenders

(2010) Typical cerebral metabolic patterns in neurodegenerative brain diseases. Mov Disord 25, 2395–2404.

63.

Oguro

, Yamaguchi

, Abe

, Ishida

, Bokura

, Kobayashi

(2006) Differentiating Alzheimer’s disease from subcortical vascular dementia with the FAB test. J Neurol 253, 1490–1494.

64.

, Zhang

, Song

, Huang

, Ding

, Fang

, Xu

, Han

(2017) Structural connectivity subserving verbal fluency revealed by lesion-behavior mapping in stroke patients. Neuropsychologia 101, 85–96.

65.

Alexander

, DeLong

, Strick

(1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann Rev Neurosci 9, 357–381.

66.

Di Stefano

, Epelbaum

, Coley

, Cantet

, Ousset

P-J

, Hampel

, Bakardjian

, Lista

, Vellas

, Dubois

, Andrieu

, GuidAge study group (2015) Prediction of Alzheimer’s disease dementia: Data from the GuidAge Prevention Trial. J Alzheimers Dis 48, 793–804.

67.

Burrell

, Hornberger

, Villemagne

, Rowe

, Hodges

(2013) Clinical profile of PiB-positive corticobasal syndrome. PLoS One 8, e61025.

68.

Garbutt

, Matlin

, Hellmuth

, Schenk

, Johnson

, Rosen

, Dean

, Kramer

, Neuhaus

, Miller

, Lisberger

, Boxer

(2008) Oculomotor function in frontotemporal lobar degeneration, related disorders and Alzheimer’s disease. Brain 131, 1268–1281.

69.

Gaymard

(2012) Cortical and sub-cortical control of saccades and clinical application. Rev Neurol (Paris) 168, 734–740.

70.

Vidailhet

, Rivaud

, Gouider-Khouja

, Pillon

, Bonnet

, Gaymard

, Agid

, Pierrot-Deseilligny

(1994) Eye movements in parkinsonian syndromes. Ann Neurol 35, 420–426.

71.

Armstrong

(2016) Visual signs and symptoms of corticobasal degeneration. Clin Exp Optom 99, 498–506.

72.

Rivaud-Péchoux

, Vidailhet

, Gallouedec

, Litvan

, Gaymard

, Pierrot-Deseilligny

(2000) Longitudinal ocular motor study in corticobasal degeneration and progressive supranuclear palsy. Neurology 54, 1029–1032.

73.

Pierrot-Deseilligny

, Milea

, Müri

(2004) Eye movement control by the cerebral cortex. Curr Opin Neurol 17, 17–25.

74.

Rosen

, Rao

, Caffarra

, Scaglioni

, Bobholz

, Woodley

, Hammeke

, Cunningham

, Prieto

, Binder

(1999) Neural basis of endogenous and exogenous spatial orienting. A functional MRI study. J Cogn Neurosci 11, 135–152.

75.

Laurens

, Planche

, Cubizolle

, Declerck

, Dupouy

, Formaglio

, Koric

, Seassau

, Tilikete

, Vighetto

, Ceccaldi

, Tison

(2019) A spatial decision eye-tracking task in patients with prodromal and mild Alzheimer’s disease. J Alzheimers Dis 71, 613–621.

76.

Shakespeare

, Kaski

, Yong

KXX

, Paterson

, Slattery

, Ryan

, Schott

, Crutch

(2015) Abnormalities of fixation, saccade and pursuit in posterior cortical atrophy. Brain 138, 1976–1991.

77.

Yang

, Wang

, Su

, Xiao

, Kapoula

(2013) Specific saccade deficits in patients with Alzheimer’s disease at mild to moderate stage and in patients with amnestic mild cognitive impairment. Age (Dordr) 35, 1287–1298.

78.

Holden

, Cosnard

, Laurens

, Asselineau

, Biotti

, Cubizolle

, Dupouy

, Formaglio

, Koric

, Seassau

, Tilikete

, Vighetto

, Tison

(2018) Prodromal Alzheimer’s disease demonstrates increased errors at a simple and automated anti-saccade task. J Alzheimers Dis 65, 1209–1223.

79.

Ling

, Kovacs

, Vonsattel

JPG

, Davey

, Mok

, Hardy

, Morris

, Warner

, Holton

, Revesz

(2016) Astrogliopathy predominates the earliest stage of corticobasal degeneration pathology. Brain 139, 3237–3252.

80.

Kobylecki

, Mann

(2016) Presymptomatic anterior frontal involvement in corticobasal degeneration. Brain 139, 3059–3062.

81.

Di Stefano

, Kas

, Habert

M-O

, Decazes

, Lamari

, Lista

, Hampel

, Teichmann

(2016) The phenotypical core of Alzheimer’s disease-related and nonrelated variants of the corticobasal syndrome: A systematic clinical, neuropsychological, imaging, and biomarker study. Alzheimers Dement 12, 786–795.

82.

Kovacs

(2019) Are comorbidities compatible with a molecular pathological classification of neurodegenerative diseases? Curr Opin Neurol 32, 279–291.

Clinical Phenotypes in Corticobasal Syndrome with or without Amyloidosis Biomarkers

Abstract

Keywords

INTRODUCTION

MATERIALS AND METHODS

Patients

Evaluation criteria

Statistical analyses

RESULTS

Demographic description of population

Patient clinical presentation

Neuropsychological assessment

Eye movements study

Molecular imaging

18FDG-PET imaging

DaTSCAN©

DISCUSSION

Motor features

Cognitive and behavioral features

Oculomotor features

DISCLOSURE STATEMENT

References

¹⁸FDG-PET imaging

DaTSCAN^©